High-fat diet, gut dysbiosis, and oxidative stress: A synergistic triangle in metabolic dysfunction-associated steatotic liver disease pathogenesis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prominent metabolic disease characterized by hepatic steatosis, inflammation, and progressive liver damage, in which oxidative stress plays a crucial pathogenic role. Increasing attention has been drawn to the contributions of a high fat diet (HFD) and gut dysbiosis in the onset and progression of MASLD. These factors compromise intestinal barrier integrity, promote endotoxemia, induce lipid peroxidation, and activate pro-inflammatory signaling pathways, contributing to oxidative stress. Excessive production of reactive oxygen species disrupts hepatic redox homeostasis, impairs mitochondrial function, and amplifies inflammatory responses, thereby accelerating hepatic fibrosis and disease progression. This review highlights the triangular and synergistic relationship among HFD, gut dysbiosis, and oxidative stress in MASLD pathogenesis. It provides a comprehensive overview of antioxidant interventions, including lifestyle modifications, dietary antioxidants, natural bioactive compounds, and pharmacological agents, aiming at providing promising MASLD management in future clinical applications.

Keywords: Metabolic dysfunction-associated steatotic liver disease; High-fat diet; Gut dysbiosis; Oxidative stress; Intestinal barrier dysfunction

Core Tip: This review proposes a unifying framework in which a high-fat diet, gut dysbiosis, and oxidative stress form a self-reinforcing pathogenic triad driving metabolic dysfunction-associated steatotic liver disease. We synthesize evidence showing how diet-induced microbial imbalance disrupts intestinal barrier integrity, promotes endotoxemia, and amplifies hepatic oxidative stress, mitochondrial dysfunction, inflammation, and fibrosis. By positioning oxidative stress as a central mechanistic nexus linking diet and microbiota, this review highlights antioxidant-based lifestyle, nutritional, and pharmacological strategies as promising, integrative approaches for prevention and treatment.