The Untapped Potential of Natural Products to Target G6PD and Disrupt the Inflammation-Cancer Axis

Abstract

Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), plays a crucial role in cellular metabolism and maintaining oxidative homeostasis. In recent years, G6PD has gained attention as a therapeutic target in chronic inflammatory diseases and various cancers. This enzyme contributes to tumor cell survival by generating NADPH for redox defense and ribose-5-phosphate for nucleotide synthesis. G6PD activity is significantly upregulated in many cancers, including prostate, gastric, liver, and breast cancers, where it correlates with poor prognosis. Although several of these compounds have been evaluated in clinical settings, direct evidence confirming G6PD as a primary target in human studies remains limited, highlighting the need for further translational research. Despite the considerable therapeutic potential of G6PD inhibition, the development of specific, low-toxicity synthetic inhibitors has faced significant challenges, including issues with selectivity, metabolic compensation mechanisms, and hematological complications in G6PD-deficient individuals. In this regard, natural compounds have emerged as promising alternatives for G6PD modulation. This review provides a comprehensive narrative synthesis of natural compounds targeting G6PD, including phenolics, flavonoids, alkaloids, and terpenoids. We discuss their mechanisms of action, including direct enzyme inhibition, indirect regulation, and pro-oxidant effects, as well as their dual roles in cancer therapy and potential toxicity in G6PD-deficient populations. Collectively, these compounds may disrupt the NADPH-dependent inflammation–cancer axis by impairing redox balance and tumor cell survival. However, further studies are required to improve their specificity, bioavailability, and clinical applicability while ensuring patient safety.

Keywords

glucose-6-phosphate dehydrogenase (G6PD)natural products pentose phosphate pathway cancer metabolism inflammation

1. Introduction

The metabolic reprogramming of cancer cells represents a fundamental hallmark of cancer pathogenesis, with the pentose phosphate pathway (PPP) serving as a crucial metabolic axis supporting tumor growth and survival.¹ Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, has gained recognition as a key player in both chronic inflammatory diseases and numerous malignancies.²

G6PD catalyzes the committed step in the oxidative phase of the PPP, generating NADPH for redox defense and ribose-5-phosphate for nucleotide synthesis.³ Through these essential metabolic functions, G6PD simultaneously enhances tumor cell survival and amplifies inflammatory responses, positioning itself as an attractive therapeutic target⁴ The enzyme’s activity is significantly upregulated in various cancers, including prostate, gastric, renal, hepatic, and breast tumors, where it correlates with poor prognosis.⁵

In addition, recent evidence has demonstrated that G6PD is significantly upregulated in lung cancer, where it contributes to tumor proliferation, metabolic adaptation, and resistance to oxidative stress, further supporting its role as a potential therapeutic target.^6,7

Despite the considerable therapeutic potential of G6PD inhibition, the development of specific, low-toxicity synthetic inhibitors has encountered substantial obstacles, including challenges with selectivity, metabolic compensation mechanisms, and potential hematological complications in G6PD-deficient individuals⁸ Concurrently, substantial evidence has documented the G6PD-modulating activities of various natural compounds, though a comprehensive synthesis of this evidence remains lacking^9,10

However, a comprehensive, critical, and mechanistic synthesis of the evidence linking natural products, G6PD modulation, and the inflammation-cancer axis is currently lacking. This review aims to fill this void by: (1) Cataloging natural G6PD modulators based on chemical class; (2) Elucidating their molecular mechanisms of action; (3) Evaluating their dual roles in exacerbating deficiency vs targeting cancer; and Discussing future translational challenges and opportunities.

2. Molecular Architecture and Evolutionary Conservation of G6PD

As G6PD is classified as a typical housekeeping protein, its expression occurs across virtually all tissue and cell typesThe G6PD gene is located on the long arm of the X chromosome near the telomeric region. Both the structure and functions of G6PD have been well characterized. This gene spans approximately 18.5 kilobases, comprising 13 exons and 12 introns, with the final exon containing the termination signalThe promoter region of the G6PD gene is situated within a CpG island and is characterized by the presence of a TTAAAT motif as well as numerous Stimulatory Protein binding elements, which are integral to its transcriptional regulation. Additionally, the structural organization, specifically the number and size of exons and introns, as well as their nucleotide sequences, exhibits a high degree of evolutionary conservation among higher eukaryotic species¹¹ The mRNA transcript produced by the G6PD gene is approximately 1545 base pairs in length. The protein encoded by this gene has a molecular weight of 59 kDa and consists of 514 amino acids.¹²

3. Multilevel Regulatory Mechanisms Governing G6PD Activity

G6PD expression and catalytic activity are governed through sophisticated, multilayered regulatory mechanisms that have been progressively elucidated through decades of research.

