Targeting Neurodegeneration With Naringenin: Mechanistic Perspectives and Therapeutic Implications

ABSTRACT

Neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, retinal neurodegeneration, and spinal cord injury represent a growing global health burden with limited therapeutic options. Natural compounds, particularly flavonoids, have emerged as promising neuroprotective agents. Naringenin (NAR), a citrus‐derived flavanone, exhibits potent antioxidant, anti‐inflammatory, and neuroprotective properties. Recent studies revealed that NAR modulates multiple cellular pathways, including oxidative stress reduction, mitochondrial protection, autophagy induction, inhibition of microglial activation, and suppression of neuroinflammatory signaling such as NF‐κB and NLRP3 inflammasome. Furthermore, NAR has demonstrated the ability to reduce amyloid‐β plaque deposition, inhibit α‐synuclein aggregation, preserve dopaminergic neurons, modulate immune responses in multiple sclerosis, and improve functional recovery after spinal cord injury. This review comprehensively summarizes the mechanistic insights and therapeutic potential of NAR across various neurodegenerative diseases, highlighting its promise as a multifunctional neuroprotective agent and the need for further translational research.

Naringenin, a natural flavonoid, exhibits neuroprotective effects in neurodegenerative diseases by reducing α‐synuclein and Aβ accumulation, suppressing proinflammatory molecules (TNF‐α, IL‐1β, IFN‐γ, and iNOS), and preserving mitochondrial function. It prevents neuronal loss and improves motor and sensory functions. This review explores the molecular mechanisms underlying its therapeutic potential.

1. Introduction

In recent decades, advancements in healthcare and living standards have substantially increased global life expectancy. However, this demographic shift has been paralleled by a rising incidence of neurodegenerative diseases, which have become a significant cause of disability and mortality worldwide. According to the Global Burden of Disease Study 2021, neurological disorders now account for over one‐third of global disease burden, posing immense socioeconomic challenges [1, 2].

Neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and others—are characterized by progressive and selective loss of neurons in the central nervous system (CNS). The clinical manifestations of these disorders are diverse, ranging from cognitive decline and memory loss to motor dysfunction and behavioral disturbances, profoundly affecting patients' quality of life and burdening caregivers and healthcare systems. While aging is a major risk factor, environmental toxins, genetic predisposition, mitochondrial dysfunction, oxidative stress, protein misfolding, neuroinflammation, and impaired autophagy all contribute to the complex pathogenesis of these diseases [1, 3, 4, 5].

Despite decades of intensive research, effective disease‐modifying therapies for most neurodegenerative diseases remain elusive. Current pharmacological treatments primarily provide symptomatic relief without halting or reversing disease progression. For example, cholinesterase inhibitors used in AD, and dopamine replacement therapies used in PD, offer temporary improvements but do not address underlying neurodegenerative processes. Consequently, there is a pressing need to identify novel therapeutic strategies capable of modifying disease progression through multi‐targeted approaches [6, 7, 8, 9, 10].

In this context, natural compounds derived from dietary and medicinal plants are receiving growing attention for their neuroprotective potential. Among these, flavonoids—a large class of plant polyphenols—have demonstrated remarkable pleiotropic effects, including antioxidant, anti‐inflammatory, antiapoptotic, and neurotrophic properties [11]. Flavonoids are abundant in fruits, vegetables, and several beverages. After consumption, flavonoids convert into metabolites, and these metabolites cross the blood‐brain barrier (BBB), interact with neuronal and glial cells, modulate key signaling pathways, and scavenge reactive oxygen species (ROS), thereby offering broad neuroprotective actions [12, 13].

Daily consumption of citrus foods, rich in flavonoids like, naringin, naringenin (NAR), hesperidin, has been proven to improve the brain health and combat the neurodegenerative disease. Mechanistically, citrus flavonoids exert antioxidant, antiapoptotic effect, and anti‐inflammatory effects, modulates autophagy, regulate microRNA (miRNA). These compounds also benefit metabolic health by improving glucose homeostasis, lipid metabolism, and insulin sensitivity, indirectly promoting the brain function. For instance, higher citrus consumption has been linked to lower risk of dementia among Japanese elderly population. Similarly, higher intake of flavonoid rich food has been linked to a reduced risk of PD, declined mortality rate, and improved cognitive function. The experimental and clinical studies further highlight the role of citrus food consumption to reduce amyloid beta deposition, enhance synaptic plasticity, and protect neuron from oxidative stress. Collectively, suggesting the protective role of daily citrus intake across different stages of neurodegeneration, from lowering disease risk to slowing progression and increasing survival rate [14, 15, 16, 17, 18].

One particularly promising flavonoid is NAR, a flavanone predominantly found in citrus fruits such as oranges, grapefruits, and lemons [19]. Traditionally recognized for its antioxidant and anti‐inflammatory effects, NAR has recently emerged as a potential therapeutic agent in the management of various neurodegenerative diseases. Preclinical studies have demonstrated that NAR can modulate diverse molecular pathways involved in neurodegeneration, including inhibition of neuroinflammatory cascades, suppression of oxidative stress, enhancement of mitochondrial function, regulation of autophagy, and promotion of neuronal survival [20, 21].

Importantly, NAR ability to cross the BBB, makes it an attractive candidate for CNS‐targeted therapies [13]. Recent investigations have shown that NAR can attenuate pathological hallmarks such as amyloid‐β (Aβ) accumulation in AD, α‐synuclein aggregation in PD, mitochondrial dysfunction in HD, and neuroinflammation in MS and spinal cord injury (SCI). Furthermore, NAR's favorable pharmacokinetic profile and low toxicity support its potential for clinical development property [19].

Among various naturally occurring flavonoids, NAR has attracted significant scientific interest due to its broad pharmacological activities and promising neuroprotective effects [22]. The unique chemical structure of NAR underpins its capacity to interact with multiple biological targets and traverse the BBB, enabling its action within the CNS [11]. Understanding the chemical properties of NAR is essential to appreciate its diverse bioactivities and its potential as a therapeutic agent for neurodegenerative diseases. In the following section, we provide an overview of the chemical structure and key physicochemical characteristics of NAR that contribute to its neuropharmacological profile.

2. Chemical Structure and Properties of Naringenin

Naringenin (C₁₅H₁₂O₅) is a naturally occurring flavonoid belonging to the flavanone subclass of polyphenolic compounds. It is predominantly found in citrus fruits such as grapefruits, oranges, and lemons, and is largely responsible for their characteristic bitter taste [19]. Chemically, NAR consists of a typical flavanone backbone characterized by a 15‐carbon skeleton (C₆‐C₃‐C₆), comprising two phenolic rings (A and B) linked by a heterocyclic pyran ring (C ring) (Figure 1) [23, 24].

FIGURE 1.

Structure of naringenin (NAR) (created with ChemDraw).

Structurally, NAR is defined as 5,7,4′‐trihydroxyflavanone, featuring hydroxyl groups at positions 5 and 7 on the A‐ring and at position 4′ on the B‐ring. These hydroxyl substitutions are critical for its potent antioxidant activity, allowing it to scavenge free radicals and chelate metal ions. The molecule is typically colorless and flavorless in its pure form, with moderate hydrophobicity. NAR is soluble in organic solvents like ethanol, methanol, and dimethyl sulfoxide [24, 25, 26].

