Beyond Antioxidant Activity: Redox–Inflammatory Network Modulation as a Framework for the Multi-Organ Pharmacology of Moringa oleifera

Abstract

Moringa oleifera (M. oleifera) is a multipurpose medicinal plant with over 160 catalogued bioactive compounds and reported activity across metabolic, inflammatory, infectious, and neoplastic diseases, yet its pharmacology has remained mechanistically fragmented, limiting translational interpretation. In this narrative review, we synthesize evidence from in silico analyses, cellular systems, animal models, and human studies to evaluate whether structurally diverse phytochemicals—including glucosinolates, isothiocyanates, flavonoids, and phenolic acids—converge on interconnected redox and inflammatory regulatory networks centered on NF-κB and Nrf2/Keap1 signaling, offering a plausible systems-level explanation for their coordinated effects on immune function, oxidative stress, and metabolic homeostasis. Preclinical evidence for this convergence is extensive and consistent, with documented effects on inflammatory signaling, oxidative stress regulation, and cell fate determination relevant to hepatoprotection, cardiometabolic regulation, neuroprotection, and tumor biology. Clinical evidence, by contrast, is considerably more limited: available trials report modest and inconsistent benefits for glycemic control, cardiovascular parameters, and immune-related outcomes, constrained by heterogeneous phytochemical composition, minimal pharmacokinetic characterization, and variable extraction and formulation methods. Safety data indicate general tolerability at commonly used doses, though reproductive effects and herb–drug interactions remain incompletely defined. Collectively, current evidence positions M. oleifera as a mechanistically plausible, multi-target modulator of redox and inflammatory networks rather than a validated therapeutic agent; realizing its clinical potential will require standardized preparations, rigorous pharmacokinetic profiling, biomarker-anchored trial design, and evaluation in well-powered controlled trials.

Introduction

The global burden of non-communicable diseases (NCDs) constitutes a defining challenge of twenty-first-century medicine, now accounting for approximately 75% of global mortality and driven by the convergent pathophysiology of chronic oxidative stress and inflammatory signaling across cardiovascular, renal, hepatic, and neural systems.^1–3 Hypertension alone affects an estimated 1.4 billion individuals worldwide, yet achieves adequate pharmacological control in fewer than 20% of patients,² despite cost-effective intervention strategies remaining inequitably implemented.⁴ At the molecular level, disruption of redox homeostasis—through reactive oxygen and nitrogen species (ROS/RNS)—represents a central mechanism in NCD pathogenesis, modulated in part by endogenous, dietary, and lifestyle factors.⁵ Oxidative stress-mediated interorgan crosstalk fundamentally constrains single-target pharmacological strategies.^6–8

Despite compelling preclinical evidence, antioxidant-based interventions have not translated consistently into clinical benefit. This gap is attributable not only to incomplete characterization of context-specific redox biology, but to a set of recurring translational barriers that reappear across this literature: heterogeneity in plant preparation and extraction methods, lack of phytochemical standardization and dose equivalence, limited pharmacokinetic characterization, inconsistent biomarker selection in clinical studies, and unresolved safety profiles.^9,10 Prior literature has only partially integrated redox modulation across biological scales, with limited synthesis linking molecular mechanisms to clinical outcomes within a unified framework.⁹

Within this context, M. oleifera merits systematic reassessment. A member of the 13-species Moringa genus distributed across Asia and Africa,¹¹ it possesses a diverse phytochemical repertoire—including flavonoids, glucosinolates, alkaloids, phenolic acids, carbamate glycosides, and terpenes^12–14—shown to modulate pathways central to NCD pathogenesis, including NF-κB, Nrf2/Keap1, TLR4, PI3K/AKT/MAPK, JAK2/STAT3, and mitochondrial redox networks.^15,16 Its therapeutic relevance lies not in phytochemical diversity alone, but in the apparent mechanistic convergence of structurally distinct bioactives upon a shared, disease-relevant molecular architecture—a property underexplored in existing literature. Its established nutritional role—leaves, seeds, pods, and flowers are widely consumed across Sub-Saharan Africa and South Asia,¹³ regions bearing a disproportionate NCD burden alongside constrained access to conventional therapeutics—further positions M. oleifera as a scalable candidate for both clinical and public health application.¹⁷ However, the heterogeneity of available data and the predominance of non-clinical evidence necessitate cautious interpretation.^3,18

Much of the current evidence base remains preclinical or derived from small, heterogeneous clinical studies, and mechanistic plausibility should not be conflated with clinically validated efficacy—a distinction maintained throughout this review rather than assumed. This narrative, integrative review addresses this gap through a mechanistically interpretive synthesis of evidence spanning in silico, in vitro, in vivo, and human clinical domains, contextualized against established pharmacological benchmarks, to define what current evidence justifies and what future clinical investigation requires.

Methodology

This narrative integrative review systematically integrated multidisciplinary evidence regarding the phytochemical composition, pharmacological activities, molecular mechanisms, therapeutic potential, and safety profile of Moringa oleifera. Literature searches were conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify clinical, preclinical, mechanistic, phytochemical, and computational studies investigating the biological effects and translational potential of M. oleifera. Evidence from phytochemical analyses, in silico studies, in vitro investigations, animal models, clinical studies, systematic reviews, and meta-analyses was critically synthesized. The available evidence was organized according to a four-tier evidence classification framework based on study design and translational relevance (Table 1). This framework was used to facilitate comparison across biological levels, ranging from human clinical evidence to mechanistic and computational investigations.

Table 1.

Methodological Hierarchy and Translational Scope of Synthesized Evidence

Evidence Tier	Evidence Source	Translational Relevance
Tier I	Clinical Evidence and Evidence Syntheses (RCTs, systematic reviews, meta-analyses)	Provides human-level evidence regarding efficacy, safety, tolerability, and clinically relevant outcomes.
Tier II	In vivo Preclinical Evidence (animal models)	Provides evidence of systemic pharmacological effects, physiological responses, and preliminary safety assessment.
Tier III	In Vitro Mechanistic Evidence (cell-based and biochemical assays)	Defines molecular mechanisms, signaling pathways, cellular responses, and biological interactions.
Tier IV	Phytochemical Characterization and In Silico Evidence (chemical profiling and computational modeling)	Supports compound identification, molecular characterization, target prediction, and mechanistic hypothesis generation.

Phytochemical Composition and Structural Diversity

M. oleifera is characterized by one of the most pharmacologically rich and structurally diverse secondary metabolite profiles identified in any single medicinal plant. Over 160 bioactive compounds have been catalogued across its organs,¹³ belonging to chemically and functionally distinct classes whose individual and combined activities are thought to contribute to the plant’s therapeutic breadth.^12,14 Pan-tropical in distribution and exhibiting notable drought and frost resistance, M. oleifera has been used in Ayurvedic and Unani medicine for millennia, with contemporary phytochemical analysis validating many traditional applications (Figure 1).¹⁹

Figure 1.

Systems-Level Pharmacological Framework of M. oleifera.

Notes: Schematic illustration of the convergence of structurally distinct Moringa oleifera bioactive classes on shared transcriptional regulators of redox homeostasis and inflammatory signaling, and the resulting multi-system organ-level effects documented across experimental and clinical domains. ↑ Increase/activation, ↓ Decrease/inhibition, ↔ Crosstalk between pathways, Solid arrows (→) direct signaling flow dashed arrows (⇢) indirect or modulatory effect.

The genomic underpinnings of this remarkable phytochemical diversity have been progressively elucidated. Whole-genome characterization revealed 101 significantly expanded gene families enriched in chloroplast and photosynthetic functions, with nuclear plastid DNA insertions constituting 4.71% of the total nuclear genome—an unusually large fraction that provides novel genetic resources for targeted breeding of nutritional and pharmaceutical traits.²⁰ A higher-resolution assembly comprising 14 pseudochromosomes subsequently demonstrated that tandem gene duplications, rather than additional whole-genome duplication events, are the primary drivers of the evolutionary diversification of glucosinolate, flavonoid, and alkaloid biosynthesis pathways, provide a plausible molecular basis for the species’ exceptional secondary metabolite plasticity.²¹ However, the pharmacological relevance of these compounds depends on their bioavailability, metabolic stability, and achievable systemic concentrations, which remain incompletely defined (Table 2).²² Further analysis of the nuclear plastid DNA sequences (NUPTs) revealed a bimodal age distribution indicative of two mechanistically distinct insertion events, providing unprecedented insight into the chromosomal distribution and evolutionary origins of organellar DNA integration in this species.²³ Together, these genomic datasets establish that the extraordinary phytochemical breadth of M. oleifera is not incidental but is encoded in a genome shaped by specific evolutionary pressures that favor secondary metabolite expansion. Despite extensive phytochemical characterization, direct attribution of specific clinical effects to individual compounds remains challenging due to complex synergistic interactions, variability in extraction methods, and the absence of standardized formulations across studies (Table 2).

Table 2.

Extraction Methodologies and Processing Effects on the Phytochemical Profile and Biological Activities of Moringa oleifera

Extraction/Processing	Primary Phytochemical Profile	Biological Activity	Experimental Evidence and Molecular Markers	Ref
Methanolic leaf extract	Polyphenol- and glycosylated flavonoid-rich profile	Antioxidant activity	Potent DPPH radical-scavenging activity and protection against oxidative DNA damage	[24]
Hydroethanolic extract	Enriched in isothiocyanates (moringin) and chlorogenic acid	Anti-inflammatory and pro-apoptotic activity	Modulation of NF-κB signaling and induction of mitochondrial apoptosis	[25]
Aqueous leaf extract	Soluble phenolics and glycosides	Gastroprotective activity	High bioaccessibility with preservation of antioxidant activity during simulated gastric digestion	[26,27]
Dichloromethane leaf extract	Non-polar terpenoids and aglycones	Cytotoxic activity in breast cancer models	Increased Bax, caspase-8, and p53 expression with reduced Bcl-2 expression	[28]
Ethanolic fruit extract	Diverse phytochemical profile including quercetin and kaempferol derivatives	Antiviral potential	Predicted high-affinity interactions with SARS-CoV-2 3CLpro and RdRp targets	[29]
Fermented leaf extract	GABA-enriched profile following microbial bioconversion	Neuroimmune modulatory activity	Reduced IL-1β, IL-6, and TNF-α responses in LPS-stimulated models	[30]
Seed protein nanoparticles	Bioactive protein-based nanostructures	Cytotoxic activity in leukemia models	Dose-dependent growth inhibition in THP-1 human monocytic leukemia cells	[31]
Thermal processing (boiling)	Thermostable glycosides and modified mineral composition	Nutritional bioavailability	Improved protein digestibility and mineral stability with changes in antioxidant capacity	[32]

Notes: Comparative overview of preparation-specific phytochemical compositions and associated functional outcomes across major extraction and processing approaches applied to Moringa oleifera. Data illustrate the direct dependence of pharmacological activity on preparation methodology, with implications for experimental reproducibility and clinical standardization.

Abbreviations: Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; DPPH, 2,2-diphenyl-1-picrylhydrazyl; GABA, gamma-aminobutyric acid; IL-1β, interleukin-1 beta; IL-6, interleukin-6; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; p53, tumor protein p53; RdRp, RNA-dependent RNA polymerase; 3CLpro, 3-chymotrypsin-like protease; TNF-α, tumor necrosis factor-alpha; THP-1, human monocytic leukemia cell line.

Glucosinolates and Isothiocyanates: The Dominant Pharmacophores

Moringa tissues displayed distinct glucosinolate profiles: seeds and bark predominantly contained 4-(α-L-rhamnopyranosyloxy)-benzylglucosinolate; roots additionally contained benzyl glucosinolate, while leaves showed this glucosinolate and three monoacetyl isomers, together with quercetin/kaempferol glucosides and caffeoylquinic acids, highlighting tissue-specific phytochemical distribution.³³ The principal representative, glucomoringin (GMG), yields glucomoringin isothiocyanate (GMG-ITC; moringin) upon myrosinase-mediated cleavage. Mechanistically, GMG-ITC achieves dual and complementary modulation of the cellular redox-inflammatory axis: activation of the Nrf2/Keap1 pathway—inducing cytoprotective transcription of NQO1, HO-1, and GSTP1³⁴—operates in parallel with suppression of NF-κB nuclear translocation,³⁵ a mechanistic combination without direct equivalent in the conventional pharmacopoeia.

Moringa isothiocyanate-1 (MIC-1), an optimized seed-derived fraction attainable at 38.9% purity, demonstrated greater anti-inflammatory activity in experimental models relative to curcuminoid extracts in direct comparative assays, reducing carrageenan-induced paw oedema and suppressing LPS-induced NO, iNOS, IL-1β, and IL-6 in vitro, while concurrently upregulating NQO1, GSTP1, and HO-1.³⁵ Importantly, the bioactive concentrations of these stable compounds are strongly influenced by harvesting conditions and extraction methodology³⁶—a variable with direct implications for clinical standardization (Table 2).

Glucosinolate content is a key determinant of the chemopreventive pharmacology documented across anticancer models. The leaf-seed residue extract ratio M1S9, carrying the highest glucosinolate loading among tested formulations, achieved the greatest inhibition of MDA-MB-231 breast cancer xenograft growth at 64.5%—establishing a clear structure–activity relationship between glucosinolate content and in vivo antitumor potency.³⁷ With respect to delivery, aqueous leaf infusions provide standardized yields of glucomoringin and moringin with confirmed anti-inflammatory and cytoprotective antioxidant activity, favourable extraction kinetics, aqueous stability, and palatability,³⁸ collectively supporting their deployment in clinical interventional studies. These findings are derived predominantly from preclinical models and require validation in well-designed human studies.

Flavonoids and Phenolic Acids: Redox Modulators and Multi-Enzyme Inhibitors

The flavonoid fraction of M. oleifera is dominated by quercetin, kaempferol, and their respective glycosidic conjugates, which exert antioxidant activity through direct radical scavenging, transition metal chelation, and upregulation of endogenous antioxidant enzymes.³⁹ Freeze-dried leaf extracts prepared in 80% methanol and 70% ethanol demonstrated the highest antioxidant activity—65.1% and 66.8%, respectively—in the beta-carotene–linoleic acid system, with quercetin and kaempferol identified as the principal bioactive flavonoids across agroclimatic regions.⁴⁰ Beyond radical scavenging, these compounds inhibit cyclooxygenase and lipoxygenase enzymes, modulate NF-κB signaling, and attenuate TNF-α and IL-1β expression³⁹—pharmacological actions that operate in mechanistic parallel with, rather than merely additive to, the isothiocyanate-driven pathways described above.

Phenolic acids—principally chlorogenic acid, caffeic acid, and gallic acid—contribute independently and consistently. Metabolomic profiling across leaf extracts from nine countries on four continents revealed no significant inter-regional differences in total antioxidant capacity, with all geographical variants equivalently reducing hydrogen peroxide-induced C2C12 myotube cytotoxicity.⁴¹ This geographical invariance of antioxidant activity constitutes a critical quality-assurance finding, indicating that therapeutic batch-to-batch variability attributable to geographic origin is substantially less pronounced than previously assumed—materially strengthening the case for globally scalable standardized preparations. Winter harvesting consistently yields superior phenolic content and antioxidant potency, with organ-level activity following the hierarchy: leaf > stem > stalk.⁴²

Bioaccessibility profiling of leaf bioactives reveals a pharmacokinetically nuanced absorption landscape: gallic and caffeic acids demonstrate high luminal bioaccessibility (~6–210%), strongly correlated with antioxidant capacity (R² = 0.59–0.98, p < 0.05), yet transepithelial flux remains constrained (0.62–36.65 × 10⁻⁴ cm/s). However, limited intestinal permeability and variable bioavailability may significantly constrain in vivo efficacy.⁴³ This dissociation between high luminal availability and limited intestinal permeability defines absorption bottleneck that directly motivates the nanoformulation strategies addressed subsequently.

