Protein lactylation in metabolic dysfunction-associated steatotic liver disease: a mechanistic review

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder with limited therapeutic options. While its pathogenesis is complex, the underlying molecular drivers remain incompletely understood. Recently, protein lactylation, a novel lactate-derived post-translational modification (PTM), has emerged as a key regulator linking metabolic reprogramming to cellular function. This review elucidates the pivotal roles of protein lactylation throughout the progression of MASLD, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma, establishing a conceptual framework centered on the “lactate-lactylation-gene expression” axis and examining its dysregulation across hepatocytes, hepatic stellate cells, and immune cells throughout MASLD. Furthermore, we discuss emerging therapeutic strategies targeting the axis, aiming to provide a theoretical foundation for the development of precision medicine for MASLD.