Beyond its well‐established antioxidant capacity, NAR acts as an anti‐inflammatory, free radical scavenger, modulator of immune responses, and promoter of mitochondrial function. These multifunctional properties are largely attributed to its unique chemical structure, which facilitates interactions with diverse cellular targets and signaling pathways [27].

Recent studies have highlighted that NAR modulates key molecular cascades involved in neuronal survival, including the PI3K/Akt, MAPK, NF‐κB, Nrf2/HO‐1, and AMPK‐mTOR‐autophagy pathways. Its structural characteristics enable direct and indirect modulation of these pathways, supporting its emerging role as a multifunctional neuroprotective and potential therapeutic agent [28].

In summary, the chemical structure of NAR is intricately linked to its broad pharmacological properties (Figure 2), and its BBB permeability makes it a particularly attractive candidate for targeting neurodegenerative diseases. In the following sections, we discuss in detail the molecular mechanisms through which NAR exerts its neuroprotective effects across various models of neurodegeneration.

FIGURE 2.

Schematic illustration of naringenin (NAR) multi‐diverse pharmacological effect (created with BioRender).

3. Pharmacokinetic Properties of Naringenin

3.1. Absorption

The oral bioavailability of NAR is low (∼15%) as the compound has low aqueous solubility and rapidly undergoes first‐pass metabolism [29, 30]. NAR is mainly absorbed through the intestine, and absorption mainly takes through passive transport [31]. In vitro study using Caco‐2 intestinal cells demonstrated that NAR has only modest permeability. Moreover, the study reported NAR undergoes partial passive transport. The absorption is largely restricted by active efflux through transporters such as P‐glycoprotein, multi‐drug resistance associated protein 1 (MRP1), and MRP2, while organic anion transporting protein B does not appear to contribute [32]. A study by Xu et al. reported that NAR is well absorbed from intestine, where 68% of NAR got absorbed through colon, 47% from duodenum, 42% from terminal ileum, and 37% from jejunum [33]. These efflux processes effectively recycle the compound back into the intestinal lumen, accounting for its low oral bioavailability. Consistent with this finding, a clinical study revealed, NAR upon oral ingestion showed rapid, dose‐proportional absorption. A 135 mg pure aglycone capsule achieved maximum plasma concentration (C _max) = 7.4 µM at 3.7 h, while the 150 mg dose as a whole‐orange extract doubled exposure C _max = 15 µM, time to peak drug concentration (T _max) = 3.2 h. Similarly, higher doses (600 and 900 mg) further increased C _max up to fourfold with T _max = 2–2.5 h. Furthermore, the study reported enhanced synergistic effect when given as a whole‐orange capsule extract than as a solid dispersion capsule. The elimination half‐life remained consistent across doses (2.6–3 h) [31, 34, 35, 36]. According to Kanaze et al. [34], the oral bioavailability of NAR was 5.81%.

3.2. Distribution

After absorption NAR and its conjugates binds strongly to plasma protein and are widely distributed to metabolically active tissues including liver, kidney, lung, heart, and brain. One of the important pharmacokinetic properties of NAR is its ability to cross the BBB. Youdim et al. demonstrated through in situ permeability studies that NAR exhibits sufficient lipophilicity and molecular size to traverse the BBB. This property underpins its potential as a neuroprotective agent capable of exerting effects within the CNS [13, 37].

3.3. Metabolism

NAR undergoes extensive phase II metabolism, including glucuronidation and sulfation, primarily in the intestine and liver [31, 32, 36]. Lin et al. concluded that NAR sulfates were the primary metabolites in liver, spleen, heart, and brain, while NAR glucuronides were present in liver and kidney [38]. In addition, microbial metabolism in the gut produces phenolic catabolites such as hippuric acid and 3‐(4′‐hydroxyphenyl) propionic acid, which may contribute to systemic effects [29]. In the preclinical rat study by Wang et al. pretreatment with NAR (150 mg/kg/day for 2 weeks) markedly affected tofacitinib pharmacokinetic properties: T _max was delayed from 0.75 to 3.00 h, AUC₀–₂₄ increased by 65%, mean residue time extended by 34%, and clearance decreased by 41%. This suggests the inhibition of metabolic clearance pathways, possibly involving CYP450 enzymes, results in extended systemic exposure. Although there is not any exact information on excretion, the reduced clearance and prolonged mean residue time indicate declined elimination [39].

3.4. Elimination

Excretion occurs mainly through the urinary pathway, with NAR glucuronides and sulfates being the dominant excreted metabolites. Only trace amounts of unchanged NAR are detected in urine or feces. But some metabolites can be deconjugated by gut microbiota and reabsorbed, enabling enterohepatic recirculation. The plasma half‐life ranges from 2 to 5 h, reflecting relatively rapid clearance. Aged animals exhibit higher systemic exposure and delayed elimination compared to younger ones, highlighting the influence of physiological aging on pharmacokinetics [29, 36, 37].

3.5. Why Naringenin?

Although several flavonoids, including quercetin, kaempferol, and resveratrol, demonstrate neuroprotective effects, NAR exhibits some unique advantages. Quercetin and kaempferol are potent antioxidants but show limited BBB permeability due to glycosylation and high polarity [40, 41]. Resveratrol, despite its broad bioactivity, has been shown rapid metabolism and extremely low oral bioavailability (<1%) [41, 42]. In contrast, NAR is relatively small, lipophilic, and exists primarily in its aglycone form, conferring higher BBB penetration and enabling direct action on neuronal and glial targets. Moreover, while quercetin and resveratrol mainly modulate oxidative stress and sirtuin signaling, NAR exerts a broader spectrum of activity, including inhibition of NLRP3 inflammasome activation, promotion of autophagy, and modulation of dopaminergic signaling. These features suggest that, compared to other flavonoids, NAR offers a more favorable balance between pharmacokinetics, CNS bioavailability, and mechanistic diversity, positioning it as a promising candidate for translational development [43, 44, 45, 46].

4. Neuroprotective Effects of Naringenin in Neurodegenerative Diseases

4.1. Naringenin and Alzheimer's Disease

4.1.1. Overview of AD Pathophysiology

AD is characterized by extracellular accumulation of Aβ plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau is a microtubule associated protein situated in the axons of healthy neurons. This protein is essential for proper neuronal functioning and transporting molecules and organelles. The exact mechanism for tau and Aβ is unknown. Some of the hypothesis states that in AD, the toxic Aβ deposit and axonal damage result in axonal sprouting. This phenomenon is influenced by tau detachment from microtubules after tau undergoes numerous modifications like phosphorylation, acetylation, and O‐glycosylation. This detachment disrupts axons and contributes to cell death. Similarly, other pathological hallmarks like oxidative stress, inflammation, mitochondrial dysfunction, and neuronal apoptosis disrupt BBB and leads to AD [20, 47, 48, 49].

4.1.2. Genetic Factor

Genetic predisposition plays a pivotal role in the pathogenesis of AD, especially in early‐onset familial cases. Mutations in the amyloid precursor protein (APP) gene on chromosome 21 have been shown to increase the accumulation of neurotoxic Aβ peptides. Similarly, mutations in presenilin‐1 (PSEN1) and presenilin‐2 (PSEN2), located on chromosomes 14 and 1 respectively, disrupt the normal processing of APP and enhance the production of the more aggregation‐prone Aβ42 isoform. The apolipoprotein E (ApoE) gene, particularly the ε4 allele, is a well‐established risk factor for late‐onset AD due to its involvement in amyloid deposition and impaired clearance. Other genes, such as ABCA1, CLU, BIN1, and ECSIT, have also been associated with AD [50, 51].

