Crateva religiosa and Allied Species in Traditional Knowledge and Modern Pharmacology: A Review

ABSTRACT

Crateva religiosa G. Forst. is a highly valued medicinal plant in Ayurvedic tradition and has been extensively investigated for its botanical characteristics, phytochemical composition, and diverse pharmacological properties. Related taxa within the genus such as C. nurvala and C. magna, along with allied species including C. adansonii and C. tapia, are frequently discussed alongside C. religiosa because of their shared ethnomedicinal applications and overlapping chemical classes. The genus exhibits promising effects in managing urolithiasis, cancer, inflammatory and neurodegenerative disorders, hepatic and renal dysfunctions, as well as microbial infections, supported by a rich array of secondary metabolites, including flavonoids, phenolic acids, alkaloids, phytosterols, and triterpenoids. While lupeol is consistently emphasized across different Crateva species, several studies have also attributed the key pharmacological effects of the genus to flavonoids and phenolics, suggesting a broader chemical basis for its therapeutic benefits. Integrating data from allied taxa strengthens the review by highlighting cross‐species consistency in phytochemistry and biological relevance, thereby supporting a unified genus‐level perspective. Furthermore, the advances in tissue culture techniques have facilitated efficient micropropagation and conservation of Crateva species, thus providing a valuable foundation for future biological investigations. This review bridges traditional knowledge with modern pharmacological evidence for C. religiosa and its relatives and highlights the need for deeper mechanistic, clinical, and metabolomic studies to fully validate their medicinal potential.

This review provides a genus‐level overview of Crateva religiosa and related species, connecting the ethnomedicinal applications with experimentally supported pharmacological findings and comparative phytochemical evidence, with particular emphasize on bioactive compounds such as lupeol. The review also highlights micropropagation and tissue‐culture techniques as valuable approaches for conservation, biotechnological applications, and the sustainable utilization of Crateva resources.

Abbreviations

2,4‐D

Dichlorophenoxyacetic acid

3T3‐L1

Murine preadipocyte cell line

AChE

Acetylcholinesterase enzyme

AD

Alzheimer's disease

AGE–RAGE

Advanced glycation end product receptor

AKT1

RAC‐alpha serine/threonine‐protein kinase

ALP

Alkaline phosphatase

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

ATPase

Adenosine triphosphatase

BACE1

β‐site amyloid precursor protein cleaving enzyme 1 (β‐secretase)

BAP

6‐Benzylaminopurine

BChE

Butyrylcholinesterase

BPH

Benign Prostatic Hyperplasia

B. subtilis

Bacillus subtilis

Ca^{2 +}‐ATPase

Calcium‐dependent adenosine triphosphatase

CAT

Catalase

CCAAT/EBP

CCAAT/enhancer‐binding protein

CC

Column Chromatography

CC₅₀

50% Cytotoxic concentration

CCl₄

Carbon tetrachloride

CD4⁺ T cells

Cluster of differentiation 4 positive T lymphocytes

cFLIP

Cellular FLICE‐like inhibitory protein

C. freundii

Citrobacter freundii

CMHF

Crateva magna hexane‐soluble fraction

^{1 3}C NMR

Carbon‐13 nuclear magnetic resonance

CNS

Central nervous system

COX‐2

Cyclooxygenase‐2

CPK

Creatine phosphokinase

CrataBL

Crateva bark lectin

CYP19A1

Cytochrome P450 family 19 subfamily A member 1, aromatase

DMBA

7,12‐dimethylbenz[a]anthracene

E. coli

Escherichia coli

ER

Estrogen Receptor

GC–MS

Gas Chromatography–Mass Spectrometry

HCT‐116

Human Colorectal Carcinoma cell line

HDL

High‐Density Lipoprotein

HepG‐2

Human Hepatocellular Carcinoma cell line

HMG‐CoA

3‐Hydroxy‐3‐methylglutaryl coenzyme A

¹H NMR

Proton Nuclear Magnetic Resonance

HPTLC

High‐Performance Thin‐Layer Chromatography

HR‐LCMS‐QTOF‐MS/MS

High‐Resolution Liquid Chromatography‐Mass Spectrometry Quadrupole Time‐of‐Flight Mass Spectrometry

IAA

Indole‐3‐acetic acid

IBA

Indole‐3‐butyric acid

IL‐17

Interleukin‐17 signaling pathway

I.P

Intraperitoneal

IR

Infrared spectroscopy

K. pneumoniae

Klebsiella pneumoniae

LC–MS

Liquid Chromatography–Mass Spectrometry

LDH

Lactate dehydrogenase

LDL

Low‐density lipoprotein

LUTS

Lower urinary tract symptoms

MAPK1

Mitogen‐activated protein kinase 1

MCF‐7

Michigan Cancer Foundation‐7 (human breast cancer cell line)

MCP‐1

Monocyte chemoattractant protein‐1

MDA

Malondialdehyde

MECN

Methanolic extract of Crateva nurvala

Mg^{2 +}‐ATPase

Magnesium‐dependent adenosine triphosphatase

MIP

Macrophage inflammatory protein

MPO

Myeloperoxidase

MS

Murashige and Skoog (medium)

NAA

α‐Naphthaleneacetic acid

Na⁺/K⁺‐ATPase

Sodium–potassium adenosine triphosphatase

NF‐κB

Nuclear factor kappa‐light‐chain‐enhancer of activated B cells

nAChR

Nicotinic acetylcholine receptor

P.O

Oral administration

P. aeruginosa

Pseudomonas aeruginosa

P. mirabilis

Proteus mirabilis

P. pestis

Pasteurella pestis

PCOS

Polycystic ovary syndrome

PI3K

Phosphatidylinositol 3‐kinase

PI3K–AKT

Phosphatidylinositol 3‐kinase–AKT signaling pathway

PPARγ

Peroxisome proliferator‐activated receptor gamma

PGE2

Prostaglandin E2

PTGS2

Prostaglandin‐endoperoxide synthase 2

PTLC

Preparative thin‐layer chromatography

RANTES

Regulated on activation, normal T cell expressed and secreted

S. agalactiae

Streptococcus agalactiae

S. aureus

Staphylococcus aureus

S. sonnei

Shigella sonnei

S. typhi

Salmonella typhi

SC‐XRD

Single‐Crystal X‐ray Diffraction

SOD

Superoxide dismutase

TDZ

Thidiazuron

TLC

Thin Layer Chromatography

TNF‐α

Tumor Necrosis Factor alpha

TRAIL

Tumor necrosis factor‐related apoptosis‐inducing ligand

UHPLC‐MS

Ultra‐High‐Performance Liquid Chromatography‐Mass Spectrometry

UPLC‐Orbitrap‐HRMS

Ultra‐Performance Liquid Chromatography coupled with Orbitrap High‐Resolution Mass Spectrometry

VLDL

Very low‐density lipoprotein

WISH

Wistar institute susan hayflick (human amnion‐derived epithelial cell line)

Y. enterocolitica

Yersinia enterocolitica

1. Introduction

Medicinal plants constitute a valuable reservoir of bioactive compounds, which play a critical role in the prevention and management of various diseases, thereby contributing significantly to human health and well‐being [1, 2]. Among these, several plant families have attracted scientific interest due to their rich phytochemical diversity and therapeutic relevance. One such family is Capparaceae, commonly known as the caper family, which comprises numerous medicinally important species recognized for their diverse medicinal properties [3]. The Capparaceae (or Capparidaceae) family belongs to the order Brassicales and consists of 33 genera with approximately 700 species. The largest genera within this family include Capparis (over 150 species), Maerua (around 100 species), Boscia (37 species), and Cadaba (30 species) [4, 5]. Within this family, genus Crateva is well recognized for its medicinal potential. Crateva is a genus of flowering plants in the caper family, and its name is derived from Crataevus, a Greek herbalist who lived during the time of Hippocrates [4, 5]. One of the most highly valued medicinal species within this genus is Crateva religiosa G. Forst. This heavily branched deciduous tree is commonly known as Sacred Garlic Pear or Varuna [6, 7]. C. religiosa is considered rare in Maharashtra and is highly valued in Ayurvedic medicine owing to its varied medicinal properties [6]. The species name “religiosa” reflects its common presence near places of worship [6, 7]. The plant is indigenous to Japan, Australia, Southeast Asia, and various South Pacific Islands. In India, it is distributed across Peninsular, Western, and Eastern regions, extending to Tripura and Manipur [6]. C. religiosa is rich in phytochemicals, including flavonoids (e.g., quercetin, rutin, and isoquercetin), phenolic acids (e.g., vanillic acid, ferulic acid, and sinapic acid), saponins, alkaloids (e.g., cadabicine), phytosterols (e.g., β‐Sitosterol), and triterpenoids (e.g., lupeol), all of which contribute to its wide spectral biological activities [7, 8]. The plant is widely known for its applications in traditional medicine, pharmacology, and phytochemistry. Traditionally, C. religiosa and its allies have been used as an immunostimulants, cholagogues, diuretics, laxatives, antidotes for snake bites, antiflatulents, and management of stomach pain [4, 7, 9]. The leaves and roots were applied as pastes to treat abscesses, swollen wounds, cervical adenitis, and reduce body fat, while also exhibiting stomachic, rubefacient, and counter‐irritant properties [9, 10, 11]. The bark and roots were reported to manage urinary, hepatic, gastrointestinal, and endocrine disorders, stimulate appetite, promote bile secretion, and exert lithotriptic effects [9, 10, 12]. Crateva species were also incorporated into polyherbal preparations for treatment of different ailments [9, 13]. Different studies underscore the pharmacological relevance of C. religiosa and its allies including anti‐urolithic, nephroprotective, hepatoprotective, anti‐inflammatory, antimicrobial, anti‐hyperglycemic, hypolipidemic, anticancer, wound healing, and neurological activities. In addition to its ethnomedicinal and pharmacological significance, C. religiosa has also attracted attention in plant biotechnology research. Tissue culture studies have established reproducible micropropagation and clonal propagation protocols, offering effective strategies for conservation and sustainable cultivation. These in vitro approaches, including shoot regeneration from nodal and apical explants and optimized rooting systems, enable large‐scale propagation of this medicinal plant. Comparable protocols have also been reported for allied species such as C. magna, C. nurvala, and C. adansonii, further highlighting the value of tissue culture techniques for conservation, sustainable utilization, and the reliable supply of plant material for future pharmacological investigations. Taxonomically, the genus Crateva involves complex synonymy that requires clarification. While C. religiosa is a primary accepted species, C. nurvala is officially recognized as a heterotypic synonym of C. magna according to World Flora Online Consortium (2026). Despite these formal botanical distinctions, historical literature and previous research often discuss both C. magna and C. nurvala within a broader C. religiosa complex [4, 8, 10]. In contrast, species like C. adansonii and C. tapia remain distinct. In the present review, these taxa are treated as allied species because they belong to the same genus and share overlapping ethnomedicinal applications, phytochemical profiles, and chemotaxonomic markers, particularly lupeol. This approach allows a comparative evaluation of their metabolomic profile as well as their pharmacological potential. This review consolidates current knowledge on C. religiosa, supported by selected findings from its allied species, to provide an integrated overview of its traditional uses, phytochemical profile and pharmacological properties. Emphasis is placed on the distribution of bioactive compounds across different plant parts and the chemical structures of identified constituents to support future pharmacological investigations and further scientific interest in this traditionally valued medicinal plant.