3.1. Epigenetic Regulation

Histone modifications substantially influence G6PD transcriptional activity Enhanced histone acetylation, particularly at H3K27, facilitates transcription factor recruitment (including Sp1) and potentiates G6PD expression a process modulated by histone deacetylases such as HDAC10(Conversely, methylation at specific residues, including H3K9, exerts repressive effects, although the complete spectrum of responsible methyltransferases remains incompletely characterized. DNA methylation patterns within the G6PD promoter region additionally contribute to tissue-specific expression profiles and pathological dysregulation).¹³

3.2. Non-Coding RNA Networks

Multiple RNA species fine-tune G6PD expression through post-transcriptional mechanisms.Small interfering RNAs (siRNAs) facilitate targeted G6PD knockdown, though their design must accommodate the substantial genetic polymorphism characteristic of the G6PD gene.⁵

GAS5 (Growth arrest-specific transcript 5), a long noncoding RNA, regulates cell cycles in cancers. In advanced melanoma, lower GAS5 levels correlate with larger tumors and increased metastasis. Knocking down GAS5 encourages cell proliferation and diminishes apoptosis. GAS5 directly binds to and inhibits G6PD and NOX activity, which reduces superoxide and NADP⁺ levels, impacting cellular redox balance.¹⁴

MicroRNAs, including miR-1, part of the miR-1/206 family, regulates gene expression and is linked to heart diseases like hypertrophy and infarction. High glucose levels raise miR-1 and miR-206 levels in heart cells, promoting glucose-induced apoptosis.¹⁵cardiovascular disease sees increased oxidative stress through miR-1-mediated suppression of superoxide dismutase 1 and G6PD. High glucose can inhibit G6PD via miR-1 upregulation. Liver-specific miR-122 directly targets the 3′ UTR of G6PD, lowering its expression in liver cancer cells. Both miR-1 and miR-122 regulate the pentose phosphate pathway by inhibiting G6PD.¹⁶

Telomerase, a ribonucleoprotein comprised of human telomerase RNA, an associated telomerase protein, and the catalytic subunit hTERT, adds telomere repeats to chromosome ends, facilitating continuous cell growth, particularly in stem cells and many cancers. Costunolide inhibits hTERT in glioma cells, inducing apoptosis through a ROS-dependent pathway. Decreased G6PD expression resulting from hTERT inhibition by costunolide, siRNA, or dominant-negative hTERT suggests G6PD involvement in a Nrf2-TERT axis that maintains oxidative defense in astrocytes or glial cells.^5,17

3.3. Protein-Protein Interactions and Allosteric Regulation

Protein-protein interactions assume crucial roles in G6PD regulation. BAG3 (Bcl-2-associated athanogene 3) participates in autophagy, cell cycle regulation, development, and pathogen replication, interacting with the ATPase domain of Hsc/Hsp70 family proteins and possessing multiple chaperone-binding motifs. In hepatocellular carcinoma, BAG3 directly binds G6PD, inhibiting G6PD dimerization and activity, resulting in reduced pentose phosphate pathway flux and slower cell growth without NADPH level changes. This suggests the BAG3-G6PD interaction has tumor-suppressor-like activity in liver cancer.^5,18

The tumor suppressor protein p53 inhibits G6PD by disrupting its active dimerization, which is indispensable for enzymatic function. Neoplastic p53 mutants forfeit this inhibitory capacity toward G6PD, augmenting glucose consumption and PPP flux. This metabolic reprogramming fuels intensified synthesis of macromolecules that sustain rapid cancer cell expansion and proliferation, emphasizing the indispensable role of functional p53 in regulating cellular glucose metabolism via G6PD modulation.¹⁶

4. G6PD as a Metabolic Nexus in Inflammation and Cancer

4.1. The G6PD-Nitric Oxide Redox Interrelationship

A complex, bidirectional relationship exists between G6PD activity and nitric oxide (NO) signaling that profoundly influences both inflammatory and carcinogenic processes. G6PD-derived NADPH serves as an indispensable cofactor for nitric oxide synthase (NOS) enzymes, directly coupling G6PD activity to NO production.¹⁹ In response to stimulation with lipopolysaccharide (LPS) or 12-myristate 13-acetate (PMA), human granulocytes produce nitrite (derived from NO). In the presence of LPS or PMA, human granulocytes lacking G6PD cannot produce NO)²⁰ IL-1β cytokine induces cell death and insulin secretion disorder in pancreatic islet cells by increasing the expression of inducible nitric oxide synthase (INOS) and the production of NO.²¹ IL-1β decreases the levels of cyclic adenosine monophosphate (cAMP) and enhances the activity of G6PD. G6PD activity is increased by 8-bromo-cAMP, a protein kinase-dependent cAMP activator, and reduced by protein kinase A(PKA) inhibitors.⁵