4.1.3. Environmental Factor

Similarly, environmental factors also significantly contribute to the development and progression of AD by exacerbating neuroinflammation and oxidative stress. Chronic exposure to air pollutants such as nitrogen oxides, particulate matter, and ozone has been linked to increased formation of amyloid plaques and hyperphosphorylated tau, particularly in brain regions critical for memory [52]. Furthermore, certain metals, including aluminum, lead, and cadmium, have neurotoxic effects that promote protein misfolding and synaptic dysfunction [49]. Dietary habits can also cause AD. Diets high in saturated fats and advanced glycation end products are associated with elevated oxidative stress and inflammation, while deficiencies in essential nutrients like folate, vitamin B12, and vitamin D may impair cognitive function and increase susceptibility to AD [53].

4.1.4. Anti‐inflammatory and Antiapoptotic Effects of NAR

NAR has been shown to inhibit pro‐inflammatory signaling pathways in LPS/Aβ‐stimulated BV2 microglial cells. Specifically, it suppresses MAPK (p38, JNK, ERK1/2) and NF‐κB signaling, leading to decreased expression of tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), inducible nitric oxide synthase (iNOS), and cyclooxygenase‐2 (COX‐2) [20]. In vivo, long‐term NAR treatment reduced Aβ plaque burden in APP/PS1 transgenic mice and attenuated hippocampal astrogliosis and microgliosis. Additionally, NAR modulated the PI3K/Akt pathway to inhibit neuronal apoptosis by reducing caspase‐3 and pro‐apoptotic markers while enhancing Bcl‐2 and Bcl‐xL levels (Table 1) [54, 55].

TABLE 1.

Neuroprotective effect of naringenin in Alzheimer's disease.

Model type	Dose and route of administration	Key findings	References
In vitro; LPS/Aβ‐stimulated BV2 microglial cells	50 and 100 µM	Inhibits MAPK (p38, JNK, and ERK1/2) and NF‐κB signaling, reducing TNF‐α, IL‐1β, iNOS, and COX‐2 expression	[20]
In vivo; APP/PS1 transgenic mice	50 mg/kg; per‐oral	Attenuates neuronal apoptosis by downregulating caspase‐3 level and upregulating Bcl‐2 and Bcl‐xL level through PI3K/Akt pathway, hence diminishing Aβ plaques	[54, 55]
In vitro; N2a cell	50 µM	Activates AMPK, inhibits mTOR, enhance expression of autophagy proteins (beclin1, ATG5, and ATG7), and ameliorates mitochondrial function by reducing ROS generation	[21, 56]
In vivo; TMT‐induced male Wistar rats	25 and 100 mg/kg; per‐oral	Protects neuron from oxidative stress by decreasing MDA, nitrite, TNF‐α, and acetylcholinesterase level in hippocampus, while enhancing antioxidant markers SOD, CAT, and GPx	[58, 59]
In vitro; SH‐SY5Y neuroblastoma cells	100 µM (nano‐emulsion)	Mitigates Aβ toxicity by modulating oxidative stress through the downregulation of ROS, APP & BACE1, and p‐Tau T231 levels, promotes M2 polarization, and upregulates neprilysin and insulin‐degrading enzyme, thereby reducing Aβ accumulation	[20, 60, 61]
In vivo; rat (ICV‐STZ model of AD)	50 mg/kg; per‐oral	Mitigates oxidative stress, Aβ deposition, and hippocampal injury hence improving cognitive function, and memory retention	[59]

4.1.5. Enhancement of Autophagy and Mitochondrial Function

NAR activates AMPK and inhibits mTOR, promoting autophagy and clearance of Aβ plaques. This process involves increased expression of autophagy‐related proteins (Beclin1, ATG5, ATG7) [21, 56]. Concurrently, NAR improves mitochondrial function and reduces ROS production, contributing to neuronal survival [57]. NAR (100 mg/kg) prevented trimethyl tin‐induced loss of mitochondrial membrane potential, thus preserving the mitochondrial integrity (Table 1) [58].

4.1.6. Neuroprotection via Oxidative Stress Reduction

Oxidative stress occurs when there is an imbalance between pro‐oxidants and antioxidants, leading to the accumulation of harmful ROS resulting in neurodegenerative disease. This imbalance results from either excessive production of free radicals or a decline in the body's antioxidant defenses. NAR protected the neurons from oxidative stress by reducing the marker, such as 4‐HNE, TNF‐α, nitrite, MDA, TBARS, acetylcholinesterase, and H₂O₂, while restoring the activity of antioxidant enzymes like SOD, CAT, and GPx in the hippocampus (Table 1). Additionally, NAR preserved ChAT‐positive neurons and reduced histopathological damage to hippocampal neurons [58, 59].

4.1.7. Aβ Clearance

Aβ plaque is highly neurotoxic and plays a pivotal role in AD pathogenesis. Reduction in Aβ accumulation is considered therapeutically beneficial [20]. Importantly, NAR promotes microglial polarization toward an anti‐inflammatory M2 phenotype, upregulating Aβ‐degrading enzymes such as neprilysin and insulin‐degrading enzyme [60]. Nano‐emulsion of 100 µM NAR protected the SH‐SY5Y cells from Aβ toxicity. NAR reduced oxidative stress by lowering ROS and downregulated the expression of APP and β‐secretase (BACE1), both of which are involved in amyloid plaque formation. Furthermore, NAR also decreased phosphorylated tau (p‐Tau T231) levels [61]. As summarized in Table 1, the dual action on inflammation and Aβ clearance underscores NAR therapeutic potential in AD.

4.1.8. Cognitive Improvement

Behavioral studies demonstrate that NAR improves memory retention and cognitive function in animal models of AD, suggesting its ability to mitigate functional deficits [20, 57]. NAR pretreatment (50 mg/kg, orally for 2 weeks) improved the cognitive dysfunction, hippocampal neuron injury, and reduced oxidative stress in a rat model of AD‐type neurodegeneration with cognitive impairment (AD‐TNDCI), induced by intracerebroventricular‐streptozotocin (ICV‐STZ) [59]. In addition to its antiapoptotic effects, NAR also exhibited neuroprotective properties by significantly reducing Aβ plaque deposition, highlighting its potential as a multifunctional therapeutic agent in neurodegenerative disorders (as summarized in Table 1).

4.2. Naringenin and Parkinson's Disease

4.2.1. Overview of PD Pathology

PD is the second most prevalent neurodegenerative disease after AD. Parkinson is characterized by dopaminergic neuronal loss from the substantial‐nigra par compacta. Most of the therapeutic agents currently being used gives symptomatic relief only thus, creating a need for novel therapeutic agent to cure this disease. The exact reason behind PD is not fully understood. However, the key feature of PD is accumulation of ewy bodies. Misfolding of α‐synuclein is observed in PD which leads to impaired autophagy lysosomal pathway (ALP) and ubiquitin proteasome system (UPS), mitochondrial dysfunction, endoplasmic reticulum stress, metabolic deficiencies, oxidative stress, eventually leading to neuronal death [62, 63, 64, 65].