2. Methodology of Literature Search

A systematic and comprehensive literature search was conducted using multiple electronic databases, including PubMed, Scopus, ScienceDirect, and Google Scholar, covering studies published up to 2026. The search strategy used specific keywords and search combinations, including ‘Crateva religiosa’, ‘allied species’, ‘phytochemistry’, and ‘pharmacological activities.’ Inclusion criteria focused on peer‐reviewed original research articles providing direct experimental evidence for crude extracts or isolated compounds. Exclusion criteria included conference abstracts and duplicate records across databases to ensure high‐quality scientific data were included in this review.

2.1. Morphological Characteristics

C. religiosa is a medium‐sized deciduous tree that can grow up to 15 meters in height and 9 meters in width. It thrives in full sun to partial shade and prefers moist, fertile soils with a neutral to slightly acidic pH. The bark is grey, and the wood is yellowish white, becoming light brown with age. The leaves are arranged at the tips of the branchlets on a common petiole measuring 5 to 10 cm in length, each bearing three ovate‐lanceolate or ovate leaflets, typically 7.5 to 12 cm long and 4 to 6 cm wide, with tapering bases and narrow apices [4, 5]. The flowers are borne in terminal clusters approximately 5 cm in diameter, featuring greenish yellow petals and prominent purplish stamens. The fruit, commonly referred to as garlic pear, is ovoid or rounded, measuring 3 to 5 cm in diameter, with a rough surface and a strong, unpleasant odor accompanied by a burning taste. The seeds are numerous, kidney shaped, approximately 10 mm in length, and enclosed in yellow pulp [4, 5]. The roots are elongated, cylindrical, and woody, with a yellowish‐brown outer bark characterized by longitudinal wrinkles, lenticels, and lateral roots. The inner surface of the root is smooth and yellow, marked with longitudinal striations, and possesses a slightly bitter taste and faint odor [14]. The morphological features of various parts of C. religiosa, including leaves, flowers, fruits, roots, bark, and root bark, are illustrated in Figure 1.

FIGURE 1.

Plant parts of C. religiosa, Leaves (A); Flowers (B); Fruit (C); Roots (D); Root bark (E); Bark of the tree (from Zohrea garden) (F). The flower image is adapted under the terms of the Creative Commons Attribution‐ShareAlike 4.0 International (CC BY‐SA 4.0) license [110]. Copyright 2020, Rison Thumboor. The fruit image is adapted under the terms of the Creative Commons Attribution‐ShareAlike 4.0 International (CC BY‐SA 4.0) license [111]. Copyright 2014, Vinayaraj.

2.2. Folkloric Uses

Plants of the genus Crateva have long been used in traditional medicine across India, Southeast Asia, and West Africa to manage a wide range of conditions, including snakebite, hepatitis, enteritis, hypertension, hyperlipidemia, diarrhea, malaria, urolithiasis, diabetes, and inflammatory disorders [7, 9, 15]. Among these, Crateva religiosa G. Forst. holds particular ethnomedicinal prominence, especially within Ayurveda and regional folk traditions. In India, the stem bark of C. religiosa is commonly prepared as a decoction to manage bladder stones, fever, vomiting, gastric irritation, and as a general tonic [9, 12]. Beyond India, leaf decoctions are traditionally used in China and Taiwan as tonics and stomachics and for treating dysentery, headache, and stomachache [12, 16]. The leaves are also nutritionally rich, containing significant amounts of calcium, phosphorus, and iron, along with vitamins such as beta‐carotene, thiamine, riboflavin, niacin, and ascorbic acid [16]. Other uses include consumption of leaf decoctions for abdominal pain and flatulence, topical application of leaf juice mixed with Piper betle and butter for joint inflammation, and bark paste combined with Boerhavia diffusa root for chronic sores and boils [12]. In the Solomon Islands, bark decoctions were employed to relieve constipation, while warmed leaves were applied externally for earache [12, 16]. Roots of C. religiosa, typically prepared as decoctions, were also used for diabetes and kidney stones [12]. In addition to C. religiosa, allied taxa hold notable traditional importance. In eastern India, C. nurvala stem bark juice was used for contraception and postnatal care [9, 17, 18]. Its leaf juice mixed with coconut milk and ghee was applied for rheumatism, while leaf poultices were used as rubefacients and vesicants [8, 10]. The roots were also prepared as liniments with oil for muscular strain and body pain [8, 10]. Root and root bark preparations have been used as dietary remedies for fat reduction [11], as well as in mixtures with honey for treating scrofula infections in Unani and Siddha medicine [17]. Similarly, C. magna is traditionally used in both Unani and Ayurveda systems for a wide range of ethnopharmacological purposes. It is noted as an antidote for snake bites, and the leaves have been employed for hemorrhoids, while the bark paste has been used for chest ailments [11, 19]. The stem is used for reproductive and urinary disorders, including impotency, spermatorrhoea, gonorrhoea, spermaturia, regulation of the menstrual cycle, kidney stones, and as an abortifacient [20, 21, 22]. C. adansonii has a long history of use across West Africa and parts of Asia. In West Africa, C. adansonii was used medicinally for snakebites, constipation, and postmenopausal complaints, with leaf and stem infusions being the most common preparations [15]. In Senegal, the roots were traditionally used for syphilis, jaundice, and yellow fever [23]. In Burkina Faso, the young leaves are also consumed in traditional diets, providing high protein (26.09 g/100 g), energy (297.45 kcal/100 g), and substantial levels of calcium (10.4%) and magnesium (9.2%) [24]. Beyond Africa, in India's Marathwada region, the powdered bark was employed for urinary, renal, gastrointestinal, and uterine disorders [25]. Likewise, in northeastern Brazil, bark infusions of C. tapia have traditionally been employed for their hypoglycemic properties and calculous affections [14]. Crateva species are also incorporated into various polyherbal preparations. A decoction combining bark, roots, and leaves of C. nurvala with Ginger, potassium carbonate, honey, and water was traditionally used to treat ascites and urinary disorders associated with kidney stones [8, 9, 10]. C. nurvala bark is included in formulations with Tribulus terrestris, Asparagus racemosus, Solanum xanthocarpum, Zingiber officinale, Tephrosia purpurea, and Tinospora cordifolia for urinary ailments, and in mixtures with Terminalia chebula, Terminalia bellirica, Phyllanthus emblica, Tribulus terrestris, and Zingiber officinale for obesity management [13]. Additionally, the Ayurvedic formulation “Varunal,” containing C. religiosa along with species of Eclipta, Picrorhiza, Achillea, Cichorium, Solanum, Terminalia, and Cassia seeds, has long been used to treat arthritis, ascites, edema, hepatitis, and urinary calculi [7, 9, 10].

2.3. Phytochemistry

The genus Crateva is rich in bioactive secondary metabolites, primarily comprising triterpenoids, alkaloids, sterols, flavonoids, and phenolic acids distributed across various plant tissues of C. religiosa and its allied species. Key documented flavonoids include kaempferol‐3‐O‐α‐D‐glucoside, quercetin, isoquercetin, rutin, myricetin, isovitexin, and epiafzelechin 5‐O‐β‐D‐glucoside, alongside major phenolic acids such as vanillic, ferulic, and sinapic acids. Consistent chemotaxonomic markers across the genus include lupeol, β‐sitosterol, cadabicine, friedelin, and glucocapparin [7, 8, 32, 39]. To provide a clear comparative overview, the detailed phytochemical profiles, plant parts, and corresponding analytical methods for these species are synthesized in Table 1. Furthermore, the chemical structures of representative major phytoconstituents are illustrated in Figures 2 and 3.

TABLE 1.

Phytochemical profiles and major constituents of the Crateva genus.

