Hypoxia represents a significant yet often underrecognized mechanism in the development and progression of liver diseases. Because of its high metabolic activity and pronounced oxygen gradient within the hepatic lobule, the liver is particularly vulnerable to disturbances in oxygen supply. This review discusses both systemic and local causes of hepatic hypoxia and highlights the central role of hypoxia-inducible factors (HIFs) in mediating adaptive and pathological cellular responses. Activation of HIF signaling pathways influences lipid and glucose metabolism, angiogenesis, inflammation, fibrogenesis, and tumor progression. Although these mechanisms initially promote cellular survival, persistent or intermittent hypoxia contributes to the development of metabolic dysfunction-associated steatotic liver disease, alcoholic liver disease, and hepatocellular carcinoma. A deeper understanding of hypoxia-driven molecular pathways may provide novel therapeutic opportunities, particularly through targeted modulation of HIF activity and metabolic processes involved in disease progression. Our aim is to highlight hypoxia as an important risk factor for the development of liver diseases and to emphasize its potential diagnostic and therapeutic significance.
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