4.2.2. Reduction in α‐Synuclein Aggregation

Recent studies have highlighted the anti‐amyloidogenic potential of flavonoids against α‐synuclein aggregation. Computational analyses identified NAR as a potent polyphenolic compound capable of interacting with α‐synuclein and potentially inhibiting its aggregation process [66]. In addition, structurally related citrus flavonoids such as hesperetin have been shown to inhibit α‐synuclein fibrillogenesis, destabilize preformed fibrils, and reduce fibril related cytotoxicity in both in vitro and in vivo models. Furthermore, gold nanoparticles functionalized with NAR effectively suppressed α‐synuclein fibril formation by stabilizing its monomeric conformation [67]. Collectively, these findings support the therapeutic potential of NAR and related flavonoids in preventing pathological α‐synuclein aggregation and promoting neuronal protection through modulation of protein misfolding and neuroinflammatory pathways, as summarizedin Table 2 [68].

TABLE 2.

Neuroprotective effect of naringenin in Parkinson's disease.

Model type	Dose and route of administration	Key findings	References
In vivo and in vitro; C57BL/6J MPTP‐induced male mice	25, 50 and 100 mg/kg NAR once a day; per‐oral and NAR‐gold nanoparticle	Reduce α‐synuclein aggregation and improves the locomotor function, reduce the expression of pro‐inflammatory mediators, that is, NO, TNF‐α, and IL‐1β. Inhibition of MAO and elevation in SOD and GSH level increase the expression of DAT and TH, attenuates H2O2 production and protects dopaminergic neurons	[68, 73]
In vitro; methylglyoxal‐treated SH‐SY5Y cells	80 µM NAR	Mitochondrial protection by activating Nrf2 signaling pathway, thus boosting antioxidant defense system (GSH production)	[70, 71]
In vitro; LPS‐stimulated BV2 + MN9D coculture	40 µM NAR	Dopamine neuroprotection via depleting the expression of NLRP3, ASC, cleaved caspase‐1, which in turn lowers the release of mature IL‐1β and IL‐18 through NLRP3 inflammasome signaling	[43, 72]
In vivo; LPS‐induced male rats; paraquat‐induced rat	40, 50, and 100 mg/kg NAR; intra‐gastric	Neuroprotection by modulating mRNA expression of genes like DAT, DRD2, leucine‐rich repeat kinase‐2, α‐synuclein, β‐catenin, caspase‐3, and BDNF, upregulation of TH level and decline in GFAP improving dopaminergic function	[43, 74]

4.2.3. Mitochondrial Protection via Nuclear Factor Erythroid‐2 Related Factor (Nrf2) Pathway Activation

Mitochondrial dysfunction is the major hallmark for neurodegenerative disease, which frequently leads to an excessive production of ROS and reactive nitrogen species [69]. This process aggravates neuroinflammation and leads to neuronal damage. In a study using methylglyoxal‐treated SH‐SY5Y neuroblastoma cells, NAR (80 µM) was shown to protect mitochondrial function by activating the Nrf2 signaling pathway. The Nrf2 pathway is activated by the dissociation of Nrf2 from its cytosolic inhibitor, Keap1, allowing its translocation to the nucleus where it drives the transcription of antioxidant genes. This activation led to increased expression of the γ‐glutamyl cysteine ligase subunits, GCLC and GCLM, which play a key role in boosting glutathione (GSH) production, a critical component in the body's antioxidant defense system. These results support the notion that NAR contributes to redox equilibrium and mitochondrial resilience during oxidative stress as discussed in Table 2 [70, 71].

4.2.4. NLRP3 Inflammasome Inhibition

Neuroinflammation driven by microglial NLRP3 inflammasome activation is a critical contributor to dopaminergic neurodegeneration in PD. Table 2 reports NAR neuroprotective effect in LPS‐induced neurotoxicity, where, NAR exhibit dopamine neuroprotection by suppressing microglia‐induced neuro‐inflammation via NLRP3 inflammasome inhibition. NAR significantly reduced the expression of NLRP3, ASC, and cleaved caspase‐1, thereby lowering the release of mature IL‐1β and IL‐18. In vitro, similar outcomes were observed in LPS‐stimulated BV2 microglia cocultured with MN9D neurons, where NAR attenuated microglial activation and protected neuronal viability. Notably, silencing NLRP3 with siRNA abrogated the protective effects of NAR, confirming that its neuroprotective actions are mediated, at least in part, through the suppression of NLRP3 inflammasome signaling [43, 72].

4.2.5. Anti‐inflammatory and Antioxidant Effect

NAR treatment significantly reduced the expressions of pro‐inflammatory mediators such as nitric oxide (NO), TNF‐α, and IL‐1β. Moreover, the generation of NO was decreased through downregulating the expression of iNOS and COX‐2. Furthermore, the expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH) was increased through inhibition of monoamine oxidase (MAO) activity. The inhibition of MAO not only reduces oxidative deamination of dopamine but also limits the production of neurotoxic hydrogen peroxide, thereby preserving dopaminergic function. Activation of nitric oxide–cyclic GMP–protein kinase G–ATP‐sensitive potassium channel (NO–cGMP–PKG–KATP) signaling pathway further inhibited superoxide‐driven neuro‐inflammation. Table 2 summarizes these mechanisms, combined with an increase in superoxide dismutase (SOD) activity and elevated GSH levels, thus highlighting NAR potent antioxidant capacity. Also, this effect preserves DAT and TH‐positive dopaminergic from oxidative damage [73].

4.2.6. Cellular Protection and Gene Regulation

The protective effects of NAR extend beyond antioxidative activity to the regulation of genes associated with neuronal survival and function. NAR is associated with its potential to enhance cell viability, reduced oxidative stress, elevated mitochondrial membrane potential, and increase ATP levels in SH‐SY5Y cells. In a paraquat‐induced rat in vivo model of neurotoxicity and neurodegeneration, NAR demonstrated neuroprotective effects by influencing the mRNA expression of several key genes including dopamine receptor D2 (DRD2), DAT, leucine‐rich repeat kinase‐2, synuclein, β‐catenin, caspase‐3, and brain‐derived neurotrophic factor (BDNF). NAR also upregulated the TH protein levels and altered its immunoreactivity within the striatum, suggesting improved dopaminergic function. Furthermore, a decline in glial fibrillary acidic protein (GFAP) suggested a concurrent reduction in astrogliosis activation, indicating NAR dual role as both anti‐inflammatory and neuroprotective properties as discussed in Table 2 [43, 74].

4.3. Naringenin and Retinal Neurodegeneration

4.3.1. Pathology of Retinal Degeneration

Every human being needs vision for basic survival. A visual impairment will make a person more dependent on others by restricting their daily activities. Visually impaired people not only face physical challenge but are more likely to suffer from social and mental health problems such as depression, anxiety, thus reducing their quality of life [75, 76].

Loss of vision is the ultimate consequence of retinal neurodegeneration, a multifactorial and multi‐etiological condition that affects photoreceptor cells, retinal cells, and retinal pigment epithelium [77]. Among these neurodegenerative conditions are retinitis pigmentosa (RP), age‐related macular degeneration (AMD), diabetic retinopathy (DR), and Stargardt's disease. Gene mutations, environmental stress and dysmetabolic processes are some of the major causes for retinal disorders, eventually leading to progressive decline in visual function and blindness [78].

