Gut microbiota-derived metabolites as context-dependent modulators of Nrf2 signaling in inflammation-driven carcinogenesis

Abstract

Abstract Chronic inflammation fosters cancer development by sustaining redox imbalance, oxidative stress and persistent tissue damage. A key component to this process is the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), which coordinates antioxidant and detoxification programs to maintain redox homeostasis. While transient Nrf2 activation protects non-malignant tissues by limiting cell and tissue damage, persistent or dysregulated Nrf2 signaling in premalignant tissue and established tumors can promote cancer cell survival, metabolic adaptation and resistance to chemotherapy. Growing evidence identifies gut microbiota-derived metabolites as modulators of Nrf2 signaling, thereby providing a mechanistic link between microbial metabolism and inflammation-driven carcinogenesis. Distinct functional classes of bacterial metabolites, including short-chain fatty acids, tryptophan-derived indoles, secondary bile acids, polyphenol-derived metabolites and electrophilic redox-active compounds, converge on Nrf2 regulation across epithelial, immune and tumor compartments. Importantly, the biological consequences of these interactions are highly context-dependent and shaped by disease stage, cellular metabolic state and tissue microenvironment. This review integrates current evidence on how microbial metabolites regulate Nrf2 signaling and redox homeostasis during chronic inflammation and cancer development or progression. We further discuss how dietary interventions, probiotics or postbiotics, and metabolite-based strategies may be leveraged to modulate the microbiota-Nrf2 axis for cancer prevention or therapy. Overall, we propose that microbial metabolites represent a context-dependent mechanism for modulating Nrf2 activity in inflammation-associated cancers, with important implications for translational and precision medicine approaches.