Species	Plant part	Major compound classes & specific constituents	Analytical methods	Reference
C. religiosa	Leaves	Flavonoids: Rutin, quercetin, isoquercetin, myricetin, isovitexin, quercetin‐3‐O‐α‐D‐glucoside, kaempferol‐3‐O‐α‐D‐glucoside; epiafzelechin 5‐O‐β‐D‐glucoside, and (E)‐ethyl‐4‐((3‐(4‐hydroxyphenyl)acryloyl)oxy)‐2‐methyl‐5‐oxotetrahydrofuran‐2‐carboxylate (Cg‐1), designated as Cratin. Phenolic acids: p‐coumaric acid, p‐methoxy cinnamic acid, vanillic, ferulic, and sinapic acids.	HPLC, UV, IR, NMR, SC‐XRD, MS	[7, 27, 28, 35, 37, 38]
	Root and Stem bark	Triterpenoids: Lupeol, lupenone, and betulinic acid. Alkaloids: Cadabicine, and cadabicine diacetate. Steroidal glycosides: Drebyssogenin F and the triterpene sapogenin giganteumgenin N.	CC, GC‐MS, 1H NMR, 1 3C NMR, and PTLC	[7, 27, 38]
	Fruits	Glucosinolates: Glucocapparin.	TLC	[7, 34]
C. nurvala	Leaves	Flavonoids: Rutin, quercetin, isoquercetin, myricetin, isovitexin, quercetin‐3‐O‐α‐D‐glucoside, kaempferol‐3‐O‐α‐D‐glucoside, naringenin‐6,8‐C‐diglucoside, kaempferide, rhamnetin, and isorhamnetin, eriodictyol‐8‐C‐hexoside, kaempferol‐di‐O‐glycoside, and quercetin‐di‐O‐glycoside. Phenolic acids: Vanillic, ferulic, sinapic acids, gallic acid, and 3‐O‐p‐coumaroylquinic acid (1‐Me ether).	UPLC‐Orbitrap‐HRMS, LC–MS, HPTLC	[8, 36, 39, 40]
	Root and Stem bark	Triterpenoids: Lupeol, lupeol acetate, betulinic acid, varunol, and friedelin. Alkaloids: Cadabicine, cadabicine‐O‐hexoside, cadabicine‐O‐deoxyhexoside. Sterols: β‐sitosterol, stigmasterol; α‐spinasterol acetate. Steroidal saponins: Diosgenin. Isoflavones: Formononetin and daidzein. Lignans: Scoulerin. Fatty acids: Octadecatrienoic acid, dihydroxyhexadecanoic acid, octadecadienoic acid, and eicosanedioic acid.	1H NMR, 1 3C NMR, PTLC, LC–MS, and TLC	[29, 30, 31, 32, 33]
	Fruits	Aliphatic compounds and carbonyl Derivatives: n‐pentadecane, octanamide, and 12‐tricosanone.	IR, 1H NMR, GC–MS, and TLC	[8, 36]
C. magna	Leaves and bark	Flavonoids: Quercetin and kaempferol glycosides, epigallocatechin. Phenolic acids: Gentisic and ferulic acids. Phenolic glycoside: Arbutin. Coumarin glycoside: Cichoriin, and mahaleboside. Triterpenoids: Lupeol.	HR‐LCMS‐QTOF‐MS/MS	[41]
C. adansonii	Leaves/ bark	Flavonoids & Glycosides: Kaempferol glycosides [such as Kaempferol 3‐(4''‐(E)‐p‐coumarylrobinobioside) ‐7‐rhamnoside, and Kaempferol 3‐(6″‐ rhamnosyl‐2″‐glucosyl rutinoside)], luteolin 7‐ rhamnosyl‐ galactoside, 5‐deoxymyricetin‐3‐ rutinoside, Butein 4′‐arabinosyl‐galactoside, luteolin‐7‐robinobioside, robinin, isovitexin, isovitexin‐7‐O‐rhamnoside, coreopsin, and apigenin 5‐glucoside. Phenolic Acids: m‐Coumaric acid, 4‐p‐coumaroylquinic acid. Alkaloids: Cadabicine. Triterpenoids: Lupeol. Triterpenoid Saponins: Capilliposide II.	UHPLC‐MS	[42, 70]
C. tapia	Leaves and bark	Flavonoids: Quercetin and kaempferol glycosides. Triterpenoids: Lupeol. Protein: Lectin CrataBL. Carbohydrates: Pectin.	Phytochemical screening assays; TLC, and protein purification methods.	[14, 86]

FIGURE 2.

Structures of Flavonoids and Phenolic acids.

FIGURE 3.

Structures of Triterpenoids, Sterols, Alkaloids, and Glucosinolates.

2.4. Pharmacological Activities

The genus Crateva has been increasingly recognized in modern pharmacological research, with C. religiosa and its related species exhibiting a remarkable diversity of biological and therapeutic activities: as explained in next subsections.

3. Treatment of Urinary Disorders

3.1. Urolithiasis

Within the genus, particularly C. religiosa and allied taxa such as C. nurvala, pentacyclic triterpenes such as lupeol and betulin have been studied for their potential role in preventing kidney stone formation. Across Crateva species, urinary benefits appear linked to overlapping triterpenoid profiles and similar ethnomedicinal uses. These two compounds considerably alleviated kidney injury and oxidative stress resulting from the presence of crystals in the kidneys of animals with induced stones. Additionally, they helped restore antioxidant balance, including both enzymatic and nonenzymatic components, and inhibited calcium oxalate crystal aggregation, highlighting their potential as therapeutic agents for urolithiasis prevention [43]. An ethanol bark extract of C. magna (400 mg/kg body weight) demonstrated potent anti‐urolithiatic activity in experimental kidney stone models induced by lactose (30%) + ethylene glycol (1%) or ammonium chloride (2%) + ethylene glycol (0.75%), significantly inhibiting stone formation [44]. Additional in vivo studies have validated the use of C. nurvala bark decoction for urolithiasis treatment, revealing decreased oxalate biosynthesis, diminished renal deposition of calculogenic substances, along with partial normalization of urinary excretion in rats [45]. Furthermore, a water‐based decoction of C. nurvala stem bark exhibited therapeutic effects in managing prostatic hypertrophy and hypotonic bladder, while modulating urinary electrolytes by reducing calcium excretion and increasing sodium and magnesium levels, potentially lowering the risk of kidney stone formation [46]. In a six‐month clinical trial, a polyherbal formulation known as PR‐2000, which includes C. nurvala, was administered as two tablets three times daily. The results demonstrated a significant increase in urinary peak flow rate and a noticeable reduction in prostate size, as confirmed by sonographic measurements, in patients with BPH [47]. Furthermore, Himplasia, a polyherbal formulation containing C. nurvala and other herbs, was evaluated in a randomized, double‐blind, placebo‐controlled phase III trial involving 48 men. After six months, significant improvements were observed in prostate volume, post‐void residual volume, and peak urinary flow rate (p < 0.0001), with no major adverse effects reported. Mechanistic evaluation indicated that Himplasia exerts 5α‐reductase inhibitory and α‐adrenergic antagonistic activities, with the triterpenoid lupeol from C. nurvala likely contributing to these pharmacological effects [48]. Nonetheless, the study is limited by its small sample size and short duration, and its mechanistic interpretations rely largely on prior research rather than direct experimental validation within the trial. Moreover, a new polyherbal formulation containing C. nurvala bark and Musa paradisiaca stem, termed Herbmed, was reported to facilitate the dissolution and expulsion of kidney stones and alleviate pain associated with renal and ureteric [49]. In a recent multi‐center clinical study, a polyherbal formulation containing C. nurvala as one of its constituents significantly improved lower urinary tract symptoms (LUTS), peak urinary flow (Qmax), and sexual function scores in 140 men with BPH. When administered as an adjunct to standard of care (SOC), the formulation was well tolerated, with no significant adverse effects or clinically relevant biochemical abnormalities observed over the 90‐day trial period [50]. These findings suggest a potential therapeutic contribution of C. nurvala; however, further dedicated clinical trials and long‐term toxicological evaluations are required to clarify its specific efficacy, safety, and pharmacokinetic profile. Furthermore, a combined extract of Dolichos biflorus seeds and C. nurvala bark effectively mitigated ethylene glycol–induced urolithiasis in Wistar rats. Treatment, particularly at a 3:1 ratio, normalized key urinary risk markers (calcium, oxalate, creatinine), reduced renal crystal deposition, and restored kidney histoarchitecture, indicating its anti‐urolithiatic potential [51]. As the study used a plant mixture, the specific role of C. nurvala remains to be clarified. Additionally, the active constituents, molecular mechanisms, and safety profile were not determined, suggesting that future studies involving bioassay‐guided fractionation, mechanistic evaluation, and standardized extract development could provide further insights. Overall, these findings provide pharmacological support for the traditional use of allied Crateva species in urinary disorders. However, rigorous species‐specific investigations remain essential to fully clarify the direct therapeutic potential and clinical efficacy of C. religiosa itself.

3.2. Hyperoxaluria

Oral treatment with lupeol and its structurally related triterpenoid betulin at 35 mg/kg/day for 21 days has been shown to significantly reduce tubular damage and crystal deposition in the kidneys of hyperoxaluric rats [52]. Subsequent studies have shown that lupeol, and even more effectively its esterified form lupeol linoleate, can mitigate oxalate‐induced toxicity by reducing oxidative stress and kidney injury in rats with induced hyperoxaluria [53]. Collectively, these findings suggest that lupeol, a bioactive triterpenoid, may contribute to the traditional use of this plant in managing hyperoxaluria and preventing kidney stone formation.

3.3. Urinary Tract Infection

C. nurvala exhibits distinct diuretic properties. For instance, the polyherbal formulation NR‐AG‐II (containing aqueous extracts of C. nurvala, Boerhaavia diffusa, Saccharum officinarum, and Butea frondosa) significantly increased urine output and electrolyte excretion (sodium, potassium, and chloride) in experimental rat models. This diuretic activity was comparable to the effects of the reference drug furosemide [54]. Additionally, a patented formulation (US 2004/0147459 A1) utilizes oral D‐mannose combined with botanical adjuncts to support urinary health against E. coli infections. The composition incorporates white willow bark, pollen extract, and Cratavin, a standardized C. nurvala root and stem bark extract. The inclusion of C. nurvala within this mixture is intended specifically to exploit its bladder tonic and anti‐inflammatory activities [55]. However, the patent relies on preliminary clinical reports rather than controlled validation. It lacks rigorous quality control parameters, batch consistency data, and comprehensive toxicological profiles. In a clinical study, Urox, a proprietary herbal formulation containing C. nurvala extract standardized to 1.5% lupeol, Equisetum arvense, and Lindera aggregata, significantly reduced urinary frequency, nocturia, urgency, and incontinence in an 8‐week randomized, placebo‐controlled trial [56]. This study also showed improved quality of life and good short‐term tolerability. While lupeol likely contributes to bladder tone modulation and anti‐spasmodic effects, the roles of non‐standardized components remain uncertain. Despite promising results for managing LUTS, limitations like short duration and reliance on patient‐reported outcomes necessitate further long‐term, comparative studies to confirm efficacy. Crucially, many of the clinical trials evaluated in this review utilize polyherbal formulations (e.g., Himplasia, Urox); consequently, the specific therapeutic contribution of Crateva cannot be entirely isolated from the synergistic effects of other botanical constituents. Future research should prioritize standardized, single‐herb extracts in rigorous human trials to definitively validate the efficacy, safety, and pharmacokinetic profile of Crateva species independent of other herbal adjuncts.