Proteins, Enzymes, and Seed Oil Chemistry

M. oleifera seeds are characterized by a substantial macronutrient composition, comprising approximately 19% protein and 31% lipid content. The extracted seed oil (“Ben oil”) is distinguished by a high oleic acid fraction (~73%), comparable to olive oil, alongside behenic (5–6%), gadoleic, lignoceric, and trace erucic acids, with tocopherols contributing intrinsic antioxidant capacity.⁴⁴ This compositional profile confers notable thermal and oxidative stability, supporting suitability for high-temperature applications. Functionally, the oil demonstrates measurable antioxidant activity (IC₅₀ = 110.4 mg/mL), comparable to vitamin E (IC₅₀ = 121.9 mg/mL),⁴⁵ and exhibits superior in vitro radical scavenging relative to peanut and tea seed oils across 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl radical, and superoxide anion assays.⁴⁶

Beyond its lipid fraction, the seed proteome reveals a diverse enzymatic landscape with emerging biotechnological relevance. Label-free quantitative proteomics has identified a 45.5 kDa aspartic endopeptidase exhibiting milk-clotting activity, with optimal performance at 60 °C and pH 5.⁴⁷ Complementary investigations of floral extracts have isolated two κ-casein-specific proteases (MoFP12 and MoFP13), further supporting potential applications in dairy processing.⁴⁸ In parallel, protein-based nanoparticles (PBNPs) derived from seed proteins via ultrasonication (mean diameter 134.3 nm; zeta potential −43.15 mV) have demonstrated cytotoxic activity against THP-1 leukemia cells, indicating that the seed protein matrix itself may possess intrinsic pharmacological functionality beyond its nutritional role.³¹

Tissue-Specific Phytochemical Partitioning

Tissue-specific phytochemical distribution carries direct implications for evidence-based preparation selection. Seeds are enriched in proteins and lipids; flowers and fruits concentrate tocopherols and glycosylated flavonoids; leaves harbor the highest densities of polyphenols, chlorophylls, flavonoids, and total antioxidant activity.²⁵ Studies on mixed leaf-pod powders demonstrate that equal-ratio blends optimize sensory attributes for food-based applications, whereas leaf-predominant formulations maximize pharmacological activity⁴⁹—a distinction with practical significance for both nutraceutical product development and clinical dosing strategies. Quantified vitamin A bioavailability data further substantiate the leaf organ’s nutritional primacy.⁵⁰ These parameters collectively validate M. oleifera leaves as a documented dietary vitamin A source of particular relevance to nutritionally vulnerable populations—reinforcing the plant’s dual identity as both a pharmacological agent and a food-based public health intervention.⁵⁰ This tissue-level partitioning is plausibly linked to the genomic diversification already described above: differential expression of the tandemly duplicated biosynthetic gene copies across organs offers a proximate explanation for the organ-specific profiles reported here.^21,25 Neither dataset reports the organ-resolved expression data needed to confirm this directly, so it is identified here as a specific gap for future transcriptomic study rather than a finding the cited sources already establish.^20,23,49,50

Phytochemical Stability and Extraction Determinants

Antioxidant activity and phytochemical composition vary substantively with leaf maturity and extraction solvent.⁵¹ Older leaves accumulate higher polyphenol and flavonoid concentrations, whereas younger leaves are enriched in vitamin C and chlorophyll; methanol and ethanol extract consistently demonstrate superior antioxidant activity, strongly correlated with chlorophyll and total polyphenol content. These variations underscore the critical need for rigorous standardization of extraction protocols in both experimental and clinical investigations.⁵¹ The non-alkaloidal fraction of ethanolic leaf extract—characterized by GC-MS to include Dodecamethylcyclohexasiloxane, Fluoranthene, and Hexadecanoic acid methyl ester—exhibits strong in silico binding affinity to Thymidylate Synthase and AmpC β-lactamase,⁵² indicating target-specific antimicrobial potential within a chemically complex fraction. Collectively, these extraction-dependent variations establish that therapeutic claims cannot be responsibly generalized across preparation types in the absence of explicit compositional characterization (Table 2).

Beyond direct absorption, M. oleifera phenolics and flavonoids undergo stage-specific liberation during gastrointestinal transit, with antioxidant activity sustained across gastric and small-intestinal phases. Upon colonic delivery, fermentation of unabsorbed fractions stimulates beneficial microbiota proliferation and generates short-chain fatty acids—principally acetic, propionic, and butyric acids—accompanied by measurable luminal pH reduction.²⁶ This prebiotic dimension is mechanistically discrete from direct antioxidant activity and constitutes an independent pathway through which M. oleifera modulates intestinal homeostasis and systemic metabolic health, complementing the gut microbiota-reshaping effects independently documented with seed extract supplementation.⁵³

Immunomodulatory Mechanisms

The immunomodulatory activity of M. oleifera operates across multiple tiers of immune function—spanning innate pattern recognition receptor signaling and macrophage polarization to natural killer (NK) cell activation and T lymphocyte proliferation—a mechanistic breadth commensurate with the chemical pluripotency of its bioactive constituents. However, the majority of these findings derive from in vitro and animal models, and their direct relevance to human immune function remains to be established (Figure 2).⁴⁴ Critically, M. oleifera bioactives do not function as conventional immunosuppressants; rather, they calibrate immune responses bidirectionally, suppressing pathological inflammation while concurrently potentiating protective immunity (Figure 3).^54,55

Figure 2.

Framework of critical barriers affecting preclinical-to-clinical translation.

Notes: This schematic highlights major sources of methodological variability, biological uncertainty, and translational limitations that may influence the interpretation and clinical applicability of preclinical findings.

Figure 3.

Organ-Protective Pharmacological Activity of M. oleifera Across Biological Systems.

Notes: Overview of the organ-specific protective and regulatory effects of M. oleifera bioactive constituents across hepatic, renal, cardiovascular, neurological, immunological, and metabolic systems, reflecting the unified expression of convergent NF-κB and Nrf2 pathway modulation across pathological contexts. ↑ Increase, ↓ Decrease.

Suppression of the NF-κB/TLR4 Proinflammatory Cascade

NF-κB transcription factor dysregulation constitutes a mechanistic common denominator across chronic inflammatory, metabolic, and oncological disease states. Multiple M. oleifera fractions converge on this pathway through discrete but complementary mechanisms. The ethyl acetate leaf fraction (MOEF) suppressed LPS-induced NF-κB p65 nuclear translocation in human macrophages by preventing IκB-α phosphorylation and blocking RelA activation, with LC-ESI-QTOF-MS characterisation identifying seven specific mediating bioactives.⁵⁶ The same fraction attenuated TNF, IL-6, and IL-8 at both protein and mRNA levels and was shown to suppress RelA in a cigarette smoke–induced macrophage inflammation model⁵⁷—a system of direct relevance to Chronic obstructive pulmonary disease (COPD) and smoking-associated pulmonary pathology. The seven bioactives resolved by LC-ESI-QTOF-MS in this fraction were not individually assigned to the NF-κB suppression reported above; the finding is therefore fraction-level, not compound-resolved.⁵⁶

GABA-enriched M. oleifera leaf fermentation broth (MLFB) dose-dependently was associated with inhibition of LPS-induced IL-1β, IL-6, IL-8, TNF-α, PGE₂, and iNOS in RAW264.7 macrophages, concurrently suppressing TLR-4 and NF-κB expression, while the fermentation process itself increased GABA, polyphenols, and organic acid content without compromising flavonoid integrity.³⁰ The observation that controlled fermentation amplifies rather than degrades immunomodulatory activity carries significant technological implications (Table 2): it establishes that bioprocess engineering of M. oleifera preparations may yield pharmacologically superior products without recourse to conventional chemical extraction. Corroborating the organ-level breadth of this pharmacology, the 80% hydroethanolic flower extract equivalently suppressed NO, PGE₂, TNF-α, IL-1β, IL-6, iNOS, and COX-2 whilst upregulating anti-inflammatory IL-10 and IκB-α in LPS-stimulated RAW264.7 macrophages,⁵⁸ confirming that the NF-κB immunosuppressive program is not confined to leaf preparations but is expressed consistently across plant organs.

Nrf2 Activation and Oxidative Immunoregulation

A systematic review encompassing 26 studies confirmed that M. oleifera modulates inflammatory disease pathways predominantly via NF-κB inhibition and Nrf2 activation,⁵⁹ the latter inducing a cytoprotective antioxidant transcriptional program that secondarily attenuates downstream inflammatory signaling. Mechanistically, leaf extract dose-dependently upregulated Nrf2 and HO-1 protein expression in C2C12 myotubes through the SIRT1-PPARα axis, significantly enhancing total antioxidant capacity, glutathione redox homeostasis, and the activities of SOD, CAT, GPx, and GST, while concurrently reducing TBARS and protein carbonyl accumulation.⁶⁰ The SIRT1-PPARα-Nrf2 signaling axis is of particular mechanistic significance: it establishes a molecular bridge between M. oleifera’s antioxidant and metabolic regulatory activities—pharmacological duality of direct relevance to metabolic syndrome, wherein both arms of this pathway are concurrently disrupted.¹⁶ Although M. oleifera may act through an integrated regulatory axis linking redox balance and metabolic control, current clinical evidence remains inconsistent (Figure 2). A meta-analysis by Diana Cris et al³ does not confirm reliable cardiometabolic benefits in adults, highlighting a gap between mechanistic promise and validated therapeutic efficacy.

Tumor Microenvironment Modulation and Adaptive Immunity

M. oleifera bioactives modulate the tumor microenvironment (TME) through a mechanistically coherent trifecta of anti-tumor immune potentiation: attenuation of regulatory T cell polarization, enhancement of NK cell cytotoxicity, and promotion of CD4⁺ and CD8⁺ T lymphocyte proliferation.⁴⁴ At the cellular level, leaf protein inhibited Jurkat T-ALL leukemia cell growth through concurrent induction of apoptosis, cell cycle arrest, and autophagy via the MAPK/AKT signaling pathway,⁶¹ implicating a direct anti-leukemic pharmacology operating at the immune cell interface.

Cross-species immunostimulatory evidence substantiates the biological plausibility of these adaptive immune effects. In Nile tilapia aquaculture models, fermented M. oleifera leaves enhanced immune responses, suppressed proinflammatory gene expression, reduced bacterial burden, and improved post-infection survival relative to unfermented preparations;⁶² comparable immunoprotective and growth-promoting outcomes were demonstrated in gibel carp at 40% dietary substitution.⁶³ In crucian carp, dietary leaf extract supplementation at 0.5% improved growth performance, antioxidant capacity, immune gene expression, and resistance to Aeromonas hydrophila, with 0.35–0.48% identified as the immunologically optimal inclusion range.⁶⁴ Extending these findings to marine aquaculture, M. oleifera leaf supplementation (1–5%) in gilthead sea bream (Sparus aurata) fingerlings significantly enhanced mucosal immune parameters—encompassing IgM titres, complement activity, and tight junction gene expression—alongside improved antioxidant capacity and feed utilization.⁶⁵ The upregulation of tight junction genes is mechanistically noteworthy, reflecting barrier-reinforcing mucosal immunity and establishing a direct link between M. oleifera supplementation and reduced enteric pathogen susceptibility—findings that carry extrapolative relevance for intestinal immunity research beyond aquaculture contexts.⁶⁵ While these cross-species findings provide biological plausibility, their direct applicability to human immune physiology remains uncertain.

Against Trichinella spiralis infection in murine models, both ivermectin nanoparticles and M. oleifera leaf extract nanoparticles attenuated iNOS, TNF-α, and NF-κB whilst upregulating IL-10 expression, with combined therapy demonstrating superior efficacy in reducing parasite burden and ameliorating intestinal pathology.⁶⁶

The convergence of vertebrate cross-species immunostimulatory data across parasitic, bacterial, and oncological contexts provides supportive biological plausibility for M. oleifera as a potential modulator of both innate and adaptive immune responses.^64,67 However, given the predominance of preclinical and cross-species evidence, the extent to which these effects translate to human immune physiology remains uncertain (Figure 2). Collectively, these findings suggest a multi-target immunomodulatory profile, though confirmation in well-designed human clinical studies remains limited.

Anticancer Activity

M. oleifera has been reported to target malignant transformation in experimental models through mechanistically distinct and complementary arms: chemoprevention, inhibition carcinogen activation, detoxification enhancement, anti-proliferative signaling, and direct apoptosis induction.⁶⁸ Evidence indicates that M. oleifera exerts a context-dependent modulatory effect on apoptosis, elevating the survival threshold in non-malignant cells while selectively lowering the apoptotic threshold in cancer cells, consistent with a shift in mitochondrial death signaling that favors cytoprotection in normal tissues and apoptotic commitment in malignant systems.⁵⁹ This selectivity profile is mechanistically distinct from non-selective cytotoxic agents and carries direct therapeutic implications. Oncogenic pathway engagement extends beyond NF-κB/Nrf2 to encompass YAP/TAZ—Hippo pathway transcriptional co-activators—TLR4/NF-κB, and Wnt/β-catenin, the latter a master regulator of cancer stem cell self-renewal, epithelial-to-mesenchymal transition, and acquired therapy resistance.¹⁵ Simultaneous targeting of these convergent oncogenic nodes is proposed as a mechanistic basis for the broad anticancer activity observed with M. oleifera.

Breast Cancer

M. oleifera leaf extracts have been shown to selectively inhibit MCF-7 cells via induction of apoptosis, upregulating Bax, caspase-8, and p53, with GC-MS implicating benzene acetonitrile derivatives as principal mediators.²⁸ The n-hexane leaf fraction (hMO) exhibited moderate cytotoxicity in T47D cells (IC₅₀ = 235.58 µg/mL), accompanied by cell-cycle arrest at both G0–G1 and G2–M phases and downregulation of cyclin D1 and Bcl-2, indicating disruption of proliferative control coupled with reduced anti-apoptotic capacity, consistent with cytostatic stress that may predispose cells to apoptotic progression.⁶⁹ Crude water, hexane, and dichloromethane seed fractions inhibited MCF-7 proliferation with IC₅₀ values of 280, 130, and 26 µg/mL respectively, with the hexane fraction demonstrating minimal toxicity against non-malignant MCF10A cells—indicating therapeutically relevant selectivity.⁷⁰

Evidence for the anticancer potential of M. oleifera is derived predominantly from in vitro and in vivo experimental models, within which multiple tumor-related pathways have been explored, including downregulation of CaN, VEGF, SFRP1, and SLC39A6.³⁷ Synergistic anticancer activity has been demonstrated in experimental models in combination with doxorubicin in cervical cancer and cisplatin in pancreatic cancer via NF-κB inhibition, with minimal toxicity observed in normal cell models.³⁷ A moringa oil-based nanocarrier co-loaded with curcumin inhibited MDA-MB-231 proliferation and induced apoptosis through Bcl-2/Bax modulation, with superior efficacy over either agent alone.⁷¹

HIF-1α-driven hypoxic survival, angiogenesis, and therapy resistance—central to breast cancer progression⁷²—are targeted by M. oleifera bioactives Aurantiamide Acetate and Benzyl Isothiocyanate. Molecular docking, molecular dynamics simulations, and DFT analyses predicted strong binding affinity, thermodynamic stability, and favorable pharmacokinetics against HIF-1α, VEGF, and GLUT1,⁷³ suggesting these compounds as candidates for targeting hypoxic tumor adaptation.

