Understanding the role of hypoxia inducible factors in liver fibrosis and future therapeutic applications

Liver fibrosis is a chronic and progressive outcome of liver injury and continues to be a major contributor to liver morbidity and mortality. It is characterized by the excessive accumulation of extracellular matrix, resulting in the loss of normal liver architecture. Chronic liver injury also affects the availability of oxygen in the liver tissue, resulting in a hypoxic microenvironment. Among the major mediators of the hypoxic response, hypoxia-inducible factor-1α (HIF-1α) has been identified as a major regulator of fibrogenesis. The major experimental and clinical data have shown that the HIF pathway is closely linked to the activation of hepatic stellate cells, inflammation, pathological angiogenesis, and metabolic derangements in the fibrotic liver. These events are interlinked and result in the promotion of ongoing matrix accumulation and tissue remodeling. Recent studies have also indicated that the hypoxic pathways may cross-talk with ferroptosis and iron-mediated oxidative damage, providing new information on the mechanisms underlying the progression of fibrosis. This review aims to provide an overview of the current evidence on the role of HIF-1α in liver fibrosis and its connection between the major profibrotic pathways. We also provide information on the new therapeutic approaches targeting hypoxia signaling, including pharmacological inhibitors, von hippel-lindau (VHL) pathway modulation, and naturally derived compounds that have been reported to possess antifibrotic activity. A better understanding of the mechanisms driven by hypoxia may provide new information for the development of more accurate and stage-specific therapies for chronic liver diseases.