Targeting Nrf2 in oxidative liver injury: expanding the role of gut microbiota and metabolites.

BACKGROUND: Liver diseases are a major cause of illness and death worldwide. Oxidative stress is a pivotal driver in the pathogenesis of a spectrum of liver diseases, including alcoholic liver disease (ALD), metabolic dysfunction-associated fatty liver disease (MAFLD), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). The transcription factor Nrf2, a master regulator of cellular antioxidant responses, plays a central yet context-dependent role in modulating this injury. Additionally, the gut-liver axis is a critical regulator of hepatic homeostasis. AIM OF REVIEW: This review presents recent advances to propose a refined gut-microbiota-Nrf2 axis as a key mechanistic link in the treatment of liver injury. We detail how specific gut-derived microbial metabolites, such as short-chain fatty acids (SCFAs), tryptophan derivatives, and urolithins, directly or indirectly activate the hepatic Keap1/Nrf2 signaling pathway. This activation orchestrates a cytoprotective program that enhances the redox balance, promotes detoxification, and induces selective autophagy, thereby protecting against oxidative liver injury. Conversely, we examine the dual role of Nrf2, highlighting how its dysregulated and constitutive activation in established HCC can paradoxically promote tumor progression and ferroptosis resistance. Finally, we evaluate the therapeutic potential of targeting this axis using microbiome-modulating strategies, including probiotic and prebiotic supplementation, fecal microbiota transplantation (FMT), dietary intervention, and synergy with Nrf2-targeting drugs. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides an integrated framework that connects gut microbial ecology with host redox signaling, offering novel mechanistic insights and translational perspectives for the prevention and treatment of oxidative liver diseases.