Prostate Cancer: GMG-ITC as a Precision Pharmacophore

In prostate cancer, bioactive compounds derived from M. oleifera demonstrate notable anticancer potential. Glucomoringin isothiocyanate (GMG-ITC) exhibits strong cytotoxic activity against PC-3 prostate cancer cells (IC₅₀ = 3.5 µg/mL), inducing apoptosis, causing G2/M cell cycle arrest (39.1% reduction), and activating key apoptotic signaling pathways, including p53, caspases, Bax, and JNK.⁷⁴ Additionally, ampelopsin, a natural flavonoid, shows inhibitory effects on prostate cancer cell proliferation, promotes apoptosis, and suppresses tumor progression mechanisms such as angiogenesis, invasion, and metastasis, supporting its potential as a therapeutic candidate.⁷⁵

Renal Cell Carcinoma

M. oleifera leaf extracts prepared using 50% and 70% hydroethanol and analyzed for bioactive compounds. The 50% extract showed higher antioxidant, phenolic, and flavonoid content.⁷⁶ Lysyl oxidase-like 2 (LOXL2) promotes renal cell carcinoma (RCC) progression through Src/FAK-mediated invasion and epithelial-to-mesenchymal transition; its silencing reduced MMP-9, N-cadherin, and vimentin while upregulating E-cadherin and suppressing proliferation.⁷⁷ M. oleifera -derived MIC-1 were shown to inhibit RCC cell growth, migration, and invasion, and induced apoptosis and cell cycle arrest without normal renal cell toxicity, through PTP1B inhibition and downstream suppression of Src/Ras/Raf/ERK signaling—with in vivo xenograft studies supporting translational potential in preclinical models.⁷⁸

The PTP1B inhibition mechanism warrants specific attention: PTP1B has emerged as a high-priority target across oncology and metabolic diseases,⁷⁹ and MIC-1 represents a structurally novel natural product inhibitor of this enzyme—one with potential applicability beyond RCC given the cross-disease relevance of PTP1B dysregulation.

Hepatocellular, Colorectal, and Lung Carcinoma

M. oleifera fruit extract (MOF) was shown to induce ROS-mediated apoptosis and caspase-3 activation in HepG2 hepatocellular carcinoma cells, with in silico analyses confirming strong bioactive binding to caspase-3 and favorable drug-likeness without predicted toxicity.⁸⁰ Leaf and bark extracts from Egyptian M. peregrina and M. oleifera were reported to reduce HepG2 and MCF-7 survival through apoptosis and cell cycle disruption, with low toxicity against normal HFB4 melanocyte cells.⁸¹ In HT-29 colorectal cancer cells, leaf-synthesized silver nanoparticles (MOLP-AgNPs) were shown to exert dose-dependent antiproliferative effects by suppressing Ki-67, Wnt, β-catenin, and Cyclin D1 while downregulating metastasis-associated TGF-β and Snail—simultaneously targeting tumor growth and metastatic potential.⁸² Against A549 lung cancer cells, aqueous ethanol leaf extract were shown to inhibit proliferation and migration, induced caspase-3/9-mediated apoptosis, caused S-phase arrest through cyclin D1, cyclin E, and p21 modulation, and suppressed JAK2/STAT3 phosphorylation alongside MMP2/9 downregulation.⁸³ Network pharmacology analysis across 80 M. oleifera-targeted proteins identified EGFR as the principal lung cancer pathway hub, with caffeic acid demonstrating greater molecular docking affinity than erlotinib.⁸⁴ While in silico binding affinity does not equate to clinical efficacy, the caffeic acid–EGFR interaction constitutes a tractable mechanistic hypothesis warranting dedicated experimental validation.

Anti-Angiogenic Activity

M. oleifera leaf extracts were demonstrated significant anti-angiogenic activity in the chick chorioallantoic membrane (CAM) assay, with the 100% aqueous extract resulting in 81.33% inhibition of blood vessel formation after 48 hours in a dose-dependent manner.⁸⁵ Anti-angiogenesis constitutes a mechanistically distinct and complementary dimension of anticancer activity, operating in parallel with direct cytotoxicity. A cautionary finding warrants explicit acknowledgement: seed extract improved metabolic parameters in obese mice bearing triple-negative breast cancer xenografts but, when combined with chemotherapy, was associated with worsened tumor progression in experimental settings.⁸⁶ This isolated but consequential result mandates that concurrent M. oleifera supplementation during active chemotherapy be approached with caution pending prospective pharmacological interaction data.

Organ-Specific Anti-Inflammatory Activity

The anti-inflammatory pharmacology of M. oleifera is among the most mechanistically characterized properties of any medicinal plant under current investigation. A review of 26 systematic studies confirmed targeting of NF-κB and Nrf2 pathways across inflammatory disease contexts, though predominantly low methodological quality limits confidence in aggregated conclusions.⁵⁹ At the cellular level, Moringa suppresses the inflammatory cascade with measurable consistency. Its extracts reduce the expression of IL-1, IL-6, TNF-α, PTGS2, NF-κB (P50), and RelA—key drivers of chronic inflammatory disease—at both the mRNA and protein levels.⁵⁶ This mirrors the mechanistic territory of dimethyl fumarate, which similarly dampens neuroinflammation through Nrf2 pathway activation, shifting immune responses toward a less pro-inflammatory profile.⁸⁷ The distinction is one of precision: dimethyl fumarate hits a defined molecular target with controlled pharmacokinetics, while Moringa engages overlapping pathways through a constellation of bioactive compounds (Figure 3). Less specific, but not without consequence.

Pulmonary Anti-Inflammation

M. oleifera seed oil significantly reduced pulmonary inflammation and tissue damage in an acute lung injury mouse model.⁸⁸ MOEF suppressed cigarette smoke–induced TNF, IL-6, and IL-8 and inhibited NF-κB p65/RelA signalling in human macrophages,⁵⁷ while the 80% hydroethanolic flower extract concentration-dependently suppressed LPS-induced NO, PGE₂, TNF-α, IL-1β, IL-6, iNOS, and COX-2 whilst upregulating IL-10 and IκB-α.⁵⁸ Supplementation with polar leaf extracts additionally reduced oxidative stress, promoted sensory and motor function recovery, and enhanced peripheral nerve regeneration,³⁹ extending anti-inflammatory activity into neural repair.

Gastrointestinal Anti-Inflammation

Oral M. oleifera seed hydro-alcoholic extract (MSHE, 50–200 mg/kg) and chloroform fraction (MCF, 100–200 mg/kg) dose-dependently reduced distal colon weight, ulcer severity, mucosal inflammation, crypt damage, and myeloperoxidase activity in acetic acid-induced colitis.⁸⁹ The ethyl acetate fraction suppressed LPS-induced nitric oxide and proinflammatory cytokine production in RAW264.7 macrophages by inhibiting COX-2, iNOS, and NF-κB p65, upregulating IκBα, and blocking NF-κB nuclear translocation.⁹⁰

Renal Anti-Inflammation

Seed oil (5 mL/kg, 16 days) protected against gentamicin-induced nephrotoxicity by reducing serum creatinine, urea, MDA, IL-1β, IL-6, and TNF-α, while restoring SOD, CAT, GPx, and GSH through downregulation of NF-κB, iNOS, and caspase-3—confirmed histopathologically.⁹¹ Against 5-fluorouracil-induced nephrotoxicity, prophylactic seed oil administration suppressed NF-κB/iNOS overexpression, downregulated caspase-3, and restored antioxidant defences.⁹² Across leaf, seed, stem, and whole extracts, consistent upregulation of SOD, CAT, and GSH alongside downregulation of TNF-α, IL-1β, IL-6, and COX-2 supports M. oleifera as a candidate for nephroprotective drug development.⁹³

Neuroinflammation

Seed oil (5 mL/kg, 17 days) protected against methotrexate-induced cerebral neurotoxicity by inhibiting acetylcholinesterase, suppressing oxidative stress and inflammatory cytokines, and restoring glutathione levels, with antioxidant potency comparable to reference standards in DPPH and FRAP assays.⁹⁴ MIC-1-enriched seed extract upregulated Nrf2 target genes—NQO1, GSTP1, and HO-1—whilst suppressing carrageenan-induced oedema,³⁵ positioning MIC-1 at the convergence of anti-neuroinflammatory and systemic anti-inflammatory mechanisms.

Organ-Protective Pharmacology

M. oleifera (Figure 4) can be interpreted as exerting organ-protective pharmacology through coordinated regulation of cellular stress and survival systems rather than isolated biochemical effects. Variability in extract composition, such as the M1S9 ratio, suggests that its chemopreventive potential arises from synergistic phytochemical interactions that shape functional outcomes.³⁷ Its antioxidant capacity appears to operate as a regulatory mechanism, stabilizing redox balance and preserving cellular integrity under conditions of oxidative and nitrosative stress.⁹⁵

Figure 4.

Moringa oleifera: Botanical Representation.

Notes: Photograph of a mature M. oleifera specimen illustrating characteristic morphological features, including pinnate leaf architecture and developing seed pods, reflecting the organ-specific phytochemical partitioning that underlies preparation-dependent pharmacological outcomes.

In malignant contexts, this regulatory influence shifts toward growth restraint, promoting apoptotic commitment and limiting proliferative signaling through pathways including MAPK/AKT signaling pathway,⁶¹ with seed-derived constituents reinforcing this effect across tumor models.⁹⁶ In parallel, its metabolic benefits suggest restoration of systemic homeostasis, where modulation of NF-κB signaling pathway and Nrf2/Keap1 pathway reflects an integrated control of redox and inflammatory signaling linked to organ function.¹⁶ Collectively, these effects indicate that M. oleifera acts as a systems-level modulator, supporting organ integrity by rebalancing interconnected stress-response networks (Figure 1).

Hepatoprotection: Mechanistic Consistency Across Toxic Aetiologies

The hepatoprotective activity of M. oleifera is one of the most consistently replicated organ-protective properties in the literature (Figure 3), with mechanistic convergence across diverse toxic models on a shared program: restoration of GSH/SOD/CAT/GPx, suppression of NF-κB/TNF-α/IL-1β signaling, normalization of ALT, AST, and GGT, and histological recovery.^97,98 Against carbon tetrachloride-induced hepatotoxicity, leaf extract dose-dependently restored liver enzymes, bilirubin, protein, and antioxidant markers with histoprotection comparable to silymarin,⁹⁹ attributable to quercetin, kaempferol, and β-sitosterol-mediated radical scavenging and hepatocyte membrane stabilization.¹⁰⁰ Against acetaminophen-induced hepatotoxicity, the extract suppressed NF-κB signaling, normalized lipid metabolism, and restored glutathione;¹⁰¹ against acetaminophen-induced fibrosis, it reduced TGF-β and TNF-α with efficacy maintained across both prophylactic and therapeutic administration schedules (Figure 3).¹⁰²

A systematic review of 13 studies across five databases confirmed that flavonoid- and quercetin-rich M. oleifera leaf extract significantly improved liver histopathology, glucose metabolism, and lipid profiles in non-alcoholic fatty liver disease (NAFLD), supporting its candidacy as a safe herbal adjuvant.¹⁰³ Against lead acetate-induced hepatotoxicity, methanolic leaf extract reduced ALT, AST, MDA, NO, NF-κB, TNF-α, IL-1β, Bax, and caspase-3 while restoring GSH and Bcl-2.⁹⁸ Against anti-tuberculosis drug (isoniazid/rifampicin/pyrazinamide)-induced hepatic damage, leaf extract normalized liver enzymes, bilirubin, and lipid levels with efficacy again comparable to silymarin.⁶⁵ In high-fat diet-fed mice, M. oleifera infusion and extract ameliorated NAFLD, hyperlipidemia, and hyperglycemia—infusion demonstrating superior overall efficacy, extract superior glycemic improvement—with infusion additionally reducing anxiety-like behavior and both preparations enhancing motor activity.¹⁰⁴

Mechanistic attribution is supported by an 80% hydroethanol leaf extract reducing acetaminophen-induced hepatic lipid peroxidation and restoring glutathione S-transferase, reductase, and peroxidase activity, with leaf and flower extracts (200–400 mg/kg, i.p.) attenuating hepatotoxicity without compromising renal function markers.¹² Nanoformulation of M. oleifera extracts consistently amplifies organ-protective efficacy, with niosome-encapsulated preparations demonstrating superior cardioprotective outcomes relative to crude extract.¹⁰⁵

Where Moringa’s interaction with antimalarials poses one kind of clinical question, its hepatoprotective capacity offers a partial answer to another. Artesunate–amodiaquine combination therapy carries documented hepatotoxic risk, particularly at high doses.¹⁰⁶ In Wistar rat models, aqueous-methanol Moringa extract at 1000 mg/kg demonstrated strong antioxidant activity—IC₅₀ of 51.88 μg/mL—significantly reduced AST elevations, and attenuated liver damage induced by high-dose treatment, with free radical scavenging identified as the primary protective mechanism.¹⁰⁶ The implication is notable: Moringa may simultaneously complicate the pharmacokinetics of antimalarial agents while offering a degree of organ-level protection against their toxic sequelae.¹⁰⁷ These are not contradictory findings—they are two faces of the same multi-target biology, and they demand to be read together.

Nephroprotection: Antioxidant–Anti-Inflammatory–Anti-Apoptotic Convergence

M. oleifera extract protected rat kidneys from lead acetate-induced toxicity by restoring antioxidant defences (GSH, GPx, SOD, catalase), reducing oxidative stress (lipid peroxidation, NO), suppressing inflammation (TNF-α, IL-1β, NF-κB, iNOS), and regulating apoptosis (Bax, caspase-3, Bcl-2).¹⁰⁸ Against ischemia-reperfusion injury, methanolic extract (200–400 mg/kg) reduced MDA, protein carbonyl, and AOPP, lowered BUN and creatinine, restored antioxidant enzyme activity, and ameliorated histological damage, with efficacy comparable to vitamin C.¹⁰⁹ Against tilmicosin nephrotoxicity, dose-dependent renoprotection was demonstrated with optimal efficacy at 800 mg/kg.¹¹⁰

The 50% hydroethanolic leaf extract—exhibiting higher antioxidant, phenolic, and flavonoid content than the 70% preparation—protected against gentamicin-induced nephrotoxicity by reducing urea, creatinine, and oxidative stress markers while restoring antioxidant enzyme activity.⁷⁶ Valproate- and tilmicosin-induced nephrotoxicity were each significantly attenuated by M. oleifera co-administration, with dose-dependent reductions in inflammatory and structural injury.^110,111 The mechanistic consistency of renoprotective outcomes across pharmacologically unrelated nephrotoxins indicates a general organ-protective program rather than toxin-specific antagonism.

Cardioprotection

In vivo, in vitro, and clinical evidence collectively indicate that M. oleifera exerts cardioprotective effects through modulation of oxidative stress, inflammation, and the NF-κB and Nrf2/Keap1 pathways, with nanoformulations demonstrating enhanced bioavailability and efficacy, and clinical studies reporting improvements in blood pressure, lipid profiles, and oxidative stress markers (Table 3).¹¹² Methanolic leaf extract (300 mg/kg, 60 days) protected diabetic rat cardiac tissue by reducing serum glucose, HbA1c, TBARS, hydroperoxides, and conjugated dienes while elevating plasma insulin, SOD, CAT, GPx, GRD, and GSH.¹¹³ A null finding warrants explicit reporting: in a 5-week randomized study in hypercholesterolemic rabbits (n=20), oral leaf extract (200 mg/kg/day) produced no significant effect on post-angioplasty iliac artery myointimal hyperplasia relative to saline controls.¹¹⁴

Table 3.

