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

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. ¹⁵ cardiovascular 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

4.1. 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. ²⁴ G6PD 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 death ²⁶ 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. ¹⁴ thus 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.

5.1. 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 effect ⁴² 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. ³² Similarly, 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. ⁵ These 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.

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Figure 1.

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