Retina is a polyunsaturated lipid membrane with a high aerobic metabolism, susceptible to changes in oxygen concentration and oxidative stress. Effect of oxidative stress plays a varying role in various retinal diseases, such as: in AMD, oxidative stress leads to dysmetabolic events, misfolded proteins, and drusen deposition. Likewise, in RP, oxidative stress further advances the disease progression, leading to rod death and cone degeneration. Similarly, in DR, elevated oxidative stress results in severe lipid peroxidation, protein oxidation, and oxidative DNA damage leading to retinal damage. Furthermore, alteration in signal transduction and pro/antiapoptotic protein expression can be observed in DR [78, 79, 80].

Microglia are the first line of defense in the CNS, analyze the environment and interact with neurons, astrocytes, oligodendrocytes, and invasive immune cells. In the retinal neurodegeneration, the microglia get activated and release the chemokines and cytokines thus resulting in apoptosis of photoreceptor cells [81]. The release of caspase dependent proinflammatory cytokines IL‐1β and IL‐18 causes tissue damage and cell death in retina. Figure 3 depicts the pathophysiology involved in retinal neurodegeneration [82, 83].

FIGURE 3.

Overview of retinal neurodegeneration pathology. Gradual loss of retinal cells, degeneration of photoreceptor cells, and failure of retinal pigment epithelium (RPE) due to the activation of microglia and release of proinflammatory cytokines IL‐1β and IL‐18 (created with BioRender).

4.3.2. Anti‐inflammatory Effect and Neuroprotection

While NAR does not directly influence the enzymes or steps of the retinoid cycle (the metabolic pathway of vitamin A), the overall cellular health promotes indirectly supports the function of retinoid‐dependent processes. Long‐term oral administration of NAR on aged‐mice showed protective effect against age‐associated retinal degeneration. Along with this, NAR treatment preserved retinal structure and improved the visual function as summarized in Table 3 [79, 84]. During neuroinflammation, activated microglia release various cytokines and chemokines that contribute to neuronal damage. NAR, at a concentration of 50 µM, was found to significantly reduce this inflammatory response by modulating microglial activation. In LPS‐stimulated BV2 microglial cells and primary murine microglia, NAR suppressed the expression of key pro‐inflammatory markers such as IL‐1β, IL‐6, CCL2, iNOS, and CD86. At the same time, it promoted an anti‐inflammatory phenotype, indicated by increased CD206 expression [85].

TABLE 3.

Neuroprotective effect of naringenin in retinal neurodegeneration.

Model type	Dose and route of administration	Key findings	References
In vitro; LPS‐induced BV 2 microglia cell	50 µM NAR pre‐treated BV 2 cells	Attenuates neuronal damage by reducing the expression of proinflammatory cytokines like IL‐1β, IL‐6, CCL2, iNOS, and CD86, while enhancing CD206 expression	[85]
In vitro; BV2 + 661 W photoreceptor‐like cells (co‐treatment) and primary rat cortical neurons	50 µM NAR pre‐treated BV 2 cells and 80 µM NAR	Upregulates the expression of cytochrome‐c, complex IV, Tom20 through the activation of Nrf2/ARE pathway, and mitigates apoptosis by reducing cleaved caspase‐3 levels in 661 W cells hence improving mitochondrial function	[85, 86]
In vivo; streptozotocin (STZ)‐induced diabetic rats	50 mg/kg/day NAR for 4 weeks; per‐oral	Restrain oxidative stress by inhibiting mitochondrial apoptosis through upregulation of Bcl‐2 and downregulation of Bax, caspase‐3 levels, enhanced neurotrophic signaling and synaptic protection by upregulating BDNF, TrkB, and synaptophysin expression	[79]
In vivo; kunming mice with NaIO3 induced retinal degeneration	1% NAR topical eye drop; one drop thrice a day; 1–2 day or 10 days after NaIO3 injection	Improves retinal morphology, enhance activation of Nrf2 and HO‐1 at early stage (2 day), and normalize their levels at late stage (10 day)	[80]

4.3.3. Effect on Oxidative Stress

According to AI‐Dosari et al. NAR counteracted oxidative stress by restoration of GSH and suppression of lipid peroxidation, while simultaneously inhibiting mitochondrial apoptosis via regulation of Bcl‐2, Bax, and caspase‐3. Also, NAR enhanced neurotrophic resilience by restoring BDNF/TrkB and synaptophysin expression [79].

Likewise, Chen et al. reported, NAR ability to mitigate oxidative and apoptotic stress in retinal pigment epithelium and photoreceptors, while simultaneously, improving mitochondrial function and autophagy through Sirtuin1 and Nrf2/HO‐1 mediated pathway. Even though there is no direct effect observed in the retinoid cycle enzyme, these effects may subsequently attenuate the accumulation of detrimental retinoid by‐products (e.g., bis‐retinoids and all‐trans‐retinal) [80].

4.3.4. Mitochondrial Function Regulation and Antiapoptotic Effect

NAR protective effects were linked to the regulation of mitochondrial dynamics, promoting fusion while reducing excessive fission and the activation of autophagy through the AMPK/mTOR signaling pathway. By restoring mitochondrial balance and enhancing cellular clearance NAR maintain the retinal homeostasis and delays neurodegenerative changes associated with aging [84].

Moreover, NAR enhanced mitochondrial function, as seen by upregulated expression of respiratory chain components like cytochrome c, complex IV, and Tom20, while maintaining glycolytic gene expression. These metabolic improvements were accompanied by activation of the Nrf2/ARE antioxidant pathway, which plays a critical role in its anti‐inflammatory effect. In addition, microglia pre‐treated with NAR were less toxic to 661 W photoreceptor‐like cells, as shown by reduced apoptosis and lower levels of cleaved caspase‐3. Together, these results implicate NAR has a potent therapeutic efficacy for treating retinal neurodegeneration as summarized in Table 3 [85, 86].

4.4. Naringenin and Huntington's Disease

4.4.1. Overview of HD Pathogenesis

HD is a hereditary neurodegenerative disease characterized by the gradual breakdown of nerve cells, ultimately leading to the neuronal death in certain parts of the brain. The pathophysiology of HD is not fully understood, but it is thought that the disease pathogenesis is multifactorial which involves toxic gain‐of‐function effects of mutant huntingtin (mHTT). As shown in Figure 4, this mutant protein compromises neuronal integrity through excitotoxicity, neuronal aggregates, transcriptional dysregulation, neuro‐inflammation, changes in axonal transport and synaptic signaling, mitochondrial dysfunction, and altered energy metabolism. Huntingtin protein is produced due to abnormal expansion on cytosine, adenine, and guanine trinucleotide repeats on the short arm of chromosome 4p16.3 in the Huntingtin (HTT) gene, resulting in elongated polyglutamine (PolyQ) amino acid tract elongation in the N‐terminus of the HTT protein. PolyQ‐expanded HTT misfolds and accumulates, inducing endoplasmic reticulum stress and reducing the expression of GRP78 glucose‐regulated chaperone protein. Furthermore, the accumulation of mHTT protein affects specific areas of the brain, predominantly the basal ganglia and cerebral cortex, causing a range of motor, cognitive, and psychiatric symptoms. While, the HTT protein is thought to possess antiapoptotic property and protect from mutant HTT gene, these functions are disrupted by PolyQ expansion. People with HD suffer from uncontrollable dance‐like movement (chorea), cognitive impairment, and dementia. Although no curative therapy exists, numerous promising strategies are under preclinical and clinical evaluation [87, 88, 89].