Summary of Pharmacological Activities and Biological Effects of M. oleifera Preparations Across Experimental and Clinical Models

Preparation	Model	Dose/Duration	Biological Effect	Key Outcomes	Ref
Seed kernel powder	Humans with asthma	3 g twice daily for 3 weeks	Anti-asthmatic activity	Improved respiratory symptoms and pulmonary function	[14]
Methanolic leaf extract	Diabetic rats	300 mg/kg for 60 days	Cardioprotective and antioxidant effects	↓ glucose, ↓ HbA1c, ↓ TBARS; ↑ SOD, CAT, GPx, and GSH	[113]
Seed oil	Rats with gentamicin-induced nephrotoxicity	5 mL/kg for 16 days	Nephroprotective effect	↓ creatinine, urea, MDA, IL-1β, IL-6, and TNF-α; ↑ SOD, CAT, and GPx	[91]
Seed oil	Rats with methotrexate-induced neurotoxicity	5 mL/kg for 17 days	Neuroprotective effect	↓ oxidative stress and inflammatory cytokines; ↑ glutathione levels	[94]
Seed hydroalcoholic extract (MSHE)	Rats with colitis	50–200 mg/kg	Anti-inflammatory activity	↓ ulcer severity, mucosal damage, and MPO activity	[89]
Chloroform fraction (MCF)	Rats with colitis	100–200 mg/kg	Anti-inflammatory activity	↓ inflammatory response and colon injury	[89]
Leaf capsules	Humans with obesity	400 mg for 8 weeks	Metabolic and lipid-modulating effects	↓ BMI, total cholesterol, and LDL levels	[115]
70% ethanol leaf extract	Obese rats	200–400 mg/kg for 1 month	Metabolic regulation	↓ body weight, adiposity, glucose, insulin resistance, FAS, and HMG-CoA reductase; ↑ R-QUICKI, adiponectin, omentin, GLUT-4, MC4R, and PPAR-α	[115]
Leaf powder	Infants	5–35 g for 6 weeks	Nutritional supplementation	Increased plasma retinol levels (trend)	[116]
Seed extract	Cancer cell lines	IC50: 4.85–9.15 µg/mL	Anticancer activity	Induced apoptosis (↑ p53/p21, ↓ Bcl-2) and cell-cycle arrest	[117]

Notes: Summary of pharmacologically evaluated M. oleifera preparations across in vitro, in vivo, and human study models, detailing preparation type, dosing regimen, biological system, and primary outcome. Data reflect preparation-dependent variability in therapeutic effect and underscore the necessity of compositional standardization for cross-study comparability.

Abbreviations: CAT, catalase; GPx, glutathione peroxidase; GSH, reduced glutathione; HbA1c, glycated hemoglobin; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; HOMA-IR, homeostatic model assessment of insulin resistance; IC₅₀, half-maximal inhibitory concentration; IL-1β, interleukin-1 beta; IL-6, interleukin-6; LDL, low-density lipoprotein; MC4R, melanocortin-4 receptor; MPO, myeloperoxidase; MSHE, Moringa oleifera seed hydroalcoholic extract; PPAR-α, peroxisome proliferator-activated receptor alpha; R-QUICKI, revised quantitative insulin sensitivity check index; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances; TNF-α, tumor necrosis factor alpha. Symbols: ↑ indicates increased levels or activity; ↓ indicates decreased levels or activity.

This result underscores the dose- and context-dependence of cardiovascular effects and cautions against generalizing cardioprotective efficacy from mechanistic evidence alone.

Neuroprotection: Multi-Disease Target Engagement

M. oleifera demonstrates pleiotropic neuroprotective activity across Alzheimer’s disease, dementia, Parkinson’s disease, stroke, and neurotoxicity, attributed to its diverse neuroprotective phytochemical constituents.¹¹⁸ Isolated compounds—moringin, astragalin, isoquercitrin, chlorogenic acid, kaempferol, and quercetin—exert neuroprotective and anti-neuroinflammatory effects across Parkinson’s, Alzheimer’s, multiple sclerosis, and Huntington’s disease through antioxidant and anti-inflammatory mechanisms, though extensive pharmacokinetic and toxicity profiling remains prerequisite to clinical trial development.¹¹⁹

GMG-ITC protected SH-SY5Y neuroblastoma cells against H₂O₂-induced cytotoxicity by activating Nrf2 (SOD-1, NQO1) and inhibiting NF-κB/BACE1/APP;³⁴ moringin prevented H₂O₂-induced apoptosis and preserved neurite morphology and cytoskeletal integrity in differentiated SH-SY5Y cells.¹²⁰ Glucomoringin demonstrates in silico promise for Alzheimer’s disease through strong IL-1β binding with favorable pharmacokinetics and safety profiles.¹²¹ In vivo, leaf extract (300 mg/kg, 28 days) protected against aluminium chloride-induced temporal cortical neurodegeneration by preserving Nissl substance and downregulating NSE and GFAP overexpression;¹²² M. oleifera extract additionally improved motor coordination and reduced neuroinflammation and neurodegeneration in 3-acetylpyridine-induced cerebellar ataxia.¹²³ Quercetin, kaempferol, β-carotene, flavonoids, and isothiocyanates collectively maintain brain antioxidant enzyme activity, mitochondrial function, and neurogenesis, with nanoformulations demonstrating enhanced therapeutic value.¹²⁴

Root ethanolic extract demonstrated the strongest potent acetylcholinesterase inhibition among tested plant organs (~90%, IC₅₀ = 0.0563 µg/mL), with potency following the hierarchy: root > bark > leaf > flowers > seed¹²⁵—directly relevant to Alzheimer’s pharmacotherapy given the shared mechanism of approved cholinesterase inhibitors. A systematic review and meta-analysis of experimental ischemic stroke models has demonstrated that M. oleifera extract significantly reduced infarct volume and oxidative stress indices while augmenting antioxidant enzyme activity;¹²⁶ however, the limited number of constituent studies and small sample sizes necessitate further validation before translational conclusions can be drawn (Table 3). Overall, these findings collectively highlight the broad neuroprotective potential of M. oleifera through cholinesterase inhibition and antioxidant-mediated neurovascular protection, supporting its relevance across neurodegenerative and cerebrovascular disorders.¹²⁷

Gastroprotective and Anti-Ulcer Activity

A meta-analysis of 11 animal studies confirmed that M. oleifera significantly reduced ulcer index across peptic ulcer models, with high doses demonstrating efficacy comparable to standard drugs and robust anti-ulcer activity confirmed by sensitivity analyses.¹²⁸ Leaf extract exhibited dose-dependent gastroprotection against aspirin-induced ulcers comparable to cimetidine¹²⁹ and significant antiulcer activity across stress-, ethanol-, indomethacin-, and cysteamine-induced models; fruit extracts produced no significant effect, identifying the leaf as the pharmacologically active organ.^130,131 Against bisphenol A-induced gastric ulceration, leaf extract enhanced antioxidant defenses, elevated prostaglandin E₂, and attenuated oxidative stress, inflammation, and apoptosis through convergent antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.¹³² Against HCl/ethanol-induced injury, extract reduced lesion index, enhanced mucus production, elevated gastric pH, and decreased lipid peroxidation.¹³³ Among fractionated leaf ethanol extract constituents, fraction K3 demonstrated the strongest anti-H. pylori and antisecretory activity,¹³⁴ identifying a discrete bioactive fraction of potential therapeutic specificity for H. pylori-associated gastropathy, though clinical validation and standardization remain necessary for translation.

Systemic Pharmacological Activities

M. oleifera exhibits pharmacological activity across several additional physiological domains not encompassed within the primary organ-protective and cardiometabolic framework. Beyond its primary metabolic and organ-specific effects, M. oleifera displays a wide pharmacological spectrum involving multiple physiological systems. Its activity extends to modulation of smooth muscle function, renal electrolyte handling, inflammatory tone, and immune responsiveness, reflecting a dispersed but coordinated biological influence across tissues.^12,135 In experimental models, it shows functional regulation of gastrointestinal motility, vascular reactivity, and diuresis, indicating involvement in peripheral control systems governing fluid balance and tissue responsiveness.^136,137 However, M. oleifera demonstrates dose-dependent diuretic activity in rats, with favorable safety profiles in humans up to 50 g single doses. Caution is recommended with pregnancy and antihypertensive or antidiabetic therapies.¹³⁸ In parallel, emerging evidence suggests interaction with protein aggregation processes, where certain phytochemicals interfere with misfolding and fibril formation, although this remains limited to in vitro observations.¹³⁹ Across broader studies, M. oleifera is consistently associated with antioxidant, immunomodulatory, antimicrobial, and cytoprotective effects driven by its diverse phytochemical profile, though variability in extraction and formulation significantly influences observed outcomes.¹⁴⁰

At the same time, safety data indicate a dose-dependent profile in which moderate exposure is generally well tolerated (Table 3), whereas high or prolonged intake may disrupt hepatic, renal, and hematological parameters, underscoring a narrow margin between pharmacological activity and toxicity.^141–143

Additional concerns include variability in product standardization and potential interactions with drug-metabolizing systems, reinforcing the need for controlled evaluation frameworks.⁵⁹ Collectively, the evidence positions M. oleifera as a biologically versatile agent with context-dependent pharmacological and toxicological profiles, where outcomes are strongly shaped by dose, preparation method, and biological setting.^13,144 Physical performance capacity has also been examined: a 30-day RCT in 44 young men demonstrated that aqueous extract supplementation significantly improved push-up performance and treadmill endurance versus placebo¹⁴⁵—a finding consistent with the antioxidant and anti-inflammatory mechanisms documented across metabolic and musculoskeletal domains.

Antidiabetic and Cardiometabolic Activity: From Molecular Targets to Clinical Outcomes

M. oleifera exhibits antidiabetic activity through integrated modulation of β-cell function and oxidative stress,¹⁸ alongside direct effects on insulin signaling,¹⁴⁶ indicating a multi-target metabolic effect—supporting both glucose and lipid regulation¹⁴⁷—rather than a single hypoglycemic mechanism. Its actions appear to operate along the redox–metabolic interface, preserving cellular function (Figure 1). Clinical evidence remains variable, with limited effects on fasting glucose despite signals in cardiovascular parameters, suggesting that its benefits may extend beyond direct glycemic control.¹⁴⁸ In contrast, experimental models consistently show improved metabolic efficiency, antioxidant capacity, and stress adaptation.^60,113 Overall, M. oleifera can be interpreted as a metabolic modulator that enhances systemic homeostasis, with context-dependent translation from molecular effects to clinical outcomes.

Mechanistic Evidence

Preclinical investigations provide substantial insight into the antidiabetic mechanisms of M. oleifera, with a predominant emphasis on antioxidant-mediated β-cell protection and metabolic regulation. In streptozotocin (STZ)-induced type 1–like and insulin-resistant type 2 diabetic models, aqueous extracts and seed powder (500 mg/kg) demonstrated significant glycemic improvement, largely attributed to enhanced antioxidant enzyme activity. Bioactive constituents such as quercetin and other phenolic compounds appear to scavenge mitochondrial reactive oxygen species (ROS), thereby preserving pancreatic β-cell integrity.¹⁸ Consistent with this, seed powder supplementation in STZ-induced diabetic rats reduced lipid peroxidation, fasting blood glucose, HbA1c, interleukin-6, and immunoglobulin levels, while restoring endogenous antioxidant defenses; these biochemical findings were corroborated by histological improvements in renal and pancreatic tissues.¹⁴⁹ Similarly, combined methanolic leaf and seed extracts in alloxan-induced diabetic models reduced hyperglycemia while restoring glutathione and catalase activity and attenuating lipid peroxidation and protein carbonyl stress.¹⁵⁰

However, it is important to contextualize these findings within the limitations of the experimental models employed. Both STZ and alloxan induce diabetes primarily through oxidative β-cell cytotoxicity, potentially amplifying the apparent efficacy of antioxidant interventions. As such, these models may overestimate therapeutic impact and limit direct extrapolation to human diabetes, where pathophysiology is more heterogeneous and not solely driven by oxidative injury.

At the molecular level, computational and bio-guided approaches have expanded the mechanistic landscape. In silico docking studies have identified multiple candidate compounds—including anthraquinones, anthocyanins, hemlock tannins, sitogluside, and A-phenolic steroids—with predicted binding affinities to key metabolic targets.¹⁵¹ While informative, these findings remain hypothesis-generating and require functional validation. Complementary experimental work has isolated beta-sitosterol, which demonstrated antihyperglycemic and neuroprotective effects in alloxan-induced diabetic mice, including improved insulin secretion, α-glucosidase inhibition, normalization of HbA1c, and attenuation of hyperalgesia and mechanical allodynia.¹⁵² Beyond classical diabetes models, M. oleifera leaf extract (500 mg/kg) also reduced hyperinsulinemia, glucose levels, TNF-α expression, and ovarian follicular abnormalities in testosterone propionate-induced polycystic ovary syndrome (PCOS) models, with efficacy comparable to metformin, suggesting broader endocrine-metabolic effects.¹⁵³

Mechanistically, M. oleifera exhibits multi-target activity across metabolic and inflammatory pathways. Glycosidic isothiocyanates and benzylamine derivatives are predicted to interact with proteins such as SRC and PTPN1, implicating modulation of PI3K/Akt signaling and inflammatory cascades relevant to insulin resistance.¹⁵⁴ Network pharmacology analyses further support this systems-level activity, identifying 32 bioactive compounds, 44 molecular targets, and 37 associated signaling pathways. While this multi-target profile may underlie its therapeutic versatility, it also raises considerations regarding specificity and potential off-target effects.¹⁵⁴ Functionally, M. oleifera has been shown to inhibit α-amylase and α-glucosidase activity, enhance hepatic glycogen storage, and regulate gluconeogenesis. Additionally, some evidence suggests dose-dependent reductions in blood pressure, potentially mediated through increased nitric oxide bioavailability and improved endothelial function.¹⁵⁵

Despite robust mechanistic and preclinical support, clinical translation remains modest. Meta-analyses of human studies indicate consistent but relatively small reductions in fasting glucose, HbA1c, and blood pressure across heterogeneous populations, with variability in study quality and design limiting definitive conclusions.¹⁵⁵ Importantly, M. oleifera does not replicate the efficacy of established pharmacotherapies such as metformin. Instead, its effects appear complementary. Preclinical studies demonstrate that combination therapy with metformin yields superior outcomes compared to either agent alone, including enhanced glycemic control, improved antioxidant status, preservation of β-cell architecture, and attenuation of downstream complications;¹⁵⁶ independent STZ-based evidence further confirms that this combined regimen also attenuates systemic inflammation, an axis insufficiently addressed by current monotherapies.¹⁵⁶ However, this apparent synergy is currently supported only by animal data and requires validation in well-designed clinical trials (Figure 5). Taken together, the mechanistic profile of M. oleifera supports a role as a multi-target adjunctive therapy rather than a standalone antidiabetic agent. Its biological activity is best understood within a framework of synergistic integration with established treatments, rather than substitution.

Figure 5.

Translational Development Framework for Moringa oleifera Bioactives.

Notes: Structured translational roadmap illustrating the sequential progression from phytochemical standardization and bioactive characterization through formulation optimization, early clinical development, indication-specific clinical evaluation, and safety assessment toward the evidence-based therapeutic application of priority M. oleifera bioactives.