There is a positive correlation between the activity of G6PD and the production of NO. Inhibition of G6PD by dehydroepiandrosterone (DHEA) or antisense oligonucleotides decreases IL-1b-induced NO levels, suggesting that the PKA-dependent pathway’s involvement in amplifying NO-induced G6PD activity. Sodium nitroprusside (NO donor) stimulates the growth of normal G6PD expressing fibroblasts, but induces apoptosis in cells lacking G6PD.¹⁹ Treatment with trolox or G6PD ectopic expression prevents apoptosis induced by NO, suggesting a protective role of G6PD, Decreased G6PD in endothelial cells leads to increased reactive oxygen species (ROS) and decreased NO bioavailability, while G6PD overexpression increases the activity of cGMP and NOS, leading to increased NO production. NO is necessary to prevent leukocyte adherence to the endothelium. Endothelial cells lacking G6PD show decreased eNOS, NO and GSH.⁵

4.2. Metabolic Reprogramming in Oncogenesis

The principal physiological function of G6PD within the PPP entails generating ribose-5-phosphate and NADPH, both requisite for synthesizing nucleotides, fatty acids, and other essential cellular constituents.²² The biggest and most common enzyme deficiency in the world is G6PD deficiency, which causes red blood cell disorders such as haemolytic anaemia and hepatitis caused by medicines. On the contrary, elevated G6PD may promote healthy longevity. However, it is not clear whether G6PD, which is part of PPP, affects cell division and death. By maintaining intracellular redox homeostasis, G6PD promotes tumour growth, for example. Its activity is increased in stomach, kidney, prostate, breast and other tumours. This metabolic reprogramming constitutes an adaptation to sustain rapid proliferation while managing concomitant oxidative stress.^5,23

For example, heart homogenate was found in heart failure dogs, which clearly showed increased G6PD, NADPH and superoxide production, since NADPH derived from G6PD produces superoxide.²⁴G6PD inhibitors such as 6-aminoconitinamide (6-AN) or NADPH oxidase (NOX) inhibitors such as gp91 (D-TAT) significantly reduce the formation of superoxide in heart failure homogenates. G6PD may play a redox role in the pathophysiology of heart disease, as its cardiac upregulation provides sufficient NADPH and powers superoxide producing enzymes.⁵

4.3. G6PD in Cell Death Modulation

Cell death is classified into apoptosis (type I), autophagy (type II), and necrosis (type III) based on cellular morphology. Downregulation of G6PD disrupts cell survival-related functions. G6PD primarily maintains cellular redox balance by regenerating NADPH. G6PD deficiency increases oxidative damage, heightening cellular vulnerability to stress. Embryos lacking G6PD exhibit greater oxidative damage after blood circulation begins. G6PD has a crucial antioxidant role in supporting growth and development.^5,8

G6PD occupies a decisive position at the convergence of multiple cell death pathways, profoundly influencing oncogenesis and therapeutic responses:

Apoptosis: G6PD inhibition induces apoptosis. G6PD deficiency elevates oxidative stress and apoptosis, which antioxidants can mitigate. G6PD is essential in red blood cells for NADPH production, guarding against oxidative damage. Eryptosis, red blood cell suicide, features cell shrinkage and altered membranes. In nucleated cells, G6PD inhibition sparks apoptosis and curbs cell proliferation, particularly with oxidative stress.²⁵ High glucose levels can impair G6PD through ubiquitination, causing kidney cell apoptosis. Von Hippel–Lindau protein encourages G6PD degradation, disturbing redox balance and amplifying oxidative stress.¹⁶

Ferroptosis: Ferroptosis is a newly recognized iron-dependent regulated cell death²⁶ Morphologically, it features thicker mitochondrial membranes, loss or disappearance of cristae, and rupture of the outer mitochondrial membrane. Mechanistically, lipid peroxidation accumulates via the Fenton reaction between iron and cellular ROS, driving ferroptosis. NADPH is a vital intracellular reducing agent that neutralizes ROS and maintains redox homeostasis NADP⁺ to NADPH can occur via many reactions (at least 143), but only a few significantly contribute to NADPH production in mammals.²⁷ The main sources are folate metabolism (methylenetetrahydrofolate dehydrogenase), glutaminolysis (malic enzymes), and the oxidative pentose phosphate pathway (G6PD and 6PGD), with G6PD being the largest contributor.¹⁴thus G6PD could control ferroptosis through mechanisms that depend on NADPH.²⁷

Furthermore, G6PD modulation has been linked to the induction of ferroptosis, which represents a promising strategy for eliminating therapy-resistant cancer cells.

