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 progressive liver disorder in which fibrosis represents the main determinant of long-term clinical outcomes. Beyond classical metabolic risk factors, intermittent hypoxia, a hallmark of obstructive sleep apnea and a frequent comorbidity in metabolic syndrome, has emerged as an important modifier of disease progression. Repetitive cycles of hypoxia and reoxygenation lead to the excessive generation of reactive oxygen species (ROS), redox imbalance, inflammatory activation, and microvascular dysfunction, thereby promoting the activation of hepatic stellate cells and the deposition of extracellular matrix. Although numerous oxidative stresses and fibrogenic biomarkers have been described, they are commonly evaluated as isolated parameters and do not fully reflect the integrated pathophysiological continuum linking hypoxia, oxidative injury, and fibrogenesis.

The objective of this review is to systematically integrate experimental and clinical evidence regarding hypoxia-induced oxidative stress and liver fibrosis in MAFLD and to propose a cohesive concept of a Composite Oxidative-Fibrotic Index as an early marker of fibrosis progression. We found relevant literature in major biomedical databases that focused on quantitative redox biomarkers like malondialdehyde, antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), and redox-sensitive signaling pathways (Nrf2 and hypoxia-inducible factors). We also looked at key fibrogenic markers like transforming growth factor-β1, α-smooth muscle actin, collagen deposition, matrix metalloproteinase/tissue inhibitor imbalance, and non-invasive liver stiffness measurements. Integrated analysis shows that intermittent hypoxia activates a coordinated oxidative-fibrotic axis. This happens when a persistent redox imbalance increases inflammatory and profibrotic signaling, which keeps stellate cells activated and the matrix remodeling. Consequently, the Composite Oxidative-Fibrotic Index is suggested to amalgamate pertinent oxidative and fibrogenic biomarkers into a cohesive mechanistic framework for the early identification, risk assessment, and surveillance of hypoxia-related fibrosis in MAFLD. This integrative approach may enhance the development of translational biomarkers and bolster forthcoming diagnostic and therapeutic strategies aimed at hypoxia-induced liver fibrogenesis.