FIGURE 4.

Overview of Huntington's disease (HD) pathology. Caused by mutation on cytosine, adenine, and guanine (CAG) trinucleotide repeats on the short arm of chromosome 4p16.3 in the huntingtin (HTT). This mutation causes the toxic accumulation of mHTT protein which affects the brain especially, basal ganglia. excitotoxicity, transcriptional dysregulation, changes in axonal transport and synaptic dysfunction, mitochondrial dysfunction, and altered energy metabolism causes neuronal aggregation, neuroinflammation in the brain, leading to impaired cognitive function like dementia, and motor dysfunction like chorea (created with BioRender).

4.4.2. Improved Motor Function and GRP78 Protein Expression

NAR demonstrated significant neuroprotective effect when administered at doses of 25 mg/kg and 75 mg/kg, in the 3‐nitropropionic acid (3‐NP)‐induced model of HD. NAR treatment resulted in significant improvement in motor coordination and overall, locomotor activity [90]. Similarly, the cotreatment of NAR (50 mg/kg) with 3‐NP improved the motor coordination and behavior [91].

Also, NAR upregulated the ER chaperone GRP78 expression in dose dependent manner in HeLa‐tetQ97 cell, with peak activity at 50 µM. As mentioned in Table 4, this upregulation reduced the PolyQ protein aggregation and conferred neuroprotection, highlighting the potential of NAR as a therapeutic candidate against mHTT protein toxicity [92].

TABLE 4.

Neuroprotective effect of naringenin in Huntington's disease.

Model type	Dose and route of administration	Key findings	References
In vivo; 3‐NP‐induced albino Wistar rat model	50 mg/kg NAR twice daily; per‐oral	Increase monoamine and serotonin levels in striatum, decrease GFAP astrocytes activation hence, minimizing the neuronal death, and improves motor function	[91]
In vivo; 3‐NP‐induced Wistar male rat model	25 and 75 mg/kg NAR; per‐oral	Provides mitochondrial protection by modulating oxidative stress and oxidative biomarkers; improves motor coordination and locomotor activity	[90]
In vitro; HeLa‐tetQ97	50 µM NAR	Upregulate GRP78 protein expression thus reducing poly Q aggregates; bestowing neuroprotection	[92]

4.4.3. Mitochondrial Protection and Antioxidant Effect

Additionally, NAR preserved mitochondrial function, which is often dysregulated in neurodegenerative disease. These neuroprotective outcomes are largely attributed to NAR strong antioxidant properties, which help to counteract oxidative stress, a major contributor to neuronal damage in HD. This is supported by observed reductions in oxidative biomarkers following NAR administration in 3‐NP‐treated animals, indicating that its therapeutic efficacy is largely mediated through antioxidant mechanisms as shown in Table 4 [90].

4.4.4. Anti‐inflammatory Effect

Also, significant reduction in GFAP‐positive astrocytes were reported indicating NAR anti‐inflammatory potential against 3‐NP‐induced neurotoxicity. Likewise, the striatal neuron loss, serotonin (5‐HT), and MAO activity was ameliorated by NAR treatment. Along with these effects, the neuroprotective properties of NAR, which are mediated by its anti‐inflammatory and antioxidant activities, are further highlighted by a decline in GFAP astrocyte activation. Based on these neuromodulating properties, NAR might be used as an effective therapeutic agent for mitigating the neuronal cell death and dysfunction caused by HD as shown in Table 4 [91].

4.5. Naringenin and Multiple Sclerosis

4.5.1. Overview of MS Pathology

MS is a chronic autoimmune neurological disorder characterized by formation of inflammatory plaques, causing demyelination and axonal loss in the CNS. These lesions are predominantly found in the white matter surrounding the ventricles, optic nerves, spinal cord, and other key brain regions [93]. In MS, overactive immune cells especially T‐helper 1(Th1) and T‐helper 17 (Th17) lymphocytes which cross the BBB, trigger inflammation in the CNS leading to demyelination, inflammation around blood vessels, and destruction of oligodendrocytes. Particularly Th17 subsets (specifically IL‐17 and IFN‐γ), are enriched in both relapsing‐remitting and secondary‐progressive MS, driving inflammatory relapses. In some MS patients IL17 blockage has shown reduction in new lesion formation. Together with this proinflammatory cytokine, CD4+ and CD8+ T cells, further contribute to the tissue damage. The presence of Epstein‐Barr virus‐infected (EBV) B cells can make the condition worse by boosting antigen presentation and evading immune defenses due to the fatigue of virus‐targeting CD8+ T cells. The EBV‐infected B cells may drive disease through molecular mimicry, specifically between EBV nuclear antigen EBNA1 and the glial protein GlialCAM, promoting autoreactive immune responses. Additionally, activated microglia and macrophages release neurotoxic pro‐inflammatory factors such as TNF‐α, IL‐1β, glutamate, and ROS, resulting in oxidative stress and neuronal loss as described in Figure 5 [94, 95, 96, 97, 98, 99, 100, 101, 102].

FIGURE 5.

Overview of multiple sclerosis (MS) pathology. Deposition of the white (inflammatory) plaques or lesions in the different parts of the brain is major hallmark in MS. Overactivation of Th‐1 and Th17 cells triggers cascade of inflammatory response, leading to myelin loss and neuronal damage. Th1 derived cytokines (IFN‐γ and TNF‐α) and Th17‐associated mediators (IL‐17, IL‐22) stimulate CD4⁺ and CD8⁺ T lymphocytes exacerbating neuroinflammation. Similarly, Epstein–Barr virus (EBV)‐infected B cells further aggravate the conditions by activating autoreactive CD4⁺ and CD8⁺ T lymphocytes eventually causing neuronal damage and demyelination. Furthermore, activated microglia release pro‐inflammatory cytokines (TNF‐α and IL‐1β), reactive oxygen species (ROS), and glutamate, collectively amplifying oxidative stress and neuroinflammation. The resulting oxidative damage and excitotoxicity contribute to oligodendrocyte loss, neuronal injury, and demyelination, resulting in impaired neuronal signaling and neurodegeneration (created with BioRender).

4.5.2. Suppression of Pro‐inflammatory Cytokines and Cell Migration Molecules

In an experimental autoimmune encephalomyelitis (EAE) mice model dietary supplementation with NAR at 0.5% significantly delayed disease onset and alleviated clinical severity. NAR administration reduced immune cell infiltration and demyelination within the CNS. This effect was accompanied by a downregulation of pro‐inflammatory CD4⁺ T cell subsets including Th1, Th9, and Th17, as well as their transcriptional regulators T‐bet, PU.1, and RORγt. Furthermore, NAR markedly decreased expression of pro‐inflammatory cytokines such as TNF‐α and IL‐6. NAR also inhibited the expression of cell adhesion and chemotactic molecules involved in leukocyte migration across the BBB, such as CXCL10, vascular cell adhesion molecule‐1 (VCAM‐1), and very late antigen‐4 (VLA‐4) [103].

