Divergent Hypoxia-Inducible Factor 2-Alpha Signaling in Alcoholic Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract Fatty liver disease, including both metabolic dysfunction-associated steatotic liver disease (MASLD) and alcoholic liver disease (ALD) types, is an increasing global health issue, with escalating rates of illness and death. A key player in the progression of these liver diseases is the hypoxia-inducible factor 2-alpha (HIF-2α), a transcription factor that oversees lipid metabolism, oxidative stress, and inflammation in liver cells. This review aims to summarize the intricate interactions between HIF-2α and various transcriptional regulators, including peroxisome proliferator-activated receptor alpha (PPARα), sterol regulatory element-binding protein-1c (SREBP1c), neuraminidase 3 (NEU3), and X-box-binding protein 1(XBP1), in hypoxic environments often linked to fatty liver disease. The role of HIF-2α in the pathogenesis and progression of alcoholic liver disease remains complex and incompletely understood, with evidence suggesting context-dependent and sometimes contradictory effects. However, our study emphasizes HIF-2α’s dual function in facilitating hepatic steatosis and fibrosis by hindering β-oxidation, causing mitochondrial dysfunction, and altering inflammatory pathways. Furthermore, this review focuses on summarizing how ethanol metabolism influences the expression of HIF-2α and examines its subsequent effects on the balance of bile acids and bilirubin, offering mechanistic insights into the pathophysiology of alcoholic liver disease (ALD) in comparison to MASLD. The review indicates that specifically inhibiting HIF-2α could hold therapeutic promise for treating both MASLD and ALD, justifying the need for additional experimental and clinical research.