NETosis: Necrosis, induced by toxins, trauma, or infections, involves cellular swelling, membrane rupture, and content release. G6PD deficiency enhances cellular susceptibility to infections, commonly leading to necrosis. N-acetylcysteine (NAC) pretreatment can improve infection resistance in G6PD-deficient cells. NETosis, a controlled death in neutrophils resembling necrosis, generates extracellular traps (NETs) of chromatin and antimicrobial peptides for pathogen capture. This process depends on NADPH oxidase (NOX), and severe G6PD deficiency compromises NETosis, exacerbating infection vulnerability.^28,29

In addition, reduced G6PD activity has been associated with decreased metastatic potential through the regulation of epithelial–mesenchymal transition (EMT)-related pathways.

5. Natural Products as G6PD Modulators

As summarized in Table 1, this comprehensive review identifies numerous natural products with significant G6PD-modulating activity, which can be systematically categorized according to their chemical classes, primarily phenolics, flavonoids, and alkaloids, and terpenoid.³⁰

Table 1.

Natural Products as G6PD Modulators

Compound name	Chemical class/category	Mechanism	Type of evidence	Ref
Ellagic acid	Phenolic Acids & Polyphenols	Direct inhibition of G6PD and 6PGD through interaction with the enzyme’s active site	clinical trials	31
Polydatin	Phenolic Acids & Polyphenols	Inhibition of G6PD activity (direct enzyme inhibition)	clinical trials	31
Naringenin	Phenolic Acids & Polyphenols	Inhibition of G6PD and 6PGD reduces PPP pathway flux	In vitro&clinical trials	31,32
Caffeic acid	Phenolic Acids & Polyphenols	Inhibition of G6PD activity through interaction with the active site	clinical trials	31
Ferulic acid	Phenolic Acids & Polyphenols	Inhibition of G6PD	clinical trials	31
Sinapic acid	Phenolic Acids & Polyphenols	Inhibition of G6PD	clinical trials	31
Hesperidin	Phenolic Acids & Polyphenols	Inhibition of G6PD	In vitro&clinical trials	31,32
Quercetin	Polyphenols (Flavonol)	Potent competitive inhibition of 6PGD and G6PD through binding to the active site and interference with NADP⁺ binding	In vitro	32
Myricetin	Polyphenols (Flavonol)	Strong inhibition of 6PGD/G6PD via interaction with the catalytic site and hydrogen bonding with key amino acid residues	In vitro	32
Fisetin	Polyphenols (Flavonol)	6PGDinhibition by occupying the substrate-binding pocket and disrupting NADPH generation	In vitro	32
Morin	Polyphenols (Flavonol)	Competitive inhibition of 6PGD by binding to the enzyme active site	In vitro	32
Kaempferol	Polyphenols (Flavonol)	Moderate inhibition of 6PGD through partial interaction with the active site	In vitro	32
Galangin	Polyphenols (Flavonol)	Moderate inhibition of 6PGD by binding to the enzyme active site	In vitro	32
Apigenin	Polyphenols (Flavone)	Moderate 6PGD inhibition via interaction with the substrate-binding region	In vitro	32
Luteolin	Polyphenols (Flavone)	Moderate inhibition of 6PGD/G6PD by binding to the catalytic domain	In vitro	32
Baicalein	Polyphenols (Flavone)	6PGD inhibition through interaction with the active site; activity depends on hydroxyl group positions	In vitro	32
Quercetin-7-glucoside	Polyphenols (Flavonoid glycoside)	No significant inhibitory effect on 6PGD due to steric hindrance caused by glycosylation	In vitro	32
Quercetin-3-β-D-glucoside	Polyphenols (Flavonoid glycoside)	Lack of inhibition 6PGD; glycosylation reduces affinity for the enzyme active site	In vitro	32
Quercetin-3-D-galactoside	Polyphenols (Flavonoid glycoside)	No inhibitory activity on 6PGD due to impaired interaction with the catalytic site	In vitro	32
Rutin	Polyphenols (Flavonoid glycoside)	No inhibitory effect on 6PGD/G6PD because of bulky sugar moiety preventing enzyme binding	In vitro	32
Biochanin A	Polyphenols (Isoflavone)	High binding affinity for G6PD receptor; decreases G6PD expression and inflammatory/metastasis markers	In silico & In vitro	33
Chrysin	Phenolic Acids & Polyphenols	Inhibition of G6PD	In vitro	32
Curcumin	Phenolic Acids & Polyphenols (Curcuminoid)	Inhibition of cancer metabolic pathways, NADPH depletion, and oxidative stress (indirectly via G6PD)	In vitro & in vivo	34,35
Resveratrol	Phenolic Acids & Polyphenols (Stilbenoid)	Inhibition of tumor growth and PPP-dependent metabolism	in vitro & animal models	34
Epigallocatechin gallate (EGCG)	Tea Polyphenols (Flavan-3-ols)	Increased oxidative stress in G6PD-deficient cells	In vitro & in vivo	36
Epigallocatechin (EGC)	Tea Polyphenols (Flavan-3-ols)	H₂O₂ production due to pyrogallol structure → exacerbate oxidative stress in G6PD deficiency	In vitro & in vivo	36
Epicatechin gallate (ECG)	Tea Polyphenols (Flavan-3-ols)	Neutral or weak effect on G6PD (no hemolytic effect)	In vitro & in vivo	36
Epicatechin (EC)	Tea Polyphenols (Flavan-3-ols)	Did not show significant effect on G6PD-deficient RBCs	In vitro & in vivo	36
Lawsone (from Henna)	Quinones (Naphthoquinone)	Induce severe oxidative stress → inability of G6PD-deficient RBC to neutralize ROS → hemolysis	Clinical (case reports) & In vitro	37,38
Acalypha indica	Other Botanicals	Induce hemolysis via increased oxidative stress and methemoglobinemia in G6PD deficiency	Clinical (Observational clinical)	39
Alpha lipoic acid (ALA)	Organosulfur Compounds	Increase antioxidant capacity and GSH regeneration; indirect protective effect on consequences of G6PD deficiency	Clinical	39
Berberine (e.g, from Coptis chinensis)	Alkaloids (Isoquinoline)	Increase risk of hyperbilirubinemia; indirect effect via oxidative stress	Clinical & in vitro	39,40
Costunolide	Terpenoids (Sesquiterpene Lactones)	hTERT inhibition → reduced G6PD expression via Nrf2–TERT axis	Clinical & in vitro	5,17
Phytol	Terpenoids (Diterpene alcohol)	Molecular docking: good binding affinity with G6PD; inhibits G6PD activity and induces ROS-mediated apoptosis	In silico & In vitro	41
Dehydroepiandrosterone (DHEA)	Steroids	G6PD inhibition → NADPH depletion → NO production reduction	Clinical	5
6-Aminonicotinamide (6-AN)	Synthetic Analogues (Pyridine Derivative)	G6PD inhibition → superoxide and NADPH production reduction	Clinical	5
Trolox	Chromanol Derivatives (Synthetic)	G6PD inhibition → superoxide and NADPH production reduction	Clinical	5

Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase; PPP, pentose phosphate pathway; ROS, reactive oxygen species.

5.1. Phenolic Compounds: Potent Direct Inhibitors With Dual Effects

Seven phenolic compounds were identified as inhibitors of 6PGD, with naringenin and ellagic acid demonstrating the most potent effect⁴² Research has shown that natural flavonols and flavones such as Quercetin, myricetin, fisetin, morin, baicalein, and apigenin are potent inhibitors of the 6PGD enzyme. Also, compounds such as Luteolin, apiin, baicalin galangin, and kaempferol have moderate effects on this enzyme, and compounds such as quercetin 7‐glucoside, quercetin 3‐β‐D‐glucoside, quercetin 3‐D‐galactoside, and rutin have no inhibitory effect on this enzyme.³²Similarly, several phenolics inhibited G6PD, with polydatin and ellagic acid again showing the strongest activity. Ellagic acid is particularly noteworthy for its dual inhibition of both enzymes. As a compound present in many foods, it holds potential therapeutic benefits; however, excessive consumption may lead to adverse metabolic effects due to its potent enzyme inhibition.⁴³

The inhibitory mechanisms likely involve Van der Waals forces or electrostatic interactions at the enzyme active sites.⁴³ Among the compounds tested, naringenin, caffeic acid, ellagic acid, ferulic acid, sinapic acid, hesperidin, polydatin, and chrysin exhibited inhibitory effects on one or both enzymes. In contrast, chlorogenic acid, p-coumaric acid, and syringic acid showed no significant inhibition. These findings underscore the dual nature of phenolic compounds: while naturally occurring and often beneficial, their excessive intake particularly of potent inhibitors like ellagic acid may disrupt essential metabolic pathways.³¹

A distinct subgroup within phenolics is tea polyphenols. Black tea, green tea, and decaffeinated green tea extract contain similar polyphenolic profiles, with epigallocatechin-3-gallate (EGCG) being the most abundant.¹⁰

Studies demonstrate that tea polyphenols, particularly EGC and EGCG, exacerbate oxidative stress in G6PD-deficient red blood cells by reducing GSH, increasing oxidized glutathione (GSSG), and promoting methemoglobin formation. These effects are dose-dependent and specific to deficient cells, with ECG and other polyphenols showing no such impact. The pro-oxidant activity is attributed to the pyrogallol structure of EGC and EGCG, which facilitates hydrogen peroxide generation, unlike catechol-structured compounds. Consequently, excessive intake of concentrated tea polyphenols may pose risks to G6PD-deficient individuals.³⁶