Clinical Evidence for Glycemic Control

A growing body of evidence supports the hypoglycemic potential of M. oleifera, although translational consistency remains limited. A systematic review encompassing 33 animal and 8 human studies demonstrated significant glucose-lowering effects following both acute and chronic administration, while emphasizing that heterogeneity in clinical trial design and lack of bioactive standardization constrain definitive conclusions.¹⁵⁷ Similarly, a scoping review of 30 studies (7 human, 23 animal) reported significant glycemic reductions in the majority of investigations (5/7 human; 21/23 animal), yet concluded that current evidence is insufficient to justify its adoption as a standard antidiabetic therapy.¹⁵⁸ This evidence base is supported by the phytochemical complexity of M. oleifera, which contains polysaccharides, flavonoids, alkaloids, glucosinolates, and isothiocyanates that have been investigated over the past two decades for their roles in modulating glucose metabolism and insulin signaling pathways. These mechanistic insights provide a rationale for the continued exploration of Moringa-derived compounds as potential antidiabetic therapeutics, particularly in regions such as South and Southeast Asia where the plant is widely utilized.¹⁵⁹

Clinical trial data suggest modest but biologically relevant effects. A 12-week randomized, double-blind trial in prediabetic individuals demonstrated that 2400 mg/day of M. oleifera leaf supplementation significantly reduced fasting glucose and HbA1c compared with placebo, without affecting gut microbiota composition, appetite-regulating hormones, or hepatorenal function.¹⁶⁰ In a dose-escalation pilot study involving 10 healthy volunteers, administration of 4 g leaf powder increased insulin area under the curve and the insulin-to-glucose ratio by approximately 74% (p = 0.03–0.041), suggesting a potential insulin secretagogue effect in vivo.¹⁴⁶ Complementing this, a randomized crossover study including diabetic and healthy participants showed that supplementation with 20 g leaf powder attenuated postprandial glucose excursions selectively in diabetic individuals at 90–150 minutes, a pattern more consistent with improved insulin sensitivity than direct insulin-mimetic activity.¹⁶¹

Preclinical evidence remains comparatively robust. A meta-analysis of 44 diabetic rodent studies reported a large effect size for blood glucose reduction (−3.92; 95% CI: −4.65 to −3.19), alongside improvements in lipid parameters including triglycerides and cholesterol.¹⁴⁷ However, this pronounced efficacy is notably attenuated in clinical settings, where meta-analyses indicate only modest but statistically significant reductions in fasting glucose, HbA1c, and both systolic and diastolic blood pressure, with outcomes varying by patient characteristics and study region.¹⁵⁵ Beyond glycemic control, M. oleifera may also influence diabetes-associated complications. In diabetic wound environments, aqueous extracts have demonstrated regenerative activity, with progressive wound contraction over 21 days, suppression of inflammatory mediators, and upregulation of vascular endothelial growth factor (VEGF), indicating enhanced angiogenesis and tissue repair.¹⁶² While these findings suggest potential relevance in vascular repair within cardiometabolic disease, their translational applicability to human diabetic wound management remains to be established.¹⁶³

Cardiometabolic and Anti-Obesity Effects

M. oleifera leaf extract reduced weight, adiposity, glucose, insulin, and HOMA-IR while modulating adipokines and lipid-regulating gene expression in high-fat diet rats; in obese women, 8-week capsule administration significantly decreased BMI, total cholesterol, and LDL.¹¹⁵ A systematic review of 108 studies further supported broad cardiometabolic benefits mediated through antioxidant and anti-inflammatory mechanisms, encompassing glucose and lipid metabolism, preservation of organ function, gut microbiota regulation, and involvement of NF-κB and Nrf2–Keap1 signaling pathways.¹⁶ However, a systematic review and meta-analysis of nine RCTs identified no significant benefit across most cardiometabolic outcomes, with the exception of a modest reduction in diastolic blood pressure—though evidence certainty was rated very low due to risk of bias and substantial heterogeneity,³ this discrepancy likely reflects limitations in clinical trial design (Table 4), population variability, and lack of standardization, rather than definitively excluding therapeutic efficacy.

Table 4.

Clinical Evidence for Moringa oleifera Across Human Health Outcomes and Therapeutic Applications

Clinical Condition	Study Type/Population	Intervention	Duration	Key Outcomes	Limitations	Ref
Bronchial asthma	Clinical study	Seed kernel powder (3 g twice daily)	3 weeks	Improved asthma symptoms and respiratory function	Small sample size; limited replication	[14]
Obesity/dyslipidemia	Clinical study in obese women	Leaf capsules	8 weeks	↓ BMI, ↓ total cholesterol, and ↓ LDL levels	Short intervention period; formulation variability	[115]
Malnutrition/vitamin A deficiency	Pilot study in infants	Leaf powder supplementation	6 weeks	Trend toward increased plasma retinol levels	Small sample size; lack of statistical significance	[116]
Cardiometabolic disorders	Meta-analysis of 9 RCTs (n = 341)	Various leaf-based preparations (powder, extracts, capsules)	2 weeks–6 months	Modest reduction in diastolic blood pressure; inconsistent effects on glucose and lipid parameters	Very low certainty of evidence; heterogeneity; risk of bias	[3]
Malnutrition, CKD, and HIV-associated nutritional deficits	Human studies across diverse populations	Leaf-based supplementation	Variable	Reported improvements in nutritional status and immune-related parameters	Lack of standardized dosing and protocols	[17]
Lactation support	Human clinical observations	Leaf-based intake	Early postpartum period	Reported increases in milk volume and protein content	Limited controlled clinical evidence	[164]

Notes: Presents clinical evidence on the effects of M. oleifera in human populations, summarizing outcomes across diverse conditions and study designs. It reflects variability in intervention protocols, duration, and measured endpoints, providing an overview of reported clinical responses. ↑ indicates an increase in the measured outcome; ↓ indicates a decrease in the measured outcome.

Antihypertensive and Diuretic Activity

Hot water seed infusions demonstrated significant antispasmodic (ED₅₀ = 65.6 mg/mL), anti-inflammatory, and diuretic activity in rat models.¹³⁶ Alcoholic leaf extract (50–200 mg/kg) dose-dependently increased urine volume and Na⁺, K⁺, and Cl⁻ excretion with effects comparable to hydrochlorothiazide and no adverse outcomes.¹³⁷ Preclinical evidence indicates that M. oleifera leaf extracts significantly reduce blood pressure in animal models through vasodilation, antioxidant activity, and modulation of renal and vascular pathways including ACE inhibition.¹⁶⁵ M. oleifera leaves inhibit ACE, AChE, and PDE5 simultaneously,¹⁶⁶ providing mechanistic coverage across hypertension, neurodegeneration, and erectile dysfunction—polypharmacological target profile of particular relevance to the comorbidity burden characteristic of cardiometabolic disease. Human studies report no adverse effects at single doses up to 50 g or sustained administration of 8 g/day for 40 days,¹³⁸ supporting an acceptable short-term safety profile at antihypertensive-range doses, although long-term cardiovascular outcomes and dose standardization remain insufficiently characterized. In a prospective placebo-controlled study (n = 41), consumption of 120 g cooked M. oleifera leaves (Figure 4) reduced 2-hour postprandial diastolic blood pressure and showed overall reductions in systolic and diastolic pressure versus no intake, despite prior high salt consumption (~7 g/day). However, findings are limited by small sample size, short (24-hour) follow-up, and non-randomized design.¹⁶⁷

Analgesic and Antipyretic Activity

M. oleifera demonstrates robust analgesic efficacy across leaves, seeds, and bark in both central and peripheral pain models, with effects reported as comparable to indomethacin and extending to antimigraine and neuropathic pain paradigm.¹⁶⁸ This broad-spectrum activity is supported by bibliometric evidence indicating multi-pathway mechanisms with consistently low toxicity across preparations, highlighting its potential as a safer plant-based adjunct to conventional NSAIDs, although clinical validation and standardization remain necessary.¹⁶⁹

Mechanistically, its analgesic effects are closely linked to antioxidant and anti-inflammatory properties. For instance, Kenyan ethanolic leaf extracts exhibit strong free radical scavenging capacity in DPPH, FRAP, and ABTS assays, alongside significant inhibition of carrageenan-induced oedema.¹⁷⁰ At the molecular level, bio-guided fractionation has identified β-sitosterol (BSL) as the primary active constituent in seeds; both M. oleifera extract (40–80 mg/kg) and BSL (18–35 mg/kg) significantly attenuate hyperalgesia and mechanical allodynia in alloxan-induced diabetic models, outperforming tramadol while concurrently normalizing HbA1c and blood glucose levels and enhancing antioxidant (catalase) and α-glucosidase inhibitory activities.¹⁵² Complementarily, flavonoid derivatives such as kaempferol-3-glucoside and neochlorogenic acid have been characterized as key analgesic constituents in leaf preparations.¹⁷¹ Functionally, ethanolic leaf extracts (100–400 mg/kg) demonstrate dose-dependent peripheral and central analgesic effects, inhibiting 32–79% of acetic acid-induced writhing and producing significant nociceptive threshold elevation in the hot plate test at higher doses.¹⁷² In addition to analgesia, methanolic leaf extracts from Punjab exhibit pronounced antipyretic activity in yeast-induced fever models, outperforming bark and root preparations, thereby reinforcing the plant’s broader relevance in inflammatory symptom modulation.¹⁷³

Anti-Infective and Host-Directed Immunomodulatory Activity

Unlike prior descriptive surveys of M. oleifera’s antimicrobial properties, the evidence reviewed here supports a mechanistically integrated model in which direct antimicrobial activity, host immunomodulation, and adjunctive tissue protection operate as distinct, context-dependent modes—with important implications for clinical protocol design. In Trichinella spiralis-infected mice, leaf extract nanoparticles (MOL-NP) reduced iNOS, TNF-α, and NF-κB while enhancing IL-10 expression, indicating host-mediated facilitation of parasite clearance and intestinal recovery;⁶⁶ co-administration with ivermectin nanoparticles produced the greatest reductions in parasite burden and histopathological damage. In livestock, hydroalcoholic leaf extracts (30–60 mL/animal) significantly reduced Trichuris sp. and Ostertagia sp. faecal egg counts (p = 0.002) alongside improvements in body weight and feed efficiency; GC-MS identified heneicosane (35.69%), 1,2-benzenedicarboxylic acid (22.89%), and heptacosane (18.26%) as probable mediators of direct parasite toxicity.¹⁷⁴

Antibacterial and antifungal activities are organ-specific in their phytochemical basis: root-derived N-benzylethyl thioformate and seed-derived isothiocyanates exert potent antibacterial effects, while fruit-derived alkaloids, flavonoids, and steroids inhibit Candida albicans through protein denaturation and spore germination inhibition.¹⁴ Biogenic iron oxide nanoparticles synthesized from M. oleifera extracts demonstrate significant activity against E. coli, with efficacy determined by extraction-driven phytochemical composition.⁶⁷ In a human crossover study, leaf powder achieved microbial load reductions comparable to non-medicated soap when used as a handwashing agent—a finding with direct relevance to low-resource hygiene contexts.¹⁷⁵

A pneumonia rat model provides the mechanistically decisive observation of this section: M. oleifera extract alone improved lung tissue architecture but exerted no significant effect on bacterial colony-forming units or caspase-3-mediated apoptosis; significant reductions in both parameters occurred only upon co-administration with levofloxacin.¹⁷⁶ This adjunctive-dependency pattern—consistent with the chemotherapy interaction⁸⁶—indicates that in infectious pulmonary disease M. oleifera functions as an immunomodulatory and tissue-protective adjunct rather than a standalone antimicrobial. Taken together with the antiparasitic and antibacterial data above, this positions the three modes of activity—direct antimicrobial, immunomodulatory, and tissue-protective—as mechanistically separable and context-dependent, a distinction that should inform the design of clinical protocols and future combination studies.

Anxiolytic Activity

The anxiolytic and antidepressant-like properties of M. oleifera are attributable to its diverse phytochemical profile, encompassing alkaloids, terpenes, flavonoids, and sterols.¹⁶⁸ These bioactive metabolites modulate GABA(_A) receptor activity and regulate key monoaminergic systems—including serotonergic, noradrenergic, and dopaminergic pathways¹⁷⁷—and may further contribute to anxiolytic activity through positive allosteric modulation of the benzodiazepine–GABA(_A) receptor complex and inhibition of NMDA receptor-mediated glutamatergic transmission,¹⁷⁸ collectively implicating a multimodal pharmacological profile.

M. oleifera (200 mg/kg) demonstrated significant anxiolytic effects in a chronic unpredictable mild stress (CUMS) rat model, normalizing 5-HT1A receptor expression and serotonin signaling while reducing pThr183-Erk, c-myc, miR-203, mTOR, and miR-217 expression and restoring β-catenin pathway activity.¹⁷⁹ The use of adolescent rats reflects their elevated hippocampal plasticity and heightened vulnerability to stress-induced neurobiological disruption; under CUMS conditions, M. oleifera not only ameliorated anxiety-like behavior but also exerted stress-dependent neuroprotective effects linked to hippocampal resilience.¹⁷⁹ This serotonergic normalization is mechanistically consistent with the known role of Yif1B—a regulator of 5-HT1A receptor trafficking—whose loss reduces serotonergic projection density, impairs autoreceptor function, heightens anxiety-like behavior, and abrogates fluoxetine responsiveness.¹⁸⁰ Critically, stress and depression downregulate Yif1B expression whereas SSRIs restore it,¹⁸⁰ suggesting that M. oleifera-mediated serotonergic modulation may operate through a convergent regulatory axis, reinforcing its mechanistic plausibility as a neuropsychiatric intervention.

The anxiolytic activity of M. oleifera extends beyond central serotonergic modulation to encompass gut-brain axis dysregulation—a domain of particular clinical relevance given the neuropsychiatric sequelae of inflammatory bowel disease (IBD) and the limited pharmacological options currently available.¹⁸¹ In a 20-day acetic acid-induced colitis model, aqueous leaf extract (25–100 mg/kg) produced dose-dependent antioxidant and anxiolytic effects.¹⁷⁰ At the highest dose (100 mg/kg), treatment significantly reduced the colon weight-to-length ratio, brain malondialdehyde (MDA), and nitric oxide (NO) levels, while increasing serum catalase (CAT) activity and brain glutathione (GSH) content; behavioral parameters correspondingly indicated robust anxiolytic activity.¹⁷⁰ Colitis induction produced systemic oxidative imbalance—evidenced by elevated MDA and NO alongside reduced CAT and GSH across the colon, brain, and liver—consistent with the chronic gastrointestinal inflammation, dysregulated cytokine responses, and oxidative stress that characterize ulcerative colitis and Crohn’s disease, the two principal clinical forms of IBD.¹⁸²

M. oleifera extract attenuated these perturbations by reducing lipid peroxidation, suppressing NO-mediated inflammatory signaling, and restoring endogenous antioxidant defenses¹⁸¹—effects that collectively demonstrate its capacity to interrupt the pathophysiological cascade linking intestinal inflammation to neurobehavioral dysregulation, and that substantiate its candidacy as a therapeutic agent for the neuropsychiatric sequelae of gut-brain axis dysfunction.