Additional evidence shows that NAR reduces the infiltration of pathogenic T cells into the CNS by downregulating chemokines such as CCL19 and its receptor CCR7, which are critical for lymphocyte trafficking. NAR also suppressed the accumulation and maturation of conventional dendritic cells in CNS tissues. In peripheral immune organs such as the spleen, NAR administration led to a significant reduction in IFN‐γ, IL‐17, and IL‐6 levels, indicating systemic immunomodulatory effects [104]. Moreover, dietary supplementation with 2.0% NAR significantly attenuated EAE symptoms. Spinal cord tissues analysis revealed reduced expression of genes associated with immune activation and inflammation, further supporting NAR role in modulating neuroinflammatory processes as shown in Table 5 [105].

TABLE 5.

Neuroprotective effect of naringenin in multiple sclerosis.

Model type	Dose and route of administration	Key findings	References
In vivo; EAE C57BL/6 female mice	0.5% dietary NAR supplement; per‐oral	Delayed disease onset, reduce CNS demyelination and immune cell infiltration via downregulation of Th1, Th9, Th17 subset, and their transcriptional regulators T‐bet, PU.1, RORγt, reduce expression of proinflammatory cytokines like TNF‐α and IL‐6, inhibition of CXCL10, VCAM‐1, and VLA‐4 molecules	[103]
In vivo; EAE C57BL/6 female mice	0.5% dietary NAR supplement; per‐oral	Immunomodulation by reducing T‐cell infiltration via downregulation of CCL19/CCR7, minimize the dendritic cell maturation and accumulation in CNS, decrease the level of proinflammatory cytokines (IFN‐γ, IL‐17, and IL‐6) in spleen	[104]
In vivo; EAE C57BL/6 female mice	2.0% dietary NAR supplement; per‐oral	Reduce EAE symptoms by diminishing the immune activation and inflammatory genes in spinal cord, enhance microbial diversity offering neuronal protection through microbial homeostasis	[105]
In vivo; EAE C57BL/6 male mice	50 mg/kg NAR; per‐oral	Reduce inflammatory cell infiltration and mitigate mitochondrial damage by modulation of estrogen α/β and progesterone hormone receptor	[106]

4.5.3. Effect on Microbial Homeostasis

NAR demonstrated neuroprotective effects through its influence on the gut microbiome. Dietary NAR administration led to significant shifts in microbial composition, indicating a potential immunomodulatory mechanism via the gut–brain axis. The importance of the gut–brain axis in MS was further highlighted by the fact that EAE mice fed with NAR displayed significantly higher microbial diversity and distinct taxonomic shifts, including enrichment of Paraprevotellaceae, Alistipes, and Chlorobi, alongside reductions in Bacteroidetes and Akkermansia populations. The fecal microbiota transplants from NAR‐treated mice exhibited similar neuroprotective effects to recipient mice, underscoring the microbiome's role in mediating NAR systemic immunomodulatory and microbial homeostasis effect (Table 5) [105].

4.5.4. Effect Through Hormonal Regulation

In vivo oral administration of 50 mg/kg NAR to male C57BL6 mice with EAE had a major neuroprotective effect. In addition to modifying the expression of progesterone receptors, estrogen receptor‐α, and estrogen receptor‐β, there was an increase in expression of aromatase enzyme involved in the manufacture of estrogen. These hormonal modulations were correlated with reduced inflammatory cell infiltration in spinal white matter and mitigation of neuronal and mitochondrial damage induced by EAE pathogenesis. Thus, indicating the potential therapeutic effects of NAR in MS (as discussed in Table 5) [106].

4.6. Naringenin and Spinal Cord Injury

4.6.1. Overview of SCI Pathology

SCI is CNS disorder resulting from trauma such as road traffic accident or falls or nontraumatic injuries like tumor, chronic tuberculous infection, birth defects, degenerative and vascular conditions. SCI injury leads to permanent or temporary loss of motor or sensory functions. SCI not only affects the quality of life but also becomes the psychological, financial, and emotional burden to the family and society [107, 108, 109]. There are two phases in SCI (as shown in Figure 6); the local cells are damaged due to external injury or trauma to spinal cord in primary phase. In the secondary phase, there is inflammation and increased oxidative stress level leading to increased BBB permeability, glial and neuronal apoptosis, neurotransmitter accumulation, and mitochondrial dysfunction. This in turn lead to sensory‐motor dysfunction [110]. Unfortunately, there are no exact cure for SCI thus creating a need for new medicines that can cure SCI.

FIGURE 6.

Overview of spinal cord injury (SCI) pathology. In SCI there are two phases, that are: primary phase caused by direct mechanical or external trauma; and the secondary phase triggered by increased oxidative stress that disrupts the blood brain permeability. This disruption leads to inflammation and mitochondrial dysfunction, ultimately causing impairment of motor and sensory function (created with BioRender).

4.6.2. Suppression of Pro‐inflammatory Cytokine Release and Oxidative Stress

NAR efficacy seems to be mediated by an array of important mechanism, an in vivo study has reported the decrease in expression of pro‐inflammatory cytokines IL‐1β, TNF‐α, when the experimental animals were treated with NAR. Similarly, NAR downregulated nitrite levels, while diminishing the activity of matrix metalloproteinase‐9 (MMP‐9) and increasing the activity of MMP‐2. NAR modulated oxidative stress via upregulating the GSH and catalase level [111]. NAR at a dose of 50 mg/kg significantly reduced neutrophil activation and infiltration into the injured spinal cord tissue. This effect was linked to the suppression of miR‐223, a miRNA that promotes neutrophil activity and inflammation. NAR suppressed neutrophil infiltration and reduced expression of NLRP3 and IL‑1β in the injured spinal cord. By downregulating miR‐223, NAR alleviates the inflammatory response typically seen after SCI, suggesting its potential as a neuroprotective agent in spinal trauma (as summarized in Table 6) [108].

TABLE 6.

Neuroprotective effect of naringenin in spinal cord injury.

Model type	Dose and route of administration	Key findings	References
In vivo; T8‐T9 SCI rat	5, 10, 15 mM NAR; intrathecal injection	Reduce IL‐1β, TNF‐α, and nitrite level, increase MMP‐2 and decrease MMP‐9 activity, modulate oxidative stress by upregulation of glutathione and catalase level, improve motor and sensory function, increase neuronal survival, reduce neuropathic pain and tissue damage	[111]
In vivo; adult female Wister rats	50 mg/kg; per‐oral; 7 days daily	NAR suppress miR‐223 thus attenuating neutrophil activation and inflammation via reducing NLRP3 inflammasome and IL‑1β expression	[108]

4.6.3. Improved Motor and Sensory Function, and Tissue Preservation

Intrathecal administration of NAR in experimental rat showed improved motor and sensory function, decreased neuropathic pain (Table 6). Furthermore, the histopathological analysis revealed decreased tissue damage and improved structural preservation of the spinal cord, suggesting that NAR not only improves functional outcomes after SCI, but also exerts diverse molecular effects that contribute to tissue preservation and neuronal survival [108, 111].

