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

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.