From Oxidative Stress to Fibrogenesis: A Comprehensive Review of a Composite Oxidative-Fibrotic Index in Hypoxia-Associated MAFLD

Abstract

Metabolically associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease, with fibrosis representing the strongest predictor of adverse clinical outcomes. Emerging evidence suggests that intermittent hypoxia, commonly associated with obstructive sleep apnea, contributes to fibrosis progression through oxidative stress-mediated mechanisms. This review aims to synthesize current evidence on the role of intermittent hypoxia in driving oxidative stress and hepatic fibrogenesis in MAFLD, and to propose a Composite Oxidative-Fibrotic Index as an integrative biomarker framework. A narrative review was conducted using major biomedical databases to identify experimental and clinical studies evaluating hypoxia-induced oxidative stress, redox-sensitive signaling pathways, and fibrogenic responses in MAFLD. Intermittent hypoxia induces repetitive hypoxia-reoxygenation cycles that promote reactive oxygen species generation, impair antioxidant defenses, and activate redox-sensitive pathways, including HIF-1α, NF-κB, and Nrf2 dysregulation. These mechanisms contribute to hepatic stellate cell activation, extracellular matrix remodeling, and increased liver stiffness. Evidence indicates that individual oxidative and fibrogenic biomarkers are insufficient to capture the dynamic progression of fibrosis. The proposed Composite Oxidative-Fibrotic Index integrates oxidative stress markers, signaling mediators, fibrogenic indicators, and liver stiffness measurement into a unified framework. This approach may improve early detection, risk stratification, and monitoring of fibrosis progression in hypoxia-associated MAFLD, with potential implications for biomarker-guided clinical management and targeted therapeutic strategies.