5. Novel Drug Delivery Approaches for Naringenin

Low solubility in water as well as poor absorption via the digestive system limit the therapeutic potential of NAR, necessitating the development of a novel drug delivery system. NAR‐loaded chitosan nanoparticles formulated by Md et al. exerted controlled release through nasal mucosa with permeation rate of 67.9%. This chitosan loaded NAR nanoparticle exhibited neuroprotective and antioxidant activity against 6‐OHDA induced SH‐SY5Y cell (≤50 µg/mL NAR) [112].

In Alzheimer's models, chitosan nanoparticles improved cognitive behavior and reduced oxidative stress via nose‐to‐brain delivery [113]. Yan et al. designed TTGN‐decorated erythrocyte membrane‐coated poly (lactic‐co‐glycolic acid) nanoparticles (TRNNs) and reported multifold increases in NAR transport across in vitro and in vivo BBB models, resulting in substantial accumulation of NAR in the brain. Additionally, in AD mice model, these nanoparticles exhibited improved memory and cognitive function while also supporting neuronal health through increased dendritic spine density and upregulation of the synaptic marker PSD95. In addition to this, TRNNs protected neuronal cells from Aβ induced toxicity, highlighting their dual role in drug delivery and neuroprotection [114].

Similarly, NAR‐loaded solid lipid nanoparticles demonstrated sustained release, improved stability, and increased cellular absorption. While intra‐tracheal administration of lyophilized NAR‐loaded solid lipid nanoparticles boosted relative bioavailability (∼2.53‐fold increase) considerably as compared to NAR suspension alone. Such nanoparticle‐based drug delivery not only bypass first‐pass metabolism, but also facilitate effective drug distribution to targeted tissues, underlining their potential to transform NAR into a beneficial neuroprotective medication [115]. Gaba et, al (2019) reported that intranasal administration of vitamin‐E loaded NAR nano‐emulsion alongside levodopa improved motor function and reduced oxidative stress in a 6‐OHDA PD rat. Furthermore, the study also confirmed enhanced brain bioavailability of NAR with intranasal delivery. While, the study highlights the potential of NAR combination formulations, they do not explain about the direct pharmacological synergy between NAR and levodopa [116]. As, of now, there are no confirmed clinical uses of NAR in combination with other specific drugs for neurodegenerative diseases, though research is actively ongoing.

6. Epigenetic Regulation and Multi‐Omics Integration by Naringenin

Recent studies highlight that the neuroprotective actions of dietary flavonoids, including NAR, may extend beyond classical antioxidant and anti‐inflammatory pathways into the realm of epigenetic regulation including miRNA regulation [117]. NAR upregulates the mRNA expression of insulin and its receptor in hippocampus and cortex of mice, suggesting epigenetic remodulation through regulation of DNA methyltransferase 1 and histone deacetylases (HDACs) linked to oxidative stress and neuroinflammation, thereby restoring PI3K/Akt signaling and suppressing tau hyperphosphorylation. In microglia, NAR further refines the epigenetic landscape by activating Sirtuin1, which deacetylates NF‐κB p65 and subsequently suppresses the expression of IL‐1β, TNF‐α, and NLRP3. Additionally, NAR attenuates NLRP3 inflammasome activation and promotes a shift from a glycolytic, pro‐inflammatory microglial phenotype toward a more oxidative, homeostatic state, potentially involving regulatory miRNAs such as miR‐124 and miR‐223, although their direct modulation by NAR remains to be fully established. The coordinated epigenetic remodeling suppresses inflammasome activation, mitigates neuroinflammation, and protects the dopaminergic and cortical neurons, underscoring NAR potential as a dual metabolic‐epigenetic regulator in neurodegenerative diseases [60, 113, 118, 119, 120, 121].

For instance, its impact on miRNAs such as miR‐223 in spinal cord injury models suggests that NAR can regulate inflammatory cascades through non‐coding RNA pathways. Moreover, advances in transcriptomics, proteomics, metabolomics, and microbiome profiling have revealed multi‐layered effects of NAR on cellular metabolism, mitochondrial homeostasis, and immune regulation. Integration of these multi‐omics approaches provides a systems‐level perspective, demonstrating that NAR does not act on a single pathway but reshapes interconnected networks that drive neuronal survival. Future research incorporating epigenetic and multi‐omics analyses will be critical to fully delineate the molecular signatures of NAR action and to identify predictive biomarkers for clinical translation [108, 113, 122].

7. Clinical Gaps in Naringenin Research

Despite extensive preclinical evidence, clinical research on NAR in neurodegeneration remains limited. Most available studies have focused on pharmacokinetics, safety, and antioxidant biomarkers in healthy volunteers, with no completed large‐scale trials in patients with AD, PD, or MS [35]. The modest oral bioavailability and short plasma half‐life represent major translational hurdles, though recent advances in nanoparticle‐based delivery systems may help overcome these limitations [113]. Future clinical studies should prioritize:

1. Dose‐finding and long‐term safety evaluations in neurodegenerative patient populations,

2. Biomarker‐driven trials integrating neuroimaging and multi‐omics profiling to assess mechanistic responses, and

3. Combination therapy approaches where NAR is tested alongside existing symptomatic treatments or anti‐inflammatory agents.

Such studies will be essential to establish NAR as a mainstream neurotherapeutic candidate and to translate promising preclinical results into clinical efficacy.

8. Future Perspectives on Naringenin

With increasing age and advancements in technology, the healthcare field is evolving rapidly. Despite substantial progress in neuropharmacological research, the precise mechanisms underlying many neurodegenerative diseases remain elusive. Current therapies provide only symptomatic relief and fail to offer a complete cure. Consequently, the search for novel and more effective therapeutic agents continues. Natural compounds, known for their long‐standing use and safety profile, are being extensively investigated for their therapeutic potential. Among them, NAR has gained considerable attention due to its broad‐spectrum pharmacological effects, emerging as a promising neuroprotective and anti‐inflammatory candidate [123]. However, most of the data on NAR comes from in vitro or animal models. Clinical studies on NAR efficacy are scarce and focused primarily on metabolic or cardiovascular studies, with little evidence in neurodegenerative disease. Therefore, future research on NAR should focus on several key areas to strengthen its clinical translation [37, 124]. First, epidemiological and dietary intervention studies are needed to clarify the relationship between citrus consumption and reduced risk of neurodegenerative diseases, thereby reinforcing the nutritional relevance of NAR. Second, comparative analyses with other flavonoids should be expanded to highlight NAR unique pharmacological advantages such as higher BBB permeability and diverse mechanistic activity. Third, systematic pharmacokinetic investigations in humans, including brain tissue distribution and metabolite profiling, are essential to optimize dosing strategies. Fourth, formulation innovations such as nano‐emulsions, chitosan nanoparticles, and biomimetic delivery systems should be further advanced to overcome low oral bioavailability. Fifth, integration of epigenetic and multi‐omics approaches will provide systems‐level insights into NAR regulatory effects and may identify predictive biomarkers of response. Finally, rigorously designed clinical trials in AD, PD, MS, and SCI are required to validate preclinical findings and establish the therapeutic potential of NAR, either as a standalone nutraceutical or in synergistic combination with existing therapies.

Declaration on Use of AI‐assisted Chat Generative Pretrained Transformer (Chat‐GPT)

The use of AI‐assisted chat‐GPT was solely done for the grammar check and language refinement purpose only. After modification with AI, the authors checked and edited the sentence before using it in the article and takes full responsibility for robustness and accuracy for the final version of paper.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

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