Flavonoids represent a major class of phenolic compounds with extensive pharmacological effects, particularly demonstrating antiproliferative, antimetastatic, and carcinoprotective properties. These compounds influence cancer progression through multiple mechanisms, including regulation of cell proliferation, differentiation, apoptosis, angiogenesis, and metastasis. A distinctive characteristic of flavonoids is their ability to selectively target cancer cells while protecting normal cells, highlighting their potential as safe therapeutic agents. The investigation of flavonoid-mediated G6PD modulation presents a promising innovative approach for cancer prevention and treatment.⁴⁴

Biochanin A, an O-methylated isoflavone found in red clover, soy, peanuts, and chickpeas, has also demonstrated potent G6PD-inhibitory effects. Molecular docking experiments revealed high binding affinity of biochanin A for the G6PD receptor, and in vitro studies showed that it substantially decreases G6PD expression as well as inflammatory and metastasis-related markers in non-small cell lung cancer cells.³³

Henna: Derived from the Lawsonia inermis plant, henna contains lawsone (2-hydroxy-1,4-naphthoquinone) along with various flavonoids and steroids.³⁹ In G6PD-deficient individuals, henna can cause severe hemolytic crises due to oxidative damage to red blood cells. Several case reports document severe hemolysis, sometimes leading to acute renal failure and even death, following topical application of henna in G6PD-deficient children and infants.³⁷ The oxidative stress from lawsone overwhelms the impaired antioxidant defense in these individuals, increasing the risk of hemolysis. Hence, henna poses a significant hemolytic risk for infants and children with G6PD deficiency and warrants caution and awareness in its use.^37,39

Acalypha indica , a weed used in Ayurveda across Asia, has been reported to cause acute hemolysis in individuals with G6PD deficiency after ingestion, often through consumption of a broth containing the plant. Several case reports from Sri Lanka and other studies documented this hemolysis, sometimes accompanied by methemoglobinemia. While laboratory toxicity studies in rats show no major organ toxicity at various doses, the clinical evidence suggests caution is needed when consuming Acalypha indica due to its potential to induce oxidative hemolysis and transient G6PD deficiency.³⁹

5.2. Alkaloids: Potential and Caution in G6PD Modulation

Alkaloids are a large group of nitrogen-containing secondary metabolites found in animals, microbes, and plants, derived mainly from amino acid precursors such as tyrosine and tryptophan. With over 12,000 identified compounds exhibiting diverse chemical structures and biological activities, many plant-derived alkaloids demonstrate significant antimicrobial, antimalarial, antifungal, and anticancer properties.⁴⁵ Several alkaloids have received FDA approval as chemotherapeutic agents, including vinblastine, which disrupts the cell cycle through tubulin interaction, and camptothecin, a potent topoisomerase I inhibitor.⁴⁶ Their relationship with G6PD is complex and often cautionary.

A primary alkaloid of interest in the context of G6PD is berberine, found in the traditionally used Chinese medicinal herb Coptis chinensis . Evidence regarding the safety of berberine in G6PD-deficient individuals remains conflicting. While studies from Singapore reported severe hyperbilirubinemia in neonates exposed to Coptis chinensis, investigations conducted in China did not observe an increased incidence of jaundice in similar populations.³⁹ These discrepancies may be attributed to differences in study design, genetic background, dosage forms, and preparation methods of herbal extracts. Therefore, further standardized clinical studies are required to clarify the safety profile of berberine in G6PD-deficient populations.

5.3. Other Notable Natural and Synthetic Modulators

Several other compounds with distinct chemical structures and origins demonstrate significant G6PD-modulating activities, broadening the scope of potential interventions.

Phytol and biochanin A have been identified as additional natural compounds with potential G6PD-modulatory effects.^33,41

Classical Inhibitors (Steroid and Pyridine Analogues): Dehydroepiandrosterone (DHEA) and 6-Aminonicotinamide (6-AN) are well-characterized inhibitors of G6PD. DHEA inhibition leads to NADPH depletion and reduced nitric oxide (NO) production, while 6-AN reduces superoxide and NADPH generation.⁵These compounds are pivotal research tools for studying the PPP.

Polyphenolic Anti-Cancer Agents: Natural compounds like curcumin and resveratrol have shown promise in cancer treatment by targeting metabolic pathways, which may involve NADPH depletion and oxidative stress related to G6PD modulation.³⁴

Protective Antioxidant: The synthetic antioxidant Trolox prevents NO-induced apoptosis in G6PD-deficient cells, highlighting a protective role by scavenging ROS.⁵

Transcriptional Modulator (Sesquiterpene Lactone): Costunolide inhibits hTERT, leading to reduced G6PD expression via the Nrf2-TERT axis.^2,17

Phytol, a diterpene alcohol found in chlorophyll, has recently been identified as a potential G6PD modulator. In silico molecular docking studies revealed that phytol has good binding affinity with G6PD, and it inhibits G6PD activity in lung carcinoma cells, leading to ROS-mediated apoptosis.⁴¹