3.4. Nephroprotective Activity

Studies show that C. nurvala extracts exert significant renoprotective effects against ischemia/reperfusion injury by reducing oxidative stress, inflammation, and apoptosis, with flavonoids, particularly kaempferol, being the major bioactive constituents [39]. In another study, oral treatment with ethanolic extracts of C. nurvala (250–500 mg/kg for 10 days) protected against cisplatin‐induced nephrotoxicity (5 mg/kg). The protective effects were reflected in improved renal function markers (blood urea nitrogen and creatinine), reduced oxidative stress indicators (lipid peroxidation), and enhanced antioxidant activity, as evidenced by increased glutathione and catalase levels [57]. Moreover, the aqueous bark extract of C. nurvala (Varuna) combined with Tribulus terrestris (Gokshura) aqueous fruit extract demonstrated significant nephroprotective effects in gentamicin‐induced nephrotoxic rats. Pretreatment with these extracts reduced blood urea and serum creatinine, improved urinary parameters, and preserved renal tissue structure, indicating their potential as protective agents against drug‐induced nephropathy [58]. Furthermore, network pharmacology and molecular docking analyses suggest that phytoconstituents of C. religiosa, including dillapiole, β‐ionone, 10‐epi‐γ‐eudesmol, linalool oxide, and nerolidol, may interact with key molecular targets such as RAC‐alpha serine/threonine‐protein kinase (AKT1), peroxisome proliferator‐activated receptor gamma (PPARγ), prostaglandin‐endoperoxide synthase 2 (PTGS2), and mitogen‐activated protein kinase 1(MAPK1). These targets are involved in the regulation of phosphatidylinositol‐3‐kinase–AKT (PI3K–AKT), advanced glycation end product–receptor for advanced glycation end product (AGE–RAGE), and interleukin‐17 (IL‐17) signaling pathways, which play critical roles in inflammation, oxidative stress, and immune responses associated with diabetic nephropathy [59]. While these findings provide valuable mechanistic insights at the molecular level, they are primarily predictive in nature and underscore the need for complementary experimental validation to confirm the nephroprotective effects of C. religiosa in biological systems.

3.5. Hepatoprotective Activity

In a study on C. religiosa, both aqueous and ethanolic extracts (200–400 mg/kg) significantly restored liver function in rats with paracetamol‐induced hepatotoxicity. Notably, the ethanolic extract at 400 mg/kg exhibited substantial efficacy comparable to silymarin in reducing liver damage markers [60]. In addition to renal protection, Crateva allied species and their bioactive constituents have shown hepatoprotective potential. Similarly, the aqueous extract of C. magna (200 mg/kg) demonstrated hepatoprotective effects in models of liver injury induced by carbon tetrachloride, ethanol, and paracetamol, with histopathological and biochemical analyses showing no significant difference compared to silymarin‐treated groups [61]. Lupeol and its ester, lupeol linoleate, have also been shown to confer significant protection against cadmium‐induced hepatic damage by restoring oxidative balance, enhancing antioxidant enzyme activity, and reducing markers of oxidative stress [62]. In a separate study on aflatoxin‐induced liver toxicity, lupeol remarkably restored liver enzyme levels (LDH, AST, ALT, and ALP), while also reducing lipid peroxidation and strengthening the antioxidant defense system, thereby confirming its potential as a natural hepatoprotective agent [63].

3.6. Anti‐Arthritic and Anti‐Inflammatory Activity

Lupeol linoleate has been found to be more effective than both unesterified lupeol and indomethacin in reducing foot‐pad thickness and complement activity in a rat model of arthritis [64]. In another study, an aqueous extract of C. nurvala stem bark with ω‐3 fatty acid (Lupeol‐EPA) in a dose of 50 mg/kg body weight showed strong anti‐arthritic effects in adjuvant‐induced arthritis in rats with marked reductions in lysosomal enzyme and glycoprotein activities to near control levels [65]. Lupeol isolated from C. religiosa also exerts anti‐arthritic effects by modulating the immune system and inhibiting cytokine production from CD4⁺ T cells [66]. Treatment with C. religiosa extracts further alleviated arthritic symptoms, as evidenced by reductions in paw swelling and normalization of altered hematological and biochemical parameters. These therapeutic benefits are likely attributable to a range of bioactive compounds, including flavonoids, tannins, and saponins [67]. Additionally, a diethyl ether leaf extract of C. religiosa exhibited dose‐dependent anti‐inflammatory activity, achieving 65.6% edema inhibition at 100 mg/kg, surpassing standard drugs such as aspirin and diclofenac [68]. As allied taxa, C. magna leaf extract also exhibits significant anti‐inflammatory activity through targeted modulation of the tumor necrosis factor (TNF) signaling pathway. The methanolic extract, rich in flavonoids and glycosides, suppresses key pro‐inflammatory mediators such as tumor necrosis factor alpha (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1 beta (IL‐1β). In vitro assays using SW982 human synovial cells demonstrated that this effect is mediated via downregulation of nuclear factor kappa B (NF‐κB) transcriptional activity. Furthermore, in vivo studies in arthritic rat models showed reductions in inflammatory symptoms and clinical markers, including C‐reactive protein (CRP) and rheumatoid factor (RF) [41]. Likewise, the methanolic extract of C. adansonii leaves demonstrated appreciable anti‐inflammatory activity in vitro, evidenced by protein denaturation inhibition, proteinase inhibition, membrane stabilization, and anti‐lipoxygenase assays, compared with diclofenac sodium and indomethacin [69]. Subsequent studies revealed that lupeol isolated from C. adansonii possesses potent anti‐inflammatory and analgesic properties, demonstrating superior suppression of downstream inflammatory mediators relative to standard drugs. Mechanistically, lupeol drives this therapeutic profile through a multi‐target pathway. At the enzymatic level, lupeol shows a strong binding affinity to cyclooxygenase‐2 (COX‐2; ‐9.0 kcal/mol), outperforming the reference NSAID indomethacin (‐8.4 kcal/mol). This molecular interaction correlates with the inhibition of myeloperoxidase (MPO) activity and a profound reduction in prostaglandin E₂ (PGE₂) production, surpassing the efficacy of indomethacin (10 mg/kg) in both acute carrageenan‐induced edema and chronic cotton pellet granuloma models. This enzymatic blockade subsequently suppresses a localized cascade of eight pro‐inflammatory cytokine markers, including upstream drivers TNF‐α, IL‐1β, IL‐6, and IFN‐γ, as well as chemotactic factors monocyte chemoattractant protein‐1 (MCP‐1), regulated on activation, normal T cell expressed and secreted (RANTES), and macrophage inflammatory protein (MIP). Simultaneously, its central analgesic efficacy is mediated via high‐affinity interactions with the nicotinic acetylcholine receptor (nAChR; ‐8.5 kcal/mol). This interaction exceeds the binding affinity of the standard analgesic pentazocine (‐7.0 kcal/mol). Consequently, lupeol results in superior pain suppression (69.05% inhibition) compared to pentazocine (10 mg/kg) in vivo. These findings confirm its potential as a multi‐target natural compound for safer, effective therapies for both acute and chronic inflammatory disorder [70]. While allied species like C. adansonii provide a robust molecular framework involving COX‐2 and nAChR modulation, direct mechanistic validation specifically for C. religiosa extracts remains limited. Future research prioritizing bioassay‐guided isolation and in vivo pathway analysis is essential to definitively characterize its unique pharmacological signature in chronic inflammatory disorders.

3.7. Cardioprotective Activity

Lupeol and its esters, isolated from C. nurvala stem bark, demonstrated significant cardioprotective effects against oxidative stress caused by cyclophosphamide administered at 200 mg/kg in Wistar rats. Treatment with lupeol or lupeol linoleate (50 mg/kg/day for 10 days) decreased serum lactate dehydrogenase (LDH) and creatine phosphokinase (CPK), improved antioxidant enzyme activity, and showed histological improvement in cardiac tissues [71]. These findings highlight the antioxidant and cardioprotective potential of triterpenes in Crateva species, suggesting that similar studies could be conducted in C. religiosa to identify its active constituents and cardioprotective effects.

3.8. Anti‐Mycotic Activity

The antifungal activity of C. religiosa was evaluated against Candida albicans, Candida tropicalis, Candida krusei, Cryptococcus marinus, and Aspergillus niger using petroleum ether, chloroform, and ethanolic extracts. The minimum inhibitory concentrations (MICs) ranged from 0.062 to 0.5 mg/disc, with the ethanolic extract showing the most significant inhibition, highlighting the potential of C. religiosa as a source of effective antifungal agents [72]. Similarly, among allied crateva species, the methanolic leaf extract of C. adansonii exhibited notable antifungal activity against A. niger and C. albicans, with complete growth inhibition observed at concentrations of 12.5 mg/mL [73]. Further studies focusing on the isolation of active compounds, clarification of the underlying mechanisms, and evaluation in in vivo models would help to better define its antifungal potential of these species.