Antimalarial Activity and Pharmacokinetic Drug Interactions

Beyond metabolic disease, Moringa demonstrates antimalarial potential—but its relationship with established antimalarial agents is more complex than simple additive benefit. In murine models, concurrent treatment with artesunate and Moringa plant (Figure 4) extracts produced significant, dose-dependent parasite suppression, and aqueous leaf extracts independently reduced Plasmodium berghei infection.¹⁰⁷ Powdered Moringa leaves have also shown favorable influence on amodiaquine pharmacokinetics in healthy volunteers, and methanolic seed extract demonstrated insecticidal activity against Anopheles mosquitoes, suggesting a role extending beyond direct parasitic suppression into integrated vector management.¹⁰⁷

However, the pharmacokinetic picture carries a critical caveat. In a three-period crossover study of 20 healthy subjects, Moringa co-administration reduced amodiaquine Cmax by approximately 32% while simultaneously increasing desethylamodiaquine Cmax by 79.36% and AUC by up to 188%—a pattern that signals clinically meaningful modulation of drug metabolism, likely through cytochrome P450 enzyme pathways.¹⁸³ This is not a trivial finding. Desethylamodiaquine is the pharmacologically active metabolite responsible for both therapeutic effect and cardiac toxicity risk; amplifying its exposure without clinical oversight is consequential.¹⁸⁴ With piperaquine, the interaction profile shifts. Co-administration of Moringa tea in a two-phase crossover study of ten healthy subjects reduced Cmax by 23.8% and AUC by 5.8%, while extending Tmax by 61% and half-life by 12.2%—a pattern suggesting delayed rather than diminished absorption, with overall exposure largely preserved.¹⁸⁵ The clinical significance is lower than with amodiaquine, but the directional signal is consistent: Moringa is not pharmacokinetically inert, and its interactions are drug-specific rather than uniform (Table 4).

Antiviral Activity and Vaccine Adjuvancy

M. oleifera has historically been deployed against viral infections including smallpox and chickenpox. Contemporary evidence further documents broad-spectrum inhibitory activity against influenza A virus (IAV), herpes simplex virus type 1 (HSV-1), foot and mouth disease virus (FMDV), hepatitis B virus (HBV), HIV, Epstein–Barr virus (EBV), and Newcastle disease virus (NDV),¹⁴⁰ with the SARS-CoV-2 pandemic substantially accelerating systematic investigation of its potential anti-coronavirus activity (Figure 3).^186,187 Recently, it has been shown that M. oleifera leaf extract mitigates antiretroviral drug–induced hepatotoxicity by neutralizing oxidative stress and activating the Nrf2 antioxidant pathway, highlighting its potential role as a supportive adjunct to reduce treatment-related toxicity rather than a direct antiviral effect (Table 4).³⁹

Anti-Influenza Activity: Moringa A as a Mechanistically Defined Antiviral

Moringa A, isolated from M. oleifera seed methanol extract alongside glucomoringin and vitexin, strongly inhibited H1N1 replication and reduced TNF-α, IL-6, and IL-1β.¹⁸⁸ Mechanistically, Moringa A inhibits IAV replication, reduces cytopathic effects, suppresses inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-β), and impairs autophagy via transcription factor EB (TFEB), with potent pre- and post-infection activity.¹⁸⁹ Exosome-encapsulated Moringa A further inhibits IAV infection by promoting autophagic lysosomal activity via TFEB, downregulating GCN5 acetyltransferase, enhancing lung cell autophagy, and reducing viral pneumonia and inflammation in vivo¹⁹⁰—consistent with nanodelivery-mediated potency amplification observed across other pharmacological domains.

Anti-SARS-CoV-2 Activity

Polyphenol- and flavonoid-rich leaf extracts inhibit SARS-CoV-2 cysteine proteases Mpro and PLpro through distinct mechanisms,¹⁹¹ with gamma-sitosterol identified as a candidate antiviral compound. Given that both Mpro and PLpro rely on an active Cys–His catalytic dyad/triad essential for viral replication and immune evasion, they constitute tractable targets for natural product inhibition.¹⁹¹ Kaempferol, quercetin, and apigenin enhance antiviral immunity, with apigenin specifically inhibiting the SARS-CoV-2 main protease;¹⁹² kaempferol, pterygospermin, morphine, and quercetin demonstrate strong in silico binding to SARS-CoV-2 main protease and RNA-dependent RNA polymerase.¹⁹³

Ethanolic fruit extract (MOF) yielded 33 bioactive phytocomponents, with 11 demonstrating strong molecular docking affinity to the SARS-CoV-2 spike protein and ACE2 receptor alongside favourable drug-likeness and low predicted toxicity.²⁹ Leaf infusion bioactives—including quercetin and gentiatibetine—exhibit in silico antiviral potential against SARS-CoV-2;²⁷ β-tocopherol and β-sitosterol demonstrate stable interactions with spike glycoprotein and spike RBD-ACE2 in molecular dynamics simulations.¹⁸⁷ Salento cultivar leaf extract blocked viral entry against HCoV-229E and measles virus, with microwave-assisted extracts showing low cytotoxicity.¹⁹⁴ M. oleifera modulates NF-κB, MAPK, mTOR, and NLRP3 inflammasome pathways, attenuating cytokine storm in preclinical and in silico models.¹⁸⁶ Leaf hydroethanolic extracts inhibit prion protein aggregation, with chlorogenic and neochlorogenic acids identified as potent antiprion compounds (IC₅₀: 64.41 and 35.34 µM, respectively),¹³⁹ though in vivo validation remains outstanding.

Vaccine Adjuvancy

M. oleifera leaf extract enhanced humoral immune response in mice co-administered with RSV antigen, increasing antibody production by week 3 and mitigating weight loss,¹⁹⁵ consistent with adjuvant-like activity mediated through NK cell activation and T lymphocyte potentiation. In broiler chickens, hydrophilic alcoholic leaf extract (200 mg/kg) enhanced hemagglutination inhibition titres against NDV in combination with La Sota vaccination, with treated-vaccinated birds demonstrating superior protection.¹⁹⁶ This vaccine-adjuvant potential, while preliminary, carries particular relevance to LMIC immunization programs where adjuvant costs constrain vaccine coverage.

Therapeutic and Clinical Applications

The mechanistic and preclinical evidence synthesized throughout the preceding discussion converges on a set of disease contexts in which clinical translation is supported by human evidence of varying quality and completeness. The available clinical evidence across these therapeutic contexts identifies areas where application is currently justifiable and where further investigation remains necessary.^36,166,197 These bioactive constituents exert pleiotropic effects, including suppression of oxidative stress and inflammation, improvement of glucose metabolism, and inhibition of key enzymes such as ACE, AChE, and PDE5.¹⁶⁶ Their capacity to attenuate oxidative DNA damage represents an additional dimension of cytoprotective activity documented across preclinical models.¹⁶⁶ Notably, glucosinolates and isothiocyanates—chemically stable and unique to Moringa—demonstrate health-promoting properties whose yield is substantially influenced by harvesting and extraction methodology, underscoring the importance of standardization for therapeutic application.³⁶

Leaf preparations, including standardized infusions, facilitate delivery of bioactive compounds such as glucomoringin and its active metabolite moringin, which exhibit anti-inflammatory and antioxidant properties relevant to chronic disease modulation.³⁸ Their rapid extractability, palatability, and chemical stability support both experimental and clinical investigation—particularly in metabolic and cardiovascular disorders.³⁸ Despite the strength of preclinical evidence across these domains, human clinical data remain limited, and further rigorously designed trials are warranted.¹⁹⁷

The preclinical evidence base consistently demonstrates organ-protective effects across multiple toxicity and disease models. Nanoformulation of M. oleifera constituents consistently enhances organ-protective efficacy compared with crude extracts across cardiotoxic, oncological, and antimicrobial models, representing a translational strategy.¹⁰⁵ Cardioprotective activity has been further corroborated by evidence from in vivo, in vitro, and clinical studies demonstrating modulation of oxidative stress, inflammation, and key metabolic pathways including NF-κB and Nrf2/Keap1.¹¹² In hepatorenal toxicity models, ethanolic extract mitigated melamine-induced injury through restoration of liver and renal function markers, suppression of oxidative stress and inflammation, and improvement of histopathological architecture—with prophylactic administration demonstrating greater efficacy than post-exposure treatment.¹⁹⁸ Comparable hepatoprotective effects were observed against antitubercular drug-induced hepatic injury, with normalization of liver enzymes, bilirubin, and lipid levels alongside reduced lipid peroxidation—effects quantitatively comparable to silymarin.¹⁹⁹ In high-fat diet models, M. oleifera extract alleviated hepatic injury by restoring antioxidant defenses, improving histological architecture, and reducing lipid peroxidation, exhibiting both preventive and therapeutic efficacy.²⁰⁰

Beyond organ-specific protection, M. oleifera modulates cancer-related signaling pathways—including YAP/TAZ, Nrf2-Keap1, TLR4/NF-κB, and Wnt/β-catenin—and demonstrates cytotoxic, antiproliferative, and apoptotic activity against cancer cells, alongside antimicrobial effects extending to multidrug-resistant strains.^15,201 A systematic review and meta-analysis of experimental ischemic stroke models further demonstrated reductions in infarct volume and oxidative stress with concurrent enhancement of antioxidant enzyme activity, though the limited number of studies and small sample sizes necessitate cautious interpretation pending further validation.¹²⁶ In reproductive and developmental contexts, crude M. oleifera leaf extract administered to pregnant and lactating rabbits produced increased platelet counts during gestation, reduced urea at the highest dose, and declining cholesterol during lactation—with other hematological and biochemical parameters remaining stable, indicating an acceptable safety profile and hypocholesterolemic potential.²⁰² The anti-angiogenic activity of M. oleifera—demonstrated by 81.33% inhibition of blood vessel formation at 48 hours with the 100% aqueous extract in the CAM assay⁸⁵—extends its anticancer relevance beyond direct cytotoxicity into vascular disruption, reinforcing the multi-mechanism basis of its tumor biology pharmacology.

Synergistic potential has also been identified; M. oleifera and ginger exhibit complementary anti-inflammatory and antioxidant effects—including suppression of TNF-α and IL-6, inhibition of NF-κB signaling, and enhancement of catalase, glutathione, and superoxide dismutase activity—suggesting relevance in inflammation-associated chronic degenerative disorders.²⁰³

Collectively, these findings substantiate M. oleifera as a pharmacologically versatile botanical agent, while simultaneously highlighting the need for improved standardization, optimized delivery systems, and expanded clinical trial evidence to bridge the translational gap between preclinical promise and therapeutic application.¹⁵

HIV and Immune Reconstitution

In a 6-month double-blind RCT in 200 HIV-positive adults on ART in Nigeria, M. oleifera leaf powder supplementation significantly improved all six WHOQOL-HIV-BREF quality-of-life domains, with notable gains in physical, psychological, independence, and social relationship domains versus controls.²⁰⁴ A double-blind RCT in Uganda (n = 282, baseline CD4 ≤ 350 cells/µL) evaluating co-administration of Artemisia annua and M. oleifera demonstrated, at 12 months, a CD4 count increase of 105 cells/µL (p < 0.001), significant viral load reduction (p = 0.022), and improved platelet and WBC counts, without alteration of ARV plasma levels.²⁰⁵ A single-blind RCT in Kinshasa (n = 60, ART-treated PLHIV) demonstrated significantly greater increases in BMI and serum albumin versus nutritional counselling alone.²⁰⁶ Gambo et al reported a 10.33-fold greater increase in CD4 counts versus placebo over 6 months, with no significant differences in viral load, body weight, or BMI.⁵⁴ In vitro, leaf extracts inhibited early HIV-1 lentiviral vector replication in HeLa cells (IC₅₀ = 7.59–7.72 µg/mL, selectivity index 4.26–5.8)⁵⁵ and attenuated antiretroviral drug-induced hepatotoxicity in HepG2 cells by reducing ROS, restoring glutathione, and activating the Nrf2 pathway.²⁰⁷ Of particular clinical relevance, M. oleifera leaf extracts attenuated tenofovir disoproxil fumarate (TDF)-induced oxidative cytotoxicity in hepatic cells, restoring antioxidant responses suppressed by this nucleotide reverse-transcriptase inhibitor.²⁰⁸ Given that tenofovir-based regimens constitute the backbone of first-line ART globally—including in the LMIC settings where M. oleifera is most accessible—this drug-specific hepatoprotective activity carries direct translational significance beyond general antioxidant support.²⁰⁸ Collectively, the HIV-related evidence base demonstrates variable but generally favorable outcomes across immunological and quality-of-life endpoints, with inconsistent effects on virological markers such as viral load across studies. In vitro and mechanistic findings provide additional biological plausibility supporting immunomodulatory, antiviral, and cytoprotective properties of M. oleifera, particularly in the context of antiretroviral-associated oxidative stress.

Glycemic and Cardiometabolic Outcomes

In a 12-week double-blind RCT in prediabetic adults (n = 65), 2,400 mg/day leaf powder produced no significant effects on inflammatory, lipid, antioxidant, or blood pressure markers versus placebo, though TNF-α predicted HbA1c response with 77% accuracy—identifying a potentially useful biomarker of glycemic responsiveness.²⁰⁹

A 14-day RCT in 40 adults with established type 2 diabetes found no significant inter-group differences in fasting glucose across doses of 20, 40, or 60 g/day; an observed reduction in systolic blood pressure and increase in triglycerides in one dose group were neither dose-dependent nor statistically significant after adjustment.¹⁴⁸ These null findings are consistent with short intervention windows and compositionally undefined preparations being insufficient to demonstrate glycemic benefit in established rather than early-stage dysglycemia. A separate 12-week trial in prediabetic adults at the same dose demonstrated significant reductions in fasting glucose and HbA1c,¹⁶⁰ reinforcing that disease stage and preparation standardization are critical determinants of clinical response. In a 45-day RCT (n = 60 hyperlipidemic patients), combined atorvastatin (10 mg/day), M. oleifera (2 g/day), and A. sativum (2 g/day) significantly improved total cholesterol, triglycerides, and LDL (p < 0.05),²¹⁰ suggesting that adjunctive M. oleifera supplementation may potentiate statin efficacy—a combination strategy warranting dedicated pharmacodynamic investigation (Figure 2).

Respiratory, Thyroid, and Other Endpoints

Seed kernel powder (3 g twice daily, 3 weeks) significantly improved symptoms and respiratory function (FVC, FEV₁, PEFR) in mild-to-moderate asthma patients, with hemoglobin increase, ESR reduction, and no adverse effects.²¹¹ The preclinical mechanistic basis was established in an ovalbumin-sensitized guinea pig model, wherein M. oleifera leaf extract significantly reduced bronchoconstriction, suppressed airway inflammatory cell infiltration, and lowered histamine levels, with dose-dependent histopathological improvement comparable to standard anti-asthmatic treatment.²¹² The convergence of this preclinical mechanistic evidence²¹² with clinical efficacy data²¹¹—both attributable to phenolic/flavonoid-mediated histamine suppression and anti-inflammatory activity—constitutes the strongest mechanistic–clinical alignment in the respiratory domain and provides compelling rationale for a powered, multi-center RCT in bronchial asthma. In an open observational pilot study (n = 8, primary hypothyroidism), 5 g fresh leaves twice daily for 45 days significantly reduced TSH from 16.62 ± 11.49 to 4.75 ± 3.12 µIU/mL (p < 0.025), while T3 increased from 132 ± 19.32 to 150.37 ± 20.68 (p < 0.001) and T4 from 9.28 ± 1.46 to 11.84 ± 3.81 (p < 0.044)²¹³—a therapeutically underserved indication warranting controlled replication.