Alpha-lipoic acid (LA): is a natural antioxidant that helps restore intracellular glutathione, benefiting individuals with G6PD deficiency. A study on eight G6PD-deficient adults showed that supplementation with 600 mg per day of LA for 28 days had no adverse effects and improved antioxidant capacity by modulating blood redox status. This suggests that LA supplementation may be advantageous for enhancing antioxidant defense and reducing oxidative stress in G6PD-deficient individuals.³⁹

5.4. Therapeutic Potential and Safety Imperatives

The journey of natural G6PD modulators from bench to bedside is shaped by two parallel narratives: their promising role in oncology and the critical safety management required for individuals with G6PD deficiency.

5.4.1. Therapeutic Potential in Oncology and Inflammation

Natural compounds such as curcumin, resveratrol, berberine, and EGCG have demonstrated considerable potential in targeting cancer metabolism. Their therapeutic potential stems from the ability to target the metabolic reprogramming of cancer cells. By inhibiting G6PD, either directly or indirectly, these compounds can deplete NADPH and ribose-5-phosphate, thereby disrupting redox defense and nucleotide synthesis essential for tumor growth and survival. This multi-target approach offers advantages such as potentially lower side effects and the capacity to overcome single-pathway drug resistance.⁴⁴

Mechanistically, G6PD inhibition leads to NADPH depletion, which compromises the glutathione antioxidant system, resulting in accumulation of reactive oxygen species (ROS) and subsequent induction of apoptosis in cancer cells. Simultaneously, reduced ribose-5-phosphate availability impairs de novo nucleotide synthesis, limiting DNA replication and cell division.^4,5 These dual effects make G6PD a critical node in cancer metabolism.

In addition to direct anti-proliferative effects, G6PD inhibition has been shown to enhance chemosensitivity. Preclinical studies demonstrate that pharmacological inhibition of G6PD using DHEA or 6-AN synergizes with conventional chemotherapeutic agents such as cisplatin, doxorubicin, and temozolomide by potentiating oxidative stress and DNA damage.^5,8 Similarly, natural G6PD modulators like curcumin and resveratrol have been reported to overcome chemoresistance in various cancer models through NADPH-dependent mechanisms.³⁴

Furthermore, G6PD modulation has been linked to the induction of ferroptosis, a form of iron-dependent cell death, which represents a promising strategy for eliminating therapy-resistant cancer cells.⁴⁷ In addition, reduced G6PD activity has been associated with decreased metastatic potential through the regulation of epithelial–mesenchymal transition (EMT)-related pathways.⁴⁸

Beyond tumor cells, G6PD also plays a role in inflammatory signaling. By regulating NADPH availability, natural compounds may attenuate the activity of NADPH oxidases and nitric oxide synthases, thereby reducing inflammation and disrupting the inflammation–cancer axis.^4,5 For instance, biochanin A, an isoflavone, has been shown to decrease both G6PD expression and inflammatory/metastatic markers in non-small cell lung cancer cells.³³

Collectively, these findings position natural G6PD modulators as promising adjuncts to conventional cancer therapy, although direct clinical evidence of target engagement remains limited.

A schematic overview of the proposed mechanisms by which natural compounds modulate G6PD and disrupt the inflammation-cancer axis is presented in Figure 1.

Figure 1.

Schematic diagram illustrating the mechanisms of G6PD modulation by natural compounds and its impact on the inflammation-cancer axis

5.4.2. Clinical Management and Herbal Considerations in G6PD Deficiency

In stark contrast to their therapeutic potential, the clinical use of many natural products requires extreme caution in the context of G6PD deficiency. To prevent life-threatening hemolytic crisis, lifelong avoidance of oxidative stressors is paramount. Known triggers include certain drugs (e.g., antimalarials, sulfonamides), fava beans, and naphthalene.¹⁰This caution extends to the use of herbal products. While the Hong Kong Department of Health advises avoiding certain Chinese herbal medicines like Rhizoma Coptidis and Flos Lonicerae, strong epidemiological evidence linking these herbs to hemolysis is generally limited.⁴⁰ Except for reported cases with Coptis chinensis (containing berberine), the belief that Chinese herbal medicines cause hemolysis lacks substantial pharmacological or epidemiological support.^10,39However, specific compounds like henna (lawsone) and Acalypha indica are unequivocally linked to severe hemolytic episodes and warrant strict avoidance.³⁷This underscores a critical translational challenge: the imperative for patient stratification. Robust diagnostic screening for G6PD deficiency is essential before considering therapies involving natural compounds with pro-oxidant or unclear safety profiles. Overall, while many herbal products may lack strong evidence of harm, caution is advised when using them in G6PD-deficient individuals due to potential oxidative effects on red blood cells.¹⁰

5.4.3. Clinical Evidence in Human Studies

Although several natural compounds such as curcumin, resveratrol, and EGCG have been evaluated in clinical trials for cancer, direct evidence linking their therapeutic effects to G6PD modulation in humans remains limited.