3.9. Anti‐Microbial Activity

The methanolic leaf extract of C. religiosa exhibited broad‐spectrum antibacterial activity comparable to gentamicin and chloramphenicol, showing inhibitory effects against Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi. The minimum inhibitory concentration (MIC) values ranged between approximately 0.7 and 1.72 mg/mL. The bioactivity was attributed to steroidal terpenoids, although no antifungal activity was observed [68]. Interestingly, the methanolic extract obtained from the apical bark of C. religiosa was more effective than extracts from the middle and mature bark in inhibiting the growth of B. subtilis, S. aureus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, Proteus mirabilis, and Micrococcus species [74]. Further research showed that the total alkaloid extracts from the leaves and roots of C. religiosa (50 mg/mL) displayed enhanced antimicrobial properties compared to amoxicillin–clavulanic acid (20/10 µg) against S. aureus, E. coli, K. pneumoniae, Streptococcus agalactiae, and Citrobacter freundii, highlighting the role of alkaloids in the traditional medicine as antibacterial remedies [75]. Follow‐up studies validated this efficacy of C. religiosa, where the ethyl acetate extract exhibited the strongest activity reflected with MICs of 0.62 mg/mL against E. coli and 0.31 mg/mL against S. aureus, Shigella sonnei, Pasteurella pestis, and Yersinia enterocolitica. These findings support its ethnomedicinal use against bacterial strains isolated from Thryonomys swinderianus (African cane rat) [76]. Similarly, allied species also demonstrated notable antimicrobial effects. The stem and root extracts of C. adansonii exhibited pronounced antimicrobial activity, particularly against Bacillus cereus, S. aureus, E. coli, and Serratia spp. Notably, the root extract demonstrated stronger antibacterial efficacy than the stem extract, indicating a higher concentration of bioactive constituents in the root fraction [77]. Additionally, the methanolic leaf extract of C. adansonii exhibited broad spectrum antibacterial activity, inhibiting all tested bacterial strains P. aeruginosa, E. coli, S. typhi, S. aureus, K. pneumoniae, and B. subtilis at concentrations of 25 and 12.5 mg/mL. At 6.25 mg/mL, the activity was limited to E. coli and K. pneumoniae, with no inhibition observed at 3.125 mg/mL [73]. Furthermore, the leaf and bark extracts of C. tapia exhibited significant antibacterial activity against E. coli, P. mirabilis, B. subtilis, and S. aureus. Meanwhile, the petroleum ether, ethanolic, and aqueous extracts of both parts were active, with the ethanolic bark extract showing the highest potency, displaying the lowest MIC values (10–20 mg/mL) against E. coli [78]. Collectively, these findings highlight the antimicrobial potential of C. religiosa and its allied species, supporting their traditional use in infections, and emphasize the need for further studies to identify the bioactive compounds and assess their efficacy in vivo.

3.10. Anti‐Pyretic Activity

The ethanolic extract of C. magna stem bark demonstrated significant anti‐pyretic activity in rabbits at doses of 200 and 400 mg/kg against typhoid vaccine‐induced fever. Its efficacy was comparable to orally administered paracetamol (100 mg/kg), suggesting that the extract contains bioactive compounds capable of reducing elevated body temperature [79]. Although no studies have directly tested C. religiosa, its close relatives share similar phytochemical constituents, implying potential fever‐reducing effects. This highlights a gap in research and the need for targeted experimental studies to validate the anti‐pyretic activity of C. religiosa.

3.11. Antinociceptive Activity

The crude ethanolic extract of the stem bark of C. nurvala was screened for antinociceptive activity using the acetic acid–induced writhing test in mice. Oral administration of the extract at doses of 250–500 mg/kg produced a significant, dose‐dependent suppression of chemically induced pain responses (p < 0.05–0.001), indicating that its analgesic effects are mediated through both peripheral and central mechanisms [80]. Similarly, the crude methanolic extract of C. nurvala (CME) was assessed using acetic acid–induced writhing and tail immersion tests. CME at 200 and 400 mg/kg produced 45.88% and 66.63% inhibition of writhing responses, respectively, compared with diclofenac sodium (15 mg/kg, 75% inhibition). In the tail immersion test, CME at 100, 200, and 400 mg/kg significantly increased tail withdrawal latency, indicating both peripheral and central antinociceptive activity [81]. In addition, the methanolic extract of C. nurvala leaves (MECN) was evaluated in mice using heat‐induced (hot‐plate, tail immersion) and chemical‐induced (acetic acid, formalin, glutamate) nociception models. The extract was administered at doses of 50, 100, and 200 mg/kg, p.o., while morphine sulfate (5 mg/kg, i.p.) and diclofenac sodium (10 mg/kg, i.p.) served as reference drugs. Notably, MECN produced significant dose‐dependent antinociception across all models, thereby demonstrating both central and peripheral analgesia and effectively modulating neurogenic as well as inflammatory pain [82]. Although direct evidence for the antinociceptive activity of C. religiosa is lacking, findings from the closely related species C. nurvala suggest potential pain‐relieving effects, supporting its traditional use in the management of painful and inflammatory conditions. Further studies should focus on elucidating the active constituents and underlying mechanisms in C. religiosa.

3.12. Anti‐Hyperglycemic Activity

The aqueous 80% ethanol extract of C. religiosa leaves exerted marked hypoglycemic activity in streptozotocin‐induced type‐2 diabetic rats, where it significantly lowered fasting serum glucose during both acute and chronic studies while maintaining stable body weight, compared to glibenclamide [37]. Similarly, the methanolic bark extract of C. religiosa exhibited dose‐dependent antihyperglycemic activity, partly mediated through α‐amylase inhibition, an effect attributed to the presence of bioactive phytochemicals such as flavonoids, tannins, alkaloids, and saponins, which may also contribute synergistically to its antioxidant potential [83]. In parallel, oral administration of C. magna leaf extract showed significant antidiabetic activity in alloxan‐induced Wistar rats, with the aqueous extract yielding the strongest hypoglycemic effect, comparable to glibenclamide (5 mg/kg) [84]. In another study, the ethanolic leaf extract of C. magna administered orally at doses of 100, 200, and 500 mg/kg, exhibited significant dose‐dependent antihyperglycemic activity in streptozotocin‐induced diabetic rats. The highest dose (500 mg/kg) produced the most pronounced reduction in blood glucose levels, with efficacy comparable to the standard antidiabetic drug glipizide (4 mg/kg) [85]. Additionally, the crude extract of C. nurvala exhibited significant, dose‐dependent blood glucose‐lowering effects, with oral administration at 200 mg/kg and 400 mg/kg reducing glucose levels to 119.34 mg/dL and 109.26 mg/dL, respectively (p < 0.05) [81]. Beyond C. religiosa, studies in allied species provide additional insights into compound‐specific mechanisms. For instance, the bark lectin CrataBL from C. tapia exhibited significant antidiabetic effects in alloxan‐induced diabetic mice. At doses of 10 and 20 mg/kg/day for 10 days, it reduced blood glucose by 14.9% and 55.9%, respectively, while also lowering urea, creatinine, AST, and ALT levels. Histological analyses confirmed protection of pancreatic, renal, and hepatic tissues, indicating that CrataBL improves both hyperglycemia and diabetes‐related organ damage [86]. Although CrataBL itself has not been identified in C. religiosa, the study serves as a valuable model for exploring active compounds in the Crateva genus. It demonstrates clear compound‐specific effects supported by histological and biochemical data, however, critical gaps still persist regarding its pharmacokinetics, long‐term safety, and clinical validation. Overall, these findings highlight promising anti‐hyperglycemic effects across Crateva species; yet, because current evidence for C. religiosa remains limited to preclinical animal models, future research should focus on isolating active compounds, elucidating molecular mechanisms, and conducting long‐term safety and clinical studies to validate efficacy.

3.13. Anti‐Fertility Activity and Hormonal Regulatory Effects

In rat models, the administration of aqueous and ethanolic extracts of C. nurvala (300–600 mg/kg/day) for 8 days produced dose‐dependent anti‐fertility effects, likely mediated by altered estrogenic activity leading to ova expulsion and inhibition of luteotropic activity [87]. In contrast, hydroalcoholic bark extract of C. religiosa (CRE) administered at 100 mg/kg and 200 mg/kg in polycystic ovarian syndrome (PCOS) rats significantly restored estrous cycle regularity, normalized ovarian and uterine histoarchitecture, and corrected abnormal organ weights. The extract also regulated serum hormone levels, including progesterone, testosterone, and estrogen, reduced oxidative stress markers such as malondialdehyde (MDA), and restored antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT). Additionally, it upregulated key genes involved in reproductive and metabolic regulation, including aromatase (CYP19A1) and PPARγ, in a dose‐dependent manner [88]. As with most preclinical studies, the specific active constituents were not identified, and gene expression changes were not confirmed at the protein or functional level. Key translational parameters such as fertility outcomes, metabolic profiling (glucose tolerance and insulin sensitivity), long‐term safety, and pharmacokinetics yet to be explored. These findings suggest that CRE has potential for reproductive and hormonal regulation in PCOS and highlight directions for future research.

3.14. CNS Depressant Activity

The leaf extracts of C. religiosa exhibited significant central nervous system (CNS) depressant activity. Among the various extracts tested, the aqueous extract (400 mg/kg) produced the most pronounced effect, significantly (p < 0.01) reducing sleep onset time and prolonging pentobarbitone‐induced sleep duration. It also decreased locomotor activity by 67.33%, suggesting a potent sedative effect [89]. The compounds responsible for the CNS depressant effects of C. religiosa are not yet identified. Additional studies could help clarify the underlying mechanisms, determine safe and effective doses, and explore other CNS‐related effects such as anxiety, depression, and memory.

3.15. Anti‐Cancer Activity

Hydroalcoholic bark extract of C. religiosa G. Forst. exerts potent antiproliferative activity against human ovarian cancer (PA‐1) cells, with an IC₅₀ (half‐maximal inhibitory concentration) of 33.27 µg/mL. This extract also demonstrated appreciable antioxidant activity and a high phytochemical composition, including phenolic compounds, flavonoids, alkaloids, and terpenoids, suggesting its potential as a candidate for the development of novel anticancer agents [90]. Beyond C. religiosa, the anticancer relevance of its key constituent lupeol is further supported by mechanistic studies. In vitro experiments showed that lupeol modulates nuclear factor kappa B (NF‐κB) signaling and the phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt) pathway, both involved in tumor development and progression [91]. Lupeol also reduced the protein expression of cellular FLICE‐like inhibitory protein (cFLIP) in pancreatic cancer cells by suppressing transcriptional activity, making these cells more susceptible to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) therapy. In vivo studies using a xenograft mouse model confirmed that treatment with lupeol (40 mg/kg, three times per week) suppressed tumor formation from human pancreatic cancer cells (AsPC‐1), indicating a potential mechanism underlying its anticancer activity [92]. Additional research showed that lupeol inhibits proliferation and metastasis of melanoma cells and reduces their migratory ability, associated with alterations in the actin cytoskeleton [93]. In related species, additional evidence of anticancer potential has been documented. The stem bark extract of C. adansonii exhibited cytotoxicity against estrogen receptor‐positive (ER‐positive MCF‐7) breast cancer cells (CC₅₀ = 289 µg/mL). At an oral dose of 75 mg/kg in rats, it significantly reduced 7,12‐dimethylbenz[a]anthracene (DMBA)‐induced mammary tumor yield, burden, and volume. The extract also enhanced antioxidant enzyme activities, including SOD and CAT, counteracted DMBA‐induced oxidative stress, and protected against DNA damage, likely due to its flavonoid and other phenolic constituents [94].