In a comparative clinical study (n = 72, oral leukoplakia), topical 2% M. oleifera gel applied three times daily for 3 months reduced lesion size more effectively than Retino-A cream (0.1%), with no adverse effects.²¹⁴ The acute antihypertensive effect of whole-food M. oleifera consumption is further supported by a prospective study, representing one of the few direct human observations of this effect.¹⁶⁷

A clinical study in 15 patients with urinary tract infection demonstrated that three weeks of M. oleifera bark extract treatment achieved full cure in 66.67% of participants versus 46.67% in controls, with 13.33% experiencing moderate relief and 6.67% relapsing in the treatment arm versus 20% in controls.²¹⁵ While limited by sample size and study design, this constitutes preliminary clinical evidence in an infectious urological indication and warrants controlled investigation. Additionally, a crossover study (n = 15) demonstrated that 4 g M. oleifera leaf powder used as a handwashing agent achieved log₁₀ microbial load reduction comparable to non-medicated soap (2.70–2.91 vs 2.97), substantially outperforming inert calcium sulphate (p < 0.01),¹⁷⁵ supporting a practical public health application in resource-limited settings.

Nutritional Applications and Galactagogue Properties

M. oleifera seeds are rich in proteins (~19%) and lipids (~31%). Treatments such as roasting, germination, and boiling enhance nutritional quality, producing defatted seed flour and oil used in cakes, cookies, burgers, and infant porridges, improving stability and acceptability, although high substitution may increase bitterness.³² M. oleifera is a functional food staple across Asia and Africa, with virtually all plant parts edible and nutrient-dense, deployed for nutrition, water purification, animal feed, and clinical condition management (Figure 4).¹³ In human studies, it demonstrates immunomodulatory, antioxidant, and antidiabetic effects, improving immune function, glycemic control, and nutritional outcomes with rare adverse events.¹⁷ Leaf powder provides bioavailable vitamin A: β-carotene exhibits 28% relative bioefficacy (VA equivalence 3.3:1), supporting M. oleifera leaves as a validated dietary vitamin A source.⁵⁰ A pilot study in Ghanaian infants demonstrated marginal non-significant retinol increases with supplementation, with higher gains in the supplemented group warranting larger trials.¹¹⁶ A complementary cluster-randomized trial in Kenyan mother-infant pairs—wherein lactating women received 20 g/day leaf powder—found that maternal supplementation did not improve breast-milk vitamin A concentrations, though modest milk carotenoid elevations were observed.²¹⁶ Neither maternal nor infant vitamin A status correlated with carotenoid changes, highlighting the limitations of M. oleifera as a vitamin A delivery vehicle in established deficiency contexts and underscoring the need for adequately powered trials with validated functional endpoints.²¹⁶ Across seven countries, M. oleifera administered primarily as leaf powder improved nutritional outcomes in metabolic and infectious conditions, though heterogeneous protocols limit cross-study comparability.³

M. oleifera functions as an herbal galactagogue, traditionally used to increase breastmilk volume through prolactin elevation, with effects reported within 24 hours of ingestion; limited clinical studies report increased milk volume and protein content, particularly in early postpartum and preterm deliveries, with no adverse effects in animal or human studies.¹⁶⁴ However, WHO 2004 guidelines emphasize integrating herbal medicines into pharmacovigilance systems to ensure structured adverse event reporting, improved regulatory oversight, standardized classification, and strengthened analytical capacity for monitoring safety signals effectively.²¹⁷

In aquaculture, 12% dietary supplementation in Oreochromis niloticus produced the greatest weight and length gains alongside reduced intestinal microbial load.²¹⁸ In livestock, supplementation improved immune function, gut-associated immunity, and antioxidant protection via arabinogalactans, polyphenols, and flavonoids.²¹⁹ Mechanistically, moringa-derived arabinogalactans activate gut-associated immunity by selectively expanding Muribaculaceae and Lactobacillus, promoting IL-10 secretion and inhibiting COX-2 activity²¹⁹—providing a mechanistic bridge between in vitro prebiotic short-chain fatty acid production²⁶ and systemic immune and metabolic benefits observed in supplementation models. A hydroalcoholic leaf extract characterized by GC-MS—containing heneicosane (35.69%), 1,2-benzenedicarboxylic acid (22.89%), and heptacosane (18.26%)—significantly reduced Trichuris sp. and Ostertagia sp. egg counts (p = 0.002) and improved body weight, daily gain, and feed conversion efficiency in goats.¹⁷⁴ In a 60-day trial in 40 Avishaan ewes under heat stress, concentrate pellets containing 15% M. oleifera leaves improved antioxidant status and reproductive performance, with higher conception (100% vs 70%) and multiple birth rates, without affecting nutrient utilization.²²⁰

Toxicological Profile, Safety Boundaries, and Herb–Drug Interactions

A scientifically rigorous appraisal of M. oleifera’s therapeutic potential necessitates an equally rigorous toxicological framework (Figure 2). Despite increasing global commercialization of M. oleifera-based products, standardized toxicity evaluations remain limited.⁵⁹ Notably, M. oleifera is predominantly characterized and utilized as a nutritional resource, with its pharmacological relevance comparatively underrecognized. Although preclinical investigations—particularly of leaf extracts—demonstrate antihypertensive activity, the paucity of randomized clinical evidence (Table 4) and incomplete mechanistic elucidation constrain definitive interpretation. Accordingly, robust clinical trials are required prior to therapeutic translation; at present, M. oleifera remains chiefly regarded as a nutritionally valuable plant with emerging pharmacological potential.¹⁶⁵

Acute and Subchronic Toxicology

Oral leaf extract administration up to 6,400 mg/kg in Wistar albino mice caused no mortality, though doses of 3,200–6,400 mg/kg induced dullness and reduced locomotion; LD₅₀ was established at 1,585 mg/kg with no significant effects on sperm quality, hematological, histological, or biochemical parameters.²²¹ In Sprague-Dawley rats, doses exceeding 3,000 mg/kg induced micronucleated polychromatic erythrocytes and elevated urea, attributed to high nitrogenous compound content.²²²

Across animal studies, leaf extract demonstrated safety at oral doses up to 2,000 mg/kg over 21 days without fatalities, though dose-dependent body weight reduction was observed; 3,000 mg/kg induced genotoxicity while 1,000 mg/kg remained non-toxic.¹⁴⁰

Leaf infusion was safe over 28 days, whereas leaf powder at 500–1,000 mg/kg caused dose-dependent hepatic and renal damage.¹⁴³ Prolonged methanolic leaf extract administration (200–400 mg/kg) elevated ALT, AST, BUN, and creatinine, indicating hepato- and nephrotoxic potential at sustained high doses.¹⁴² Methanolic seed extract exhibited acute toxicity at ≥4,000 mg/kg (LD₅₀ = 3,873 mg/kg), with sub-acute dosing at 1,600 mg/kg increasing liver enzymes and reducing body weight.¹⁴¹

M. oleifera isothiocyanate analogues MC-D7, MC-D9, and MC-H were non-toxic in mice at therapeutic doses; the semisynthetic derivative MC-H alleviated temporomandibular joint inflammatory pain via HO-1, NO/cGMP/PKG/K⁺ATP, and central µ- and δ-opioid receptor pathways.^223,224 Aqueous seed extract produced no systemic toxicity at 2,000 mg/kg in mice,²²⁵ and M. peregrina seeds up to 2,000 mg/kg yielded no organ toxicity, with normalized biochemical parameters and significant reductions in blood glucose, cholesterol, triglycerides, and liver enzymes.²²⁶ Collectively, these findings indicate that while M. oleifera demonstrates a favorable safety profile at moderate doses, high-dose and prolonged exposure introduce dose-dependent genotoxic and organ-specific risks, underscoring the need for standardized dosing frameworks in translational and clinical applications (Figure 2).

Reproductive and Developmental Safety

Experimental evidence indicates that M. oleifera exerts multi-level effects on reproductive physiology, involving structural, endocrine, and functional disruption in animal models. Methanolic root extracts induce dose- and time-dependent ovarian and reproductive tract alterations, including follicular damage and tissue remodeling, suggesting complex interference with reproductive system integrity.²²⁷ In parallel, cold aqueous leaf preparations provoke uterine hypercontractility and suppress implantation in experimental models, with marked preparation-dependent variability and high-dose abortifacient effects.²²⁸

Further mechanistic studies report impaired implantation and altered uterine receptivity, alongside anti-progestational activity associated with root-derived constituents, indicating disruption of hormonal support for early pregnancy.¹¹ At higher doses, aqueous extracts may induce uterine contraction–mediated pregnancy loss, suggesting potential developmental risk under gestational exposure (Figure 4).¹⁴

Complementing experimental findings, seed lectins demonstrate reproductive interference in insect systems.^229,230 Specifically, water-soluble M. oleifera seed lectin influences Aedes aegypti oviposition behavior by enhancing egg capture without increasing adult female attraction or activating olfactory pathways, highlighting species-specific insect activity.²³⁰ Separately, ethnobotanical reports among the Santal community describe traditional antifertility applications of medicinal plants, reflecting historical human perceptions of reproductive effects that require mechanistic and clinical validation.²³¹ Importantly, some reports suggest a potential role of M. oleifera leaves (Figure 4) as a nutritional and child-spacing supplement in resource-limited settings; however, scientific evidence on its effects on female reproduction remains limited, particularly regarding contraceptive or abortifacient outcomes in Wistar rat models, underscoring the need for well-controlled reproductive safety studies in defined populations.²²⁸ In contrast, some animal studies report fertility-modulating and endocrine-regulatory effects, including alterations in gonadotropins and sex hormones with dose-dependent patterns, indicating that reproductive outcomes may vary according to extract type, dose, and biological context.^232,233

Women have traditionally used medicinal plants to support childbirth, regulate menstruation, and control fertility. M. oleifera has also been reported to exhibit antifertility effects. In female albino rats, alcoholic leaf extract prevented implantation in 7/7 animals. Additionally, aqueous and 90% ethanolic extracts induced complete abortion at 175 mg/kg after 10 days post-insemination, suggesting potential contraceptive effects; however, these findings are limited to animal models and require cautious interpretation.²³⁴ Overall, the evidence suggests a context-dependent reproductive activity profile, where experimental models consistently demonstrate reproductive system sensitivity to M. oleifera exposure, but outcomes range from endocrine modulation to functional disruption depending on experimental conditions (Table 3). Given that reproductive safety in humans remains inadequately characterized,¹⁷ caution is advised in the use of M. oleifera during pregnancy and the periconceptional period. Reported herbal medicine safety concerns have been linked to substandard product quality, regulatory gaps, and inappropriate use—underscoring the need for standardized quality assurance, practitioner training, and pharmacovigilance.²¹⁷

Herb–Drug Interactions: CYP450 Considerations

M. oleifera inhibits CYP3A4 in vitro, with IC₅₀ values of 41.5–100 µM for isolated compounds;²³⁵ methanolic extract specifically inhibited CYP3A4/5 activity in vitro, indicating potential interaction risk with the principal metabolizing enzyme of approximately 50% of marketed drugs.²³⁶ The newly isolated compound omoringone and twelve known metabolites inhibited CYP3A4 (IC₅₀ = 41.5–100 µM) without significant cytotoxicity and with minimal effect on CYP2D6.²³⁵ Critically, clinical pharmacokinetic evaluation in HIV patients demonstrated that M. oleifera leaf powder co-administration at 1.85 g/day did not significantly alter nevirapine pharmacokinetics, with only minimal changes in drug exposure, maximum concentration, and 12-hour trough levels observed.²³⁷ Leaf extracts exhibiting in vitro CYP3A4 inhibition similarly showed no significant effect on drug pharmacokinetics in clinical assessment,²³⁸ indicating that in vitro inhibitory activity does not translate to clinically meaningful pharmacokinetic interactions under typical supplementation conditions. Nevertheless, caution remains warranted with narrow therapeutic index CYP3A4-metabolised drugs. Potential interactions with nirmatrelvir/ritonavir (Paxlovid™) through CYP3A inhibition or induction²³⁹ constitute a priority pharmacokinetic interaction requiring prospective clinical investigation (Figure 5). This concern extends beyond individual drug classes: herbal medicines commonly used across Africa are frequently assumed safe by default, yet many demonstrably alter CYP enzymes and P-glycoprotein, reshaping the absorption and elimination of co-administered drugs in ways that are rarely monitored—a systemic gap in pharmacovigilance that applies directly to M. oleifera in the clinical settings where it is most widely used.¹⁸⁴

Nanoformulation and Bioavailability Enhancement

The limited intestinal permeability of M. oleifera bioactives (0.62–36.65 × 10⁻⁴ cm/s)⁴³ defines the principal pharmacokinetic barrier to clinical translation of preclinical efficacy data. Nanoformulation strategies directly address this limitation in preclinical models through improvements in solubility, membrane permeability, and tissue targeting. Among organic nanoplatforms, pharmacosomal nanocarriers loaded with M. oleifera extract improved solubility, stability, and anticancer efficacy against neuroblastoma cells, achieving high entrapment efficiency, nanoscale dimensions, and biocompatibility with significantly enhanced cytotoxicity and cell cycle disruption at lower doses versus crude extract.²⁴⁰ Niosome-loaded extract attenuated doxorubicin-induced cardiotoxicity by improving cardiac biomarkers, lipid profile, and antioxidant status through NF-κB, p38 MAPK, and Nrf2 modulation, with superior efficacy over crude extract attributable to improved bioavailability.¹⁰⁵ A moringa oil-based nanocarrier co-loaded with curcumin achieved superior anticancer activity against MDA-MB-231 cells over either agent alone through Bcl-2/Bax modulation.⁷¹ Seed protein-based nanoparticles (PBNPs; 134.3 nm, −43.15 mV) demonstrated cytotoxicity against THP-1 leukemia cells.³¹

Among inorganic nanoplatforms, M. oleifera-stabilized iron oxide nanoparticles (Fe₂O₃ NPs) with uniform spherical morphology demonstrated antimicrobial activity and cytotoxicity against MDA-MB-231 cells (IC₅₀ = 69.7 µg/mL);²⁴¹ biogenic iron oxide nanoparticles exhibited antibacterial activity against E. coli, with extraction method determining potency—salting-out enhancing flavonoid content and aqueous infusion increasing carbohydrates, yielding nanoparticles with highest antibacterial efficacy.⁶⁷ Leaf extract nanoparticles (MOL-NP) combined with ivermectin nanoparticles produced additive anti-parasitic and anti-inflammatory effects in Trichinella spiralis-infected mice.⁶⁶ Collectively, nanoformulation of M. oleifera bioactives consistently amplifies therapeutic potency relative to crude extracts across oncological, cardiovascular, antimicrobial, and anti-parasitic domains—establishing delivery engineering as an indispensable translational bridge between preclinical pharmacology and clinical application.

Integrative Discussion

Building on the tissue-specific phytochemical partitioning already established in this review,⁹⁵ this distribution does not map onto pharmacological potency uniformly across indications. For anticancer activity specifically, leaf and bark extracts—not seed extracts, which showed negligible effect in direct comparison—produced the strongest activity against breast and colorectal cancer cell lines, attributed to eugenol, isopropyl isothiocyanate, and related compounds,²⁴² while a leaf–seed residue blend selected for its highest glucosinolate content among tested ratios produced the most potent chemopreventive effect against breast cancer xenografts.⁴⁶ Neuroprotective acetylcholinesterase inhibition follows yet another hierarchy entirely, with root extract outperforming bark, leaf, flowers, and seed, in that order.¹²⁵ No single plant part is therefore uniformly “most active”; potency is organ- and indication-specific, a distinction with direct bearing on preparation selection that is easily lost when activity is attributed to “Moringa” as an undifferentiated whole.