For curcumin:A randomized trial in patients with colorectal cancer receiving curcumin combined with oligomeric proanthocyanidins showed cooperative downregulation of G6PD expression and glutathione metabolism pathways, which correlated with reduced tumor growth.³⁵ In patients with type 2 diabetes mellitus, curcumin supplementation significantly improved G6PD activity and oxidative stress markers via microRNA modulation.⁴⁹

For resveratrol: A 2025 randomized controlled trial in head and neck cancer patients (n=72) receiving liposomal resveratrol (400 mg/day for 12 weeks) reported increased glutathione peroxidase activity and total antioxidant capacity, suggesting NADPH-dependent effects that may involve G6PD.⁵⁰

For EGCG (tea polyphenols) – Ex vivo studies on erythrocytes from G6PD-deficient individuals demonstrated that EGCG and epigallocatechin significantly deplete reduced glutathione (by 33–43%) and increase methemoglobin levels, confirming a pro-oxidant effect in deficient cells.³⁶ This supports the potential of EGCG to disrupt redox homeostasis in G6PD-deficient contexts, but also warns against its use in such individuals without careful monitoring.

No clinical trial to date has directly measured G6PD enzymatic activity as a primary endpoint in cancer patients treated with these natural products. Future studies should incorporate pharmacodynamic biomarkers of pentose phosphate pathway flux (e.g., NADPH/NADP⁺ ratio, G6PD activity) to establish direct target engagement and to define safe dosage ranges, especially for individuals with G6PD deficiency.

6. Methods

This study is a comprehensive narrative review aimed at synthesizing the available evidence on natural products targeting G6PD and their potential role in disrupting the inflammation-cancer axis. No original experimental data were collected; therefore, ethical approval was not required.

The literature search was conducted in the following electronic databases: PubMed, Scopus, Web of Science, and Google Scholar. The search period covered 2015 up to 2026. The search strategy combined terms related to G6PD and the pentose phosphate pathway (G6PD, Glucose-6-phosphate dehydrogenase, Pentose phosphate pathway) with terms describing natural product classes and their combination with G6PD (Natural product G6PD inhibitor, Polyphenols G6PD inhibitor, Polyphenols G6PD cancer, Flavonoids G6PD inhibitor, Flavonoids G6PD cancer, Alkaloids G6PD inhibitor, Alkaloids G6PD cancer, Terpenoids G6PD inhibitor, Terpenoids G6PD cancer). Additionally, search terms related to herbal medicine (herbal extracts G6PD inhibitor, herbal medicine G6PD inhibitor) as well as redox and inflammation (NADPH, Inhibitor of G6PD, Inflammation and Cancer) were included. All search terms were combined using the Boolean operators OR and AND as appropriate. Additional relevant articles were identified by manually screening the reference lists of included studies.

Inclusion criteria were: original research articles, clinical trials, case reports, and systematic reviews published in peer-reviewed English-language journals that reported G6PD-modulating effects of natural compounds and investigated mechanisms of action such as direct enzyme inhibition, indirect regulation, or pro-oxidant effects. Exclusion criteria were: non-English articles, conference abstracts, dissertations, unpublished data, and studies focusing solely on synthetic compounds without any natural product component.

7. Conclusion

Natural products represent a promising yet underexplored class of G6PD modulators with the potential to disrupt the metabolic and redox dependencies of cancer cells. This review highlights the dual nature of these compounds, which can exert anticancer effects through NADPH depletion while posing potential risks in G6PD-deficient individuals.

Future research should prioritize: (1) identification of selective and potent G6PD inhibitors; (2) validation of their efficacy in in vivo cancer models; (3) clarification of their safety profiles in G6PD-deficient populations; and (4) development of targeted delivery systems to enhance bioavailability and specificity.

A precision medicine approach, including patient stratification based on G6PD status, will be essential for translating these natural compounds into safe and effective therapeutic strategies. Addressing these challenges will pave the way for leveraging natural products in targeting the inflammation–cancer axis.

Footnotes

ORCID iD

Mahdieh Eftekhari

Author Contributions

Conceptualization and Methodology: Mahdieh Eftekhari; Investigation: Hanane Cheshmenooshi and Aryan Mahtabi; Writing original draft preparation: Hanane Cheshmenooshi and Aryan Mahtabi; Writing review and editing: Mahdieh Eftekhari; Supervision: Mahdieh Eftekhari; Project administration: Mahdieh Eftekhari. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran (Grant Number 50006958).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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