3.16. Hypolipidemic Activity

The ethanolic bark extract of C. religiosa demonstrated significant hypolipidemic potential by inhibiting adipocyte differentiation and lipogenesis in 3T3‐L1 cells. Oil Red O staining revealed reduced intracellular lipid accumulation. Western blot analysis showed downregulation of PPARγ and CCAAT/enhancer‐binding protein (CCAAT/EBP), key transcriptional regulators of adipogenesis. Molecular docking studies suggested that bioactive constituents such as stigmasterol, γ‐sitosterol, and lupeol interact with 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase and other lipid metabolism‐related targets, supporting their potential role in managing hyperlipidemia [95]. Further studies are needed to confirm these effects in vivo, clarify whether the activity arises from individual compounds or synergistic effects of the extract, and validate the predicted molecular targets. Similarly, related taxa such as C. nurvala and C. magna have also demonstrated hypolipidemic effects. The ethanolic leaf extract of C. magna significantly improved the lipid profile in diabetic rats, reducing total cholesterol, triglycerides, low‐density lipoprotein (LDL), and very‐low‐density lipoprotein (VLDL) levels, while increasing high‐density lipoprotein (HDL) levels, indicating effective correction of diabetes‐associated dyslipidemia [85]. Similarly, the ethyl acetate fraction of the ethanolic stem bark extract of C. nurvala produced pronounced effects in triton‐ and diet‐induced hyperlipidemic rats at a dose of 500 mg/kg, significantly lowering triglycerides, total cholesterol, LDL, and VLDL, while increasing HDL, with efficacy comparable to simvastatin [96].

3.17. Wound Healing Activity

A methanolic extract of C. religiosa (50 mg/kg) exhibited superior wound‐healing efficacy compared to penicillin. Wounds treated with the extract showed enhanced drying and contraction, accompanied by improved tissue regeneration [97]. Similarly, the methanolic leaf extract of C. magna (500 mg/kg/day, topical) significantly promoted wound healing in excision and incision models, as indicated by faster wound contraction, accelerated epithelialization, increased hydroxyproline levels, and improved histopathology, with effects comparable to the standard drug framycetin (p < 0.001) [98].

3.18. Anti‐Alzheimer Activity

The dichloromethane fraction of C. religiosa bark exhibited notable, dose‐dependent inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀ values of 455 ± 1 and 450 ± 1 µg/mL, respectively, highlighting its potential as a natural cholinesterase inhibitor [99]. Similarly, the n‐hexane soluble fraction of C. magna leaf extract (CMHF) demonstrated strong inhibitory activity against key Alzheimer's disease (AD) enzymes, (AChE; IC₅₀ = 0.114 ± 0.006 µg/mL) and β‐secretase (BACE1; IC₅₀ = 1.723 ± 0.1 µg/mL). Furthermore, CMHF showed no cytotoxicity on HepG‐2, HCT‐116, MCF‐7, and WISH cell lines, supporting its potential as a safe natural candidate for AD management [100]. In addition, the aqueous extract of C. nurvala stem bark at 500 mg/kg, orally administered, significantly reversed scopolamine‐induced memory deficits in rats. Biochemical analyses confirmed reductions in brain AChE activity and thiobarbituric acid reactive substances (TBARS) levels, markers of lipid peroxidation (p < 0.001), indicating that the extract protects against memory loss by restoring cholinergic function and mitigating oxidative stress [101]. Further evidence from allied species supports multi‐target neuroprotective potential. The hydro‐methanol extract of C. adansonii exhibited stronger AChE inhibition (4.18 ± 0.12 mg GALAE/g, galantamine equivalent) than its n‐hexane fraction (2.04 ± 0.06 mg GALAE/g), whereas the n‐hexane fraction showed higher BChE inhibition (8.64 ± 0.47 mg GALAE/g) compared to the hydro‐methanol extract (2.88 ± 0.86 mg GALAE/g). These results suggest that different extracts target complementary cholinesterase pathways, collectively demonstrating broad‐spectrum neuroprotective effects relevant to AD [42]. Overall, while these findings are promising, further studies, particularly in vivo validation, isolation of the active compounds, and safety assessments are needed to fully understand the therapeutic relevance of these extracts across the Crateva genus.

3.19. Consolidated Molecular Targets and Signaling Cascades

To highlight the precise molecular mechanisms and target‐directed pharmacology of the genus Crateva discussed throughout this section, the specific molecular targets, receptor binding affinities, and downstream signaling pathways are systematically consolidated in Table 2.

TABLE 2.

Integrated molecular targets, signaling pathways, and target‐directed pharmacological profiles of the genus Crateva phytoconstituents.

Pharmacological category	Taxon/ Compound involved	Key molecular target(s)/ receptors	Modulated downstream signaling pathway	Primary cellular or physiological endpoint	Reference
Nephroprotective	C. religiosa / Dillapiole, β‐ionone, 10‐epi‐γ‐eudesmol, linalool oxide, nerolidol	• AKT1 • PPARγ • PTGS2 (COX‐2) • MAPK1	Modulation of PI3K–AKT, AGE–RAGE, and IL‐17 signaling pathways (Predictive network pharmacology).	Targeted mitigation of inflammation, oxidative stress, and immune responses associated with diabetic nephropathy.	[59]
Anti‐Inflammatory & Anti‐Arthritic	C. magna leaf Extract / Flavonoid glycosides	• TNF‐α • IL‐6 • IL‐1β	Downregulation of Nuclear Factor kappa B (NF‐κB) transcriptional activity.	Suppression of pro‐inflammatory mediators in SW982 human synovial cells; reduction of systemic CRP and RF in vivo.	[41]
	C. adansonii / Isolated Lupeol	• COX‐2 (Binding affinity: ‐9.0 kcal/mol) • nAChR (Binding affinity: ‐8.5 kcal/mol)	Inhibition of localized MPO and PGE2 production; suppression of an 8‐cytokine cascade (TNFα, IL‐1β, IL‐6, IFN‐γ, MCP‐1, RANTES, MIP).	Outperforms indomethacin and pentazocine in vivo; achieves 69.05% pain inhibition and safe suppression of acute/chronic edema.	[70]
Hormonal & Reproductive Regulation	C. religiosa Hydroalcoholic Bark Extract (CRE)	• Aromatase (CYP19A1) • PPARγ • MDA, SOD, CAT	Dose‐dependent transcriptional upregulation of reproductive and metabolic genes (CYP19A1/PPARγ).	Restored estrous cycle regularity, normalized ovarian/uterine tissue structure, and balanced serum hormones in PCOS models.	[88]
Anticancer	Lupeol (Evaluated as a representative major bioactive triterpene of genus Crateva)	• NF‐κB signaling • PI3K/Akt pathway • cFLIP protein	Transcriptional suppression of cellular FLICE‐like inhibitory protein (cFLIP).	Sensitizes pancreatic cancer cells to TRAIL‐induced apoptosis; suppresses AsPC‐1 human xenograft tumor formation in vivo.	[91, 92]

3.20. Cross‐Species Comparative Analysis and Knowledge Gaps

A critical evaluation of the ethnopharmacological literature reveals a divergence between traditional therapeutic claims and species‐specific scientific validation within the genus Crateva. Several pharmacological claims, including anti‐urolithic, neuroprotective, and anticancer activities, rely predominantly on studies involving C. nurvala, C. magna, or isolated triterpenes such as lupeol, while direct experimental evidence from C. religiosa itself remains less explored. As summarized in Table 3, evidence specific to C. religiosa is comparatively stronger for antioxidant, antimicrobial, and hormonal/PCOS‐related activities, whereas direct validation for urolithiasis and oncological applications remains limited or largely predictive. Consequently, extrapolating pharmacological findings from allied taxa directly to C. religiosa introduces significant chemotaxonomic ambiguity. These limitations highlight an urgent need for direct, standardized in vitro and in vivo investigations using authenticated C. religiosa material to fully substantiate its specific traditional therapeutic applications.

TABLE 3.

Cross‐species pharmacological evidence matrix and scientific gaps specific to C. religiosa.