Layered onto this tissue-specific picture is a recurring mechanistic thread: convergent modulation of NF-κB and Nrf2/Keap1, two transcription factors governing inflammatory and oxidative-stress responses across tissue types rather than any single organ system.²⁴³ This convergence is a property of specific isolated constituents, not of crude extracts as a category. Isothiocyanates such as GMG-ITC activate Nrf2/Keap1 while suppressing NF-κB;²⁴⁴ more broadly, isothiocyanate-containing phytoconstituents—including quercetin, kaempferol, and β-carotene—demonstrate neuroprotective effects against Parkinson’s, Alzheimer’s, Huntington’s, and ALS by maintaining brain antioxidant enzyme levels and mitochondrial function,¹²⁴ while GMG-ITC specifically shows potent activity against prostate cancer cells via apoptosis and G2/M cell cycle arrest⁷⁴—the same compound class producing distinct, tissue-specific downstream effects rather than one uniform mechanism. Prior integrative studies have catalogued this breadth without resolving whether it reflects a shared mechanism or coincidental polypharmacology,⁸ a distinction this review treats as central rather than incidental.

This mechanistic coherence should not be mistaken for clinical validation, and the standardization problem underlying that gap recurs across every organ system discussed in this review, not only where preclinical-to-clinical translation is explicitly at issue. Conflicting glycemic outcomes across trials using nominally identical doses most plausibly reflect the absence of pharmacological dose specification—weight or volume of extract rather than standardized phytochemical content—rather than genuine biological inconsistency,²⁴⁵ a reading reinforced by a separate synthesis attributing divergent outcomes across seven countries specifically to heterogeneous protocols, doses, and treatment durations rather than to inconsistent biology.³ Metabolomic consistency across leaf extracts from nine countries indicates that preparation method, not geographic origin, drives most batch-to-batch variability⁴¹—which is, if anything, an encouraging finding: the variability is method-driven, and therefore addressable through standardization, rather than an unpredictable property of the plant itself.

Cardiometabolic outcomes are a clear example of how conflicting evidence can be informative rather than merely inconvenient, and this pattern is corroborated independently in reviewed studies: across nine pooled randomized trials, only diastolic blood pressure showed any signal, and even that finding carried very-low certainty³—a result more consistent with underpowered, inconsistently dosed trials than with a genuinely absent biological effect. A similar pattern appears at the preclinical level: a controlled rabbit study found no significant effect on post-angioplasty arterial remodeling,¹¹⁴ echoed by a separately reported absence of benefit in a vascular injury model.¹¹⁴ Rather than being explained away, these convergent null findings across two independently reviewed evidence bases likely reflect the same standardization and dosing limitations discussed above, and should temper cardiometabolic-specific enthusiasm not yet matched by trial rigor.

Trial design itself compounds this picture: mechanistic biomarkers are rarely pre-specified at all, and the one exception on record—a post hoc association between TNF-α and HbA1c response—was discovered by accident rather than by design,²⁰⁹ underscoring how much relevant mechanistic signal current trials may simply not be built to capture. Reproductive safety follows a similar pattern of structural neglect: convergent preclinical abortifacient and antifertility signals^11,227,228 remain unexamined in prospective human cohorts, a gap made more significant given that reproductive-age women are a primary demographic in regions where the plant is most accessible.

Among the indications reviewed, HIV-related evidence occupies a distinct position: an immunologically measurable endpoint, a coherent adjunct mechanism—antioxidant mitigation of antiretroviral-associated oxidative stress^207,208—and existing trials showing directional benefit without pharmacokinetic interference with antiretroviral therapy.²³⁷ Anticancer evidence, while mechanistically specific at the compound level, lacks human pharmacokinetic data at tumor-relevant concentrations and carries a potential chemotherapy interaction signal;⁸⁶ nanoformulation shows consistent bioavailability gains across delivery platforms,^105,240,241 though clinical confirmation at tumor-relevant doses remains absent. Taken together, this evidence describes not a preclinical depth problem but a structural mismatch between the mechanistic characterization already available and the methodological rigor applied to testing it clinically. Addressing this gap plausibly requires a sequenced program rather than incremental trial replication (Figure 5). Its foundation is glucosinolate and flavonoid quantification as a trial-enrolment prerequisite—a standardization step consistent with the cultivation-level,²¹ genomically informed approach discussed above, rather than a separate proposal.

A small number of pharmacophores appear to have accumulated sufficient mechanistic characterization to justify Phase I investigation: GMG-ITC, for dual NF-κB/Nrf2 modulation and prostate anticancer activity;⁷⁴ MIC-1, for PTP1B-inhibitory activity relevant to renal cell carcinoma and diabetic nephropathy via Nrf2-ARE and TGF-β1 modulation, with reported pharmacokinetic parameters (~2-hour half-life, ~60% bioaccessibility) that could inform dosing-interval design;^78,243,246 Moringa A, for TFEB-mediated antiviral activity against influenza A;^189,190 and the Aurantiamide Acetate/benzyl isothiocyanate combination, for HIF-1α/VEGF/GLUT1 inhibition²⁰—each requiring nanocarrier pharmacokinetic characterization prior to first-in-human dosing, building on the delivery-platform data noted above.^43,105,240

Beyond individual pharmacophore development, several indications appear ready for consideration in powered, multicentre randomized trials, stratified here by relative strength of existing evidence: HIV support as the highest-priority indication; prediabetes, ideally with a gut-microbiome sub-study; non-alcoholic fatty liver disease; bronchial asthma;^211,212 cancer chemotherapy supportive care, with exclusion of concurrent chemotherapeutic administration given the interaction signal noted above;⁸⁶ hypothyroidism;²¹³ and ischemic stroke.¹²⁶ Safety evaluation should proceed in parallel rather than downstream of efficacy work: prospective reproductive-safety characterization in periconceptional cohorts in low- and middle-income settings; pharmacokinetic interaction studies with CYP3A4-dependent agents;^208,239 and formal determination of a human no-observed-adverse-effect level prior to any chronic high-dose protocol. A further and distinct gap—beyond the cultivation-level standardization discussed earlier—is systematic genotype–chemotype mapping across geographically diverse accessions, guided by the biosynthesis gene loci already identified,^20,23 which would generate the chemotypic data needed for precision pharmacophore development going forward. The overall picture, then, is one of mechanistic and translational promise that currently exceeds methodological execution: coherent multi-target activity, broad geographic accessibility, and apparent safety at conventional doses, set against a clinical trial record that has not yet consistently applied comparable rigor. Closing this gap does not require additional demonstrations of biological plausibility—that case is already reasonably well made—but rather treating M. oleifera as a pharmacologically characterized multi-target candidate whose further development warrants the same methodological discipline routinely applied to synthetic agents with comparable mechanistic and safety profiles.

Conclusion

The evidence reviewed here indicates that Moringa oleifera’s therapeutic breadth is not simply a catalogue of unrelated effects, but traces back to a small number of shared signaling nodes—chiefly NF-κB and Nrf2/Keap1—engaged repeatedly across metabolic, inflammatory, hepatic, renal, cardiovascular, neurological, and oncological contexts. This recurring pattern gives the plant’s pharmacology internal coherence, even as the depth of supporting evidence varies considerably across domains: strongest at the cellular and animal level, thinner and more variable in human trials. Closing that gap requires resolving specific methodological obstacles rather than accumulating further studies of the same design—chiefly preparation standardization, dosing, pharmacokinetics, and safety characterization, including reproductive effects and herb–drug interaction risk. Until these are resolved, cross-study comparison will remain difficult, and clinical signals, however promising, will remain hard to reproduce or generalize. Cardiometabolic regulation, inflammatory and immune modulation, HIV-related nutritional and immune support, and organ-protective applications stand out as the domains where mechanistic and early clinical signals most consistently align, making them logical starting points for future investigation. This should not be read as evidence sufficient to support clinical use today—the current literature supports a rationale for better-designed research, not yet a basis for therapeutic recommendation. Rigorous, methodologically standardized clinical investigation—anchored in compositionally defined preparations and mechanistically informed trial design—is required to determine whether this evidence base can translate into clinically meaningful, reproducible therapeutic benefit.

Funding Statement

No funding was received for this work.

Abbreviations

ABTS, 2, 2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); ACE, Angiotensin-converting enzyme; ACE2, Angiotensin-converting enzyme 2; ADME, Absorption, distribution, metabolism, and excretion; AgNPs, Silver nanoparticles; ALT, Alanine aminotransferase; AOPP, Advanced oxidation protein products; APP, Amyloid precursor protein; ARE, Antioxidant response element; ART, Antiretroviral therapy; ARV, Antiretroviral; AST, Aspartate aminotransferase; ATP, Adenosine triphosphate; AUC, Area under the concentration–time curve; BACE1, Beta-secretase 1; BMI, Body mass index; BP, Blood pressure; BUN, Blood urea nitrogen; CAM, Chick chorioallantoic membrane; CaN, Calcineurin; CAT, Catalase; CD4, Cluster of differentiation 4; CD8, Cluster of differentiation 8; CKD, Chronic kidney disease; Cmax, Maximum plasma concentration; COPD, Chronic obstructive pulmonary disease; COX-2, Cyclooxygenase-2; CUMS, Chronic unpredictable mild stress; DFT, Density functional theory; DNA, Deoxyribonucleic acid; DPPH, 2,2-diphenyl-1-picrylhydrazyl; EBV, Epstein–Barr virus; EGFR, Epidermal growth factor receptor; ERK, Extracellular signal-regulated kinase; ESR, Erythrocyte sedimentation rate; FAK, Focal adhesion kinase; FAS, Fatty acid synthase; FMDV, Foot and mouth disease virus; FRAP, Ferric reducing antioxidant power; FVC, Forced vital capacity; GABA, Gamma-aminobutyric acid; GC-MS, Gas chromatography–mass spectrometry; GCN5, General control non-repressed protein 5; GFAP, Glial fibrillary acidic protein; GGT, Gamma-glutamyl transferase; GLUT1, Glucose transporter 1; GMG, Glucomoringin; GMG-ITC, Glucomoringin isothiocyanate (moringin); GPx, Glutathione peroxidase; GRD, Glutathione reductase; GSH, Glutathione (reduced); GST, Glutathione S-transferase; GSTP1, Glutathione S-transferase pi 1; HBV, Hepatitis B virus; HCoV, Human coronavirus; HIF-1α, Hypoxia-inducible factor 1 alpha; HIV, Human immunodeficiency virus; HIV-1, Human immunodeficiency virus type 1; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HO-1, Haem oxygenase-1; HOMA-IR, Homeostatic model assessment of insulin resistance; HSV-1, Herpes simplex virus type 1; HT-29, Human colorectal adenocarcinoma cell line; IAV, Influenza A virus; IBD, Inflammatory bowel disease; IC₅₀, Half-maximal inhibitory concentration; IFN-β, Interferon beta; IgM, Immunoglobulin M; IκB-α, Inhibitor of Nuclear Factor kappa B alpha; IL-1, Interleukin-1; IL-1β, Interleukin-1 beta; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-10, Interleukin-10; iNOS, Inducible nitric oxide synthase; in silico, Computational/computer-based modelling; in vitro, Cell or tissue-based experimental systems; in vivo, Animal model experimental systems; i.p., Intraperitoneal; JAK2/STAT3, Janus kinase 2/Signal transducer and activator of transcription 3; JNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; LC-ESI-QTOF-MS, Liquid chromatography–electrospray ionisation–quadrupole time-of-flight mass spectrometry; LDL, Low-density lipoprotein; LMIC, Low- and middle-income country; LOXL2, Lysyl oxidase-like 2; LPS, Lipopolysaccharide; M.O, Moringa oleifera; M1S9, Moringa leaf-to-seed residue extract ratio 1:9; MAPK, Mitogen-activated protein kinase; MC4R, Melanocortin 4 receptor; MCF-7, Human breast cancer cell line; MDA, Malondialdehyde; MDA-MB-231, Human triple-negative breast cancer cell line; MIC-1, Moringa isothiocyanate-1; MLFB, Moringa oleifera leaf fermentation broth; MMP-2/9, Matrix metalloproteinase-2/9; MOE, Moringa oleifera extract; MOEF, Moringa oleifera ethyl acetate leaf fraction; MOF, Moringa oleifera fruit extract; MOL-NP, Moringa oleifera leaf nanoparticles; MOLP-AgNPs, Moringa oleifera leaf protein-silver nanoparticles; Moringa A, TFEB-activating antiviral pharmacophore isolated from M. oleifera; MPO, Myeloperoxidase; MSHE, Moringa seed hydroethanolic extract; NAFLD, Non-alcoholic fatty liver disease; NCD, Non-communicable disease; NCDs, Non-communicable diseases; NDV, Newcastle disease virus; NF-κB, Nuclear Factor kappa B; NK, Natural killer (cell); NLRP3, NLR family pyrin domain containing 3 (inflammasome); NMDA, N-methyl-D-aspartate; NO, Nitric oxide; NOAEL, No-observed-adverse-effect level; NPs, Nanoparticles; NQO1, NAD(P)H quinone oxidoreductase 1; NSAIDs, Non-steroidal anti-inflammatory drugs; NSE, Neuron-specific enolase; Nrf2, Nuclear Factor erythroid 2-related Factor 2; NUPTs, Nuclear plastid DNA sequences; PBNPs, Protein-based nanoparticles; PCOS, Polycystic ovary syndrome; PDE5, Phosphodiesterase type 5; PEFR, Peak expiratory flow rate; PGE₂, Prostaglandin E2; PI3K, Phosphoinositide 3-kinase; PI3K/AKT/MAPK, Phosphoinositide 3-kinase/Protein kinase B/Mitogen-activated protein kinase; PKG, Protein kinase G; PLHIV, People living with HIV; PLpro, Papain-like protease; PPARα, Peroxisome proliferator-activated receptor alpha; PTGS2, Prostaglandin-endoperoxide synthase 2 (COX-2 gene); PTP1B, Protein tyrosine phosphatase 1B; PTPN1, Protein tyrosine phosphatase non-receptor type 1; R-QUICKI, Revised quantitative insulin sensitivity check index; RBD, Receptor binding domain; RCC, Renal cell carcinoma; RCT, Randomised controlled trial; RdRp, RNA-dependent RNA polymerase; RelA, v-rel avian reticuloendotheliosis viral oncogene homolog A (NF-κB p65 subunit); RNA, Ribonucleic acid; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; RSV, Respiratory syncytial virus; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SFRP1, Secreted frizzled-related protein 1; SIRT1, Sirtuin 1; SIRT1-PPARα, Sirtuin 1–Peroxisome proliferator-activated receptor alpha axis; SLC39A6, Solute carrier family 39 member 6; SOD, Superoxide dismutase; SOD-1, Superoxide dismutase 1; SRC, Proto-oncogene tyrosine-protein kinase Src; SSRIs, Selective serotonin reuptake inhibitors; STZ, Streptozotocin; T-ALL, T-cell acute lymphoblastic leukaemia; T3, Triiodothyronine; T4, Thyroxine; TBARS, Thiobarbituric acid reactive substances; TDF, Tenofovir disoproxil fumarate; TFEB, Transcription factor EB; TGF-β, Transforming growth factor beta; TGFβ1, Transforming growth factor beta 1; THP-1, Human monocytic leukaemia cell line; TLR4, Toll-like receptor 4; Tmax, Time to maximum plasma concentration; TME, Tumour microenvironment; TNF-α, Tumour necrosis factor alpha; TSH, Thyroid-stimulating hormone; USD, United States Dollar; VA, Vitamin A; VEGF, Vascular endothelial growth factor; WBC, White blood cell count; WHO, World Health Organization; WHOQOL-HIV-BREF, World Health Organization Quality of Life HIV Brief Version; Wnt/β-catenin, Wingless-related integration site/Beta-catenin signalling pathway; YAP/TAZ, Yes-associated protein/Transcriptional coactivator with PDZ-binding motif.

Disclosure

The authors declare that they have no competing interests.