Hypoxia in MASLD: a spatial determinant of the pathogenesis

The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids critical for defining the liver zonation. In metabolic dysfunction-associated steatotic liver disease (MASLD), fat accumulation and fibrosis disrupt this architecture, contributing to localised hypoxia. Mounting evidence implicates hypoxia in MASLD, including the activation of canonical hypoxia sensors such as hypoxia-inducible factors. Moreover, chronic intermittent hypoxia, characteristic of obstructive sleep apnoea (OSA), is epidemiologically and mechanistically associated with MASLD progression. This review examines the intrahepatic oxygen dynamics, the interplay between OSA and MASLD, and molecular responses to hypoxia, proposing intrahepatic hypoxia as a spatial determinant of liver injury.