Traditional Claim / Biological Domain	Status of Evidence for Allied Species / Compounds	Status of Direct Evidence for C. religiosa	Core Knowledge Gap & Future Research Direction	References
Urolithiasis & nephroprotection	Extensive in vivo rodent models validate C. nurvala bark decoctions in restoring antioxidant enzymes, halting calcium oxalate crystal aggregation, and lowering urinary calcium. Furthermore, pure lupeol and betulin (35 mg/kg p.o.) sourced from C. nurvala reversed stone‐induced oxidative stress and restored key antioxidant pools.	Predictive Only: Direct evidence for C. religiosa is restricted exclusively to in silico network pharmacology and molecular docking predictions (mapping compounds like dillapiole and nerolidol to AKT1/MAPK1 cascades).	Functional Validation Deficient: Bioactivity mechanisms are currently credited across the genus based on allied taxa data. While computational mapping is promising, direct in vitro or in vivo bioassays validating authenticated C. religiosa extracts against calcium oxalate crystallization or nephropathy remain entirely absent.	[43, 59]
Hepatoprotective activity	Robust validation observed for allied species; for example, aqueous leaf extract of C. magna (200 mg/kg) significantly reduces CCl4, paracetamol, and ethanol‐induced liver lesions in rats, restoring serum markers (AST, ALT, ALP).	Strong Direct Validation: Both aqueous and ethanolic leaf extracts (200–400 mg/kg) significantly restored liver function in rats with paracetamol‐induced hepatotoxicity. Notably, the ethanolic extract at 400 mg/kg exhibited substantial efficacy comparable to silymarin.	Downstream Mechanism Profiling: While direct in vivo efficacy is established, the exact species‐specific pathways regulating cellular antioxidant defenses and membrane stabilization remain unverified. Future bioassay‐guided isolation is required to pinpoint the precise active constituents driving this liver protection.	[60, 61]
	Isolated stem bark lupeol from C. nurvala (100 mg/kg) mitigates Aflatoxin B1 hepatotoxicity by suppressing lipid peroxidation and restoring glutathione defenses.	No direct functional evaluation or in vivo profiling has been conducted on authenticated C. religiosa extracts to validate its protective actions against complex fungal mycotoxins like Aflatoxin B1.	Mechanistic Extract Validation: It is unverified if the native chemical matrix of whole C. religiosa extract can replicate the glutathione‐restoring antioxidant cascades achieved by isolated lupeol.	[63]
Anti‐inflammatory & anti‐Arthritic	C. magna methanolic leaf extracts suppress TNF‐α‐ induced inflammation in SW982 human synovial cells by downregulating mRNA expressions of NF‐κB, TNF‐α, IL‐6, and IL‐1β. Additionally, isolated lupeol from C. adansonii blocks COX‐2 (‐9.0 kcal/mol), decreases MPO/ PGE2, and suppresses an 8‐cytokine cascadein vivo, and centrally binds nAChR to achieve 69.05 % pain inhibition.	Potent Direct In viv o Efficacy: A diethyl ether leaf extract exhibited strong, dose‐dependent anti‐inflammatory activity, achieving 65.6% edema inhibition at 100 mg/kg, which notably surpassed standard NSAIDs such as aspirin and diclofenac.	Upstream Signaling & Target Resolution: While in vivo potency is highly competitive with commercial drugs, direct structural/functional validation evaluating specific molecular target interactions (e.g., COX‐2 or nAChR binding dynamics) and upstream cellular transcription factor networks remains absent for authenticated C. religiosa extracts.	[41, 68, 70]
Antimicrobial activity	Systematic isolation and comparative screening of targeted sub‐fractions such as targeted secondary metabolite bands or total alkaloid complexes remain undocumented for allied Crateva taxa.	Promising Fractional Potency: Column‐fractionated leaf and root extracts exhibit broad‐spectrum in vitro zones surpassing standard amoxicillin‐clavulanic acid, yielding active steroidal terpenoid elution fractions (MIC: 0.31 ‐ 0.91 mg/mL) alongside total alkaloidal arrays (MIC: 50 mg/mL).	Structural & Spectroscopic Deficit: Resolved bio‐active fractions are limited to uncharacterized molecular groups, requiring high‐resolution LC‐MS/MS or NMR tracking to identify individual pure active structures and establish in vivo efficacy.	[68, 75]
Antidiabetic/ hyperglycemic regulation	Sourced from of C. magna leaf extract (100 –500 mg/kg) show dose‐ dependent anti hyperglycemic action comparable to glipizide, while reversing dyslipidemia and restoring GSH, SOD, and CAT pools.	Primarily Preclinical: Direct evidence for C. religiosa is restricted to baseline, unrefined phenotypic evaluations of crude extracts, lacking clear target‐directed molecular mechanisms.	Characterization & Translational Deficit: Active metabolites in C. religiosa remain unisolated, and there is a total absence of pharmacokinetic mapping or long‐term chronic toxicity data.	[85]
	Purified stem bark lectin (CrataBL) isolated from C. tapia reverses hyperglycemia and protects pancreatic, hepatic, and renal tissues in rodent models.	No homologous lectins or target‐directed macromolecules have been screened, isolated, or functionally evaluated from C. religiosa tissues.	Homology Screening Gap: Future research must prioritize screening and fractionating C. religiosa extracts for homologous lectins to evaluate if they replicate the tissue‐protective effects of CrataBL.	[86]
Anti‐cancer	No evaluation or comparative screening has been conducted using allied taxa against human ovarian cancer (PA‐1) cells.	Promising In Vitro Cytotoxicity: Hydroalcoholic bark extract exhibits potent, dose‐dependent antiproliferative activity against PA‐1 cells (IC 50 = 33.27 µg/mL), inducing structural apoptosis induction (membrane blebbing, cell shrinkage).	Translational Deficient: While cell line cytotoxicity, apoptotic mechanisms, and qualitative phytochemistry are established in vitro, a critical deficit remains regarding in viv o animal tumor models, and pharmacokinetic profiling.	[90]
	Pure lupeol is fully proven to transcriptionally suppress cFLIP and modulate PI3K/Akt to arrest AsPC‐1 xenograft tumor growth in vivo.	Direct mechanistic evidence for C. religiosa remains restricted to raw phenotypic screenings (in vitro antioxidant and crude anti‐proliferative cell assays), completely lacking any verified isolated‐compound pathways.	Translational Gap: There is a total absence of in vivo animal tumor model validation, pharmacokinetic mapping, or human cancer xenograft studies using whole C. religiosa extracts	[91, 92]
Fertility & anti‐implantation	Crude ethanol and aqueous stem bark extracts of C. nurvala display dose‐dependent anti‐fertility and early abortifacient activities via altered estrogenic pathways.	No direct functional evaluation has been conducted on authenticated C. religiosa extracts to validate traditional folklore contraceptive or abortifacient claims.	Uterine Homeostasis Profiling: It is completely unverified if C. religiosa extracts trigger identical blastocytotoxicity or blastocyst‐disrupting alterations as observed in allied taxa.	[87]
Ovarian & PCOS Regulation	No direct evaluation regarding PCOS or ovarian steroidogenesis has been reported for allied Crateva taxa.	Highly Robust Validation: Hydroalcoholic bark extract directly reverses letrozole‐induced PCOS by restoring ovarian tissue architecture, balancing serum hormones, and upregulating reproductive genes.	Translational Characterization: Active constituents remain unisolated. Future work must validate gene expressions at the protein level and evaluate long‐term safety, pharmacokinetics, and fertility outcomes.	[88]
Neuroprotection/ anti‐Alzheimer's	Polar (hydro‐methanol) extract of C. adansonii selectively targets AChE and BchE, while aqueous bark extract of C. nurvala (500 mg/kg, p.o.) significantly reverses scopolamine‐induced amnesia in vivo.	Limited Baseline Validation: Direct evidence for C. religiosa is limited to in vitro cholinesterase inhibition screening (DMF fraction), with in vivo cognitive evaluations remain completely unverified experimentally for this specific species.	Tissue & Model Gaps: Lacks direct in vivo validation for C. religiosa, and the comparative neuroprotective potential of leaf versus bark fractions remains completely untested.	[42, 99, 101]

3.21. Safety and Toxicological Evaluation

Establishing the toxicological profile of the genus Crateva is a critical prerequisite for its clinical translation and therapeutic deployment. Experimental evaluation of the acute oral toxicity profile of standalone Crateva extracts demonstrates a highly favorable safety window. For instance, a standardized trial evaluated the aqueous and methanolic leaf extracts of C. adansonii in Swiss albino rats. Using Lorke's method, researchers tested a two‐phase dose‐escalation design ranging from 10 to 5000 mg/kg body weight. The results demonstrated zero mortality (0%) and no severe signs of toxicity. Furthermore, there were no statistically significant differences (p > 0.05) in body weight changes compared to healthy controls. Consequently, the study determined the median lethal dose (LD₅₀) to be greater than 5000 mg/kg body weight [109]. However, comprehensive pharmacokinetic parameters, oral bioavailability profiles, metabolic fate, and long‐term chronic exposure studies for isolated Crateva preparations remain insufficiently characterized. In human subjects, the clinical safety and tolerability of Crateva‐based interventions have been validated exclusively through commercial polyherbal formulations (such as Himplasia, Urox, and multi‐center nutraceutical adjuvants), as extensively detailed in Section 5.1. Across these clinical trials, treatments were consistently well‐tolerated with stable hepatic, renal, and hematological indices [48, 50, 56]. While these human data substantiate clinical safety, separating the independent long‐term safety of individual Crateva species from these mixed herbal formulas remains a key regulatory challenge. This highlights a clear necessity for future research to transition toward standardized, single‐herb clinical trials. Such studies are required to establish independent toxicological baselines for C. religiosa.

3.22. Plant Biotechnology Applications in Crateva

Given the growing pharmacological and phytochemical interest in Crateva species, plant biotechnology has emerged as an important strategy for sustainable biomass production, conservation, and future phytopharmaceutical applications. Plant tissue culture provides an efficient, cost‐effective platform for the propagation, conservation, and stress screening of medicinal plants under both biotic and abiotic conditions. This in vitro approach is based on the cell theory and the pioneering concepts of plant tissue culture developed in the early 20th century [102]. Building on these foundational concepts, several studies have demonstrated effective micropropagation protocols for C. religiosa under in vitro conditions. Multiple shoots were regenerated directly from nodal explants cultured on Murashige and Skoog (MS) medium supplemented with 1 mg/L 6‐benzylaminopurine (BAP) and 0.5 mg/L naphthaleneacetic acid (NAA). In contrast, internodal explants produced callus when cultured on MS medium containing 2 mg/L BAP and 0.5 mg/L NAA. Nodal segments showed a higher multiplication frequency than internodal explants (Figure 4). Optimal root induction was achieved on solidified MS medium supplemented with 3 mg/L indole‐3‐butyric acid (IBA), resulting in an efficient propagation protocol for this fast‐growing medicinal plant [103]. In addition to nodal explants, alternative explant sources have also been explored for the micropropagation of C. religiosa. A reliable large‐scale propagation protocol was established using apical bud explants. Maximum shoot proliferation was achieved on MS medium supplemented with 8 mg/L BAP, while optimal rooting occurred on half‐strength MS medium containing 3 mg/L IBA or IAA, providing a practical strategy for commercial‐scale propagation [104]. Clonal propagation has also been achieved using leaf, nodal, and internodal explants. Among these, nodal segments showed superior shoot regeneration on MS medium supplemented with 1.5 mg/L BAP and 0.5 mg/L NAA in the presence of 5% coconut water. Microshoots rooted efficiently on half‐strength MS medium containing 1 mg/L NAA and 0.5 mg/L IBA. In contrast, compact callus formation was induced from leaf and internodal explants on MS medium supplemented with 1.5 mg/L 2,4‐dichlorophenoxyacetic acid (2,4‐D). Acclimatized plantlets grown in a sand:soil:vermiculite (1:1:1) mixture and treated with fungicide showed an 88% survival rate and were morphologically identical to the parent plants (Figure 5) [105]. To further contextualize these findings within the genus, comparable in vitro regeneration strategies have been reported for allied Crateva species. In C. magna, nodal explants cultured on MS medium containing 8.8 µM BAP produced an average of 4.4 ± 0.09 shoots per explant. Rooting was successfully achieved using 9.84 µM IBA and 0.54 µM NAA, with a pot establishment success rate of 68% [106]. Similarly, C. nurvala has been efficiently propagated via callus‐mediated pathways. Maximum callus induction occurred on MS medium supplemented with 2 mg/L 2,4‐D and 0.4 mg/L kinetin. Somatic embryogenesis was predominantly induced from leaflet‐ and petal‐derived callus on 0.4–0.5 mg/L TDZ (thidiazuron), whereas organogenic shoot regeneration from node‐, internode‐, and petiole‐derived callus was optimal on 0.5 mg/L 6‐benzyladenine (BA) or 0.2–0.3 mg/L TDZ. Rooting was most effective on half‐strength MS medium supplemented with 0.5 mg/L α‐NAA, achieving a rooting frequency of 70.83%. Acclimatized plantlets exhibited higher survival rates following organogenesis (83%) compared to somatic embryogenesis (66%) [107]. Further studies have established an efficient in vitro micropropagation protocol for C. adansonii. Regeneration was achieved via axillary proliferation, organogenesis, and somatic embryogenesis using different explants. Optimal shoot multiplication occurred from nodal explants and shoot tips on MS medium supplemented with 3 mg/L BA and 0.05–0.1 mg/L NAA, while adventitious shoots from leaves were induced on 3 mg/L BA and 0.1 mg/L NAA. De novo shoots and somatic embryos were obtained from anthers cultured on 3 mg/L BA and half‐strength MS medium containing 0.1 mg/L 2,4‐D, respectively. Well‐rooted plantlets were successfully acclimatized under ex vitro conditions, confirming the suitability of this protocol for large‐scale propagation and conservation of C. adansonii [108]. Beyond propagation and conservation, plant tissue culture systems may support pharmacological and phytochemical research by providing sustainable and genetically uniform plant biomass. These in vitro approaches can improve the reproducibility of bioactivity studies by minimizing environmental variability and may also help preserve plant varieties rich in bioactive metabolites such as lupeol. Furthermore, they offer promising platforms for future metabolite enhancement and standardized phytopharmaceutical development. Overall, these protocols underscore the potential of C. religiosa for sustainable propagation and biotechnological applications, highlighting its continued relevance in medicinal plant research.

FIGURE 4.

Schematic stage‐by‐stage workflow of the in vitro micropropagation protocol for C. religiosa. (A) Selection and preparation of field‐derived nodal and internodal explants. (B) Morphogenic induction pathways showing direct multiple shoot regeneration from nodal segments versus indirect callus formation from internodal segments. (C) Optimal rhizogenesis on MS medium supplemented with 3 mg/L IBA. (D) Comparative average number of shoots generated per explant type.

FIGURE 5.

Comprehensive schematic workflow of the in vitro clonal propagation and callogenesis pathways of C. religiosa. The flowchart details direct shoot proliferation from nodal segments (1.5 mg/L BAP + 0.5 mg/L NAA + 5% CW) and indirect organogenesis via compact green‐brown callus induction (1.5 mg/L 2,4‐D), concluding with optimal microshoot rhizogenesis and an 88% ex vitro acclimatization survival rate.

4. Conclusion

C. religiosa is a highly valued medicinal plant, demonstrating a wide spectrum of pharmacological activities that support many of its ethnomedicinal uses. Recent studies have highlighted the efficacy of C. religiosa and its allied species (C. magna, C. nurvala, C. adansonii, and C. tapia) in managing urinary disorders, diabetes, inflammatory conditions, cancer, microbial infections, hyperlipidemia, CNS disorders, and hepatic and renal dysfunctions. These therapeutic effects are largely attributed to diverse phytoconstituents, particularly triterpenes such as lupeol, along with flavonoids, alkaloids, and phenolic compounds. Evidence from closely related taxa further reinforces the pharmacological potential of the genus, often demonstrating complementary bioactivities. Notably, a recent integrative study on C. magna provided pathway‐level evidence for its anti‐arthritic effects via TNF signaling modulation, linking specific flavonoid and phenolic glycosides to reductions in pro‐inflammatory cytokines and joint damage. This highlights the value of mechanistic investigations for future research across Crateva species. Overall, future studies should prioritize standardized extracts, detailed phytochemical characterization, mechanistic exploration, and well‐designed clinical trials to validate efficacy and safety, facilitating the development of evidence‐based medicines derived from the Crateva genus.

5. Summary and Future Outlook

Future research should prioritize comprehensive phytochemical profiling of C. religiosa and allied species, as most studies have relied on crude extracts with only partial characterization of their constituents. While LC–MS/MS, GC–MS, and NMR have identified several compounds, many remain uncharacterized, and the specific bioactive compounds responsible for pharmacological effects are largely unknown. Furthermore, while predictive approaches for C. religiosa, including molecular docking and network pharmacology, provide valuable mechanistic insights, these findings remain purely computational. There is a critical need for rigorous experimental validation through in vitro enzyme assays and in vivo gene knockout studies to confirm these predicted molecular targets and pathways. Systematic in vitro, in vivo, and clinical studies using standardized extracts are essential to validate traditional uses, clarify mechanisms of action, and assess safety. To move beyond the limitations of current data, future clinical research must transition toward monotherapy study designs utilizing standardized Crateva extracts. Implementing randomized, double‐blind, placebo‐controlled protocols will allow for the definitive isolation of the genus's therapeutic efficacy and the establishment of clear dose‐response relationships, independent of the synergistic effects of polyherbal mixtures. Integrating metabolomics, chemoinformatics, and bioactivity‐guided fractionation could accelerate discovery of novel therapeutic compounds and support the development of standardized Crateva‐based formulations. Interdisciplinary efforts bridging ethnobotany, pharmacology, and phytochemistry will be crucial to fully realize the medicinal potential of this genus.

Author Contributions

Rania T. Saleh: writing – original draft, writing – review and editing. Sherif A. Hamdy: writing – review and editing. Sahar A. Khairy: review and editing. Seham S. Elhawary: conceptualization, review and editing. All authors have read and approved the submitted manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not for profit sectors.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Rania T. Saleh graduated from the Faculty of Pharmacy, October 6 University, Egypt. She previously served as a teaching assistant in the Phytochemistry Department and is currently working as a specialist pharmacist at the National Nutrition Institute (NNI). Her research interests focus on medicinal plants, phytochemistry, ethnobotany, nutrition science, and the therapeutic potential of plant‐derived bioactive compounds. She is currently registered for a Master's degree and has published one review article in the field of nutrition.

Professor Dr. Seham S. Elhawary is a distinguished academic who graduated from the Faculty of Pharmacy at Cairo University, where she obtained her B.Sc. in pharmaceutical sciences in 1967, followed by her M.Sc. in 1972 and Ph.D. in 1976. Since being promoted to professor in 1991, she has continued her academic service through 2026 and served as the Head of the Pharmacognosy Department. Her leadership roles include three years as the Director of the Higher Scientific Committee of Egyptian Universities for the promotion of professors and associate professors, along with twelve years of service as a member of this committee. Her global scientific impact is evidenced by her inclusion in Stanford University's list of the top 2% of most effective scientists in the world for 2025, an honor she also received in 2022, 2023, and 2024. In addition to participating in most conferences in Egypt and various international conferences, she attended advanced workshops in the USA in 1994, including training in advanced methods for chromatography at Roche Diagnostics in New Jersey and thermoseparation in Orange County. Furthermore, she served as a lecturer for the Toxi‐lab Company and completed a post‐doctoral fellowship in 2000 at the University of Mississippi (Oxford) in the United States. Throughout her tenure, with fifty‐eight (58) years of experience in natural product research and teaching from 1967 to 2025, she has taught pharmacognosy, phytochemistry, phytotherapy, advanced chromatography, quality control of herbal drugs, tissue culture, and natural cosmetics at Cairo University and various other institutions within and outside Egypt. She also serves as a reviewer for numerous projects, master and doctoral theses, and the Scientific Committee of the National Research Center (NRC), while also participating as a director of the Cairo Scientific Pharmaceutical Students Association (C.S.P.S.). Her extensive research portfolio includes supervising 121 master and doctoral students whose dissertations have been discussed, with 46 students currently still under her supervision. Her work focuses on the isolation, structure elucidation, and study of the biological activity of plant natural products and marine drugs. Academically, she has published 225 articles in international journals and 67 articles in national journals. Her scholarly metrics include an H‐index of 29 from Scopus with 2,888 citations across 2,647 documents and a Field Weighted Citation Impact (FWCI) of 0.98, while her Google Scholar profile shows an i10‐index of 171 and 3,894 citations.

Professor Dr. Sahar A. Khairy, MD, is a Professor of Pediatrics and Clinical Nutrition and a Consultant at the National Nutrition Institute (NNI), Egypt. She previously served as Head of NNI and as a Technical Officer in the Nutrition Department at the WHO Regional Office, and has worked as a WHO Expert Consultant on childhood obesity and as a WFP consultant on vitamin A and micronutrient deficiency programs in Egypt. Her expertise focuses on childhood obesity and malnutrition, with extensive experience in national nutrition policy and program development. She is a member of the Obesity Road Map Egypt Committee (WHO), the Anemia Initiative Committee (UNICEF), and the Iodine Deficiency Disorders Scientific Secretariat of Egypt, and has contributed to national food and nutrition policy initiatives. She has published over 40 scientific papers, reviews, and technical reports in peer‐reviewed journals and international nutrition and public health platforms.

Dr. Sherif A. Hamdy was born in 1988, and graduated from College of Pharmacy, Cairo University in 2011. He received my PhD in 2022 from Institute of Natural Medicine, University of Toyama, Japan. His research expertise lies in the isolation, structural elucidation, and biological evaluation of natural secondary metabolites, with a particular focus on bioactive compounds and their potential therapeutic applications. During his doctoral studies in Japan, he specialized in chemoenzymatic synthesis of biologically active hyphenated natural products (prenylated β‐carbolines) through microbial biotransformation and enzymatic engineering, in addition to functional and structural analysis of proteins using X‐ray Cryastallography. He has published several articles in internationally peer‐reviewed journals on topics ranging from biosynthesis to isolation and characterization of natural bioactives by different spectroscopic techniques.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.