The role of lysine acylation in metabolic dysregulation and inflammatory responses within the hepatic immune microenvironment of MASLD

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a chronic liver disorder characterized by metabolic abnormalities, persistent low-grade inflammation, and alterations in hepatic immune function. In addition to lipid accumulation and dysregulated energy metabolism, metabolism-associated post-translational modifications of proteins may also contribute to the initiation and progression of MASLD. Among these modifications, lysine acylation is regulated by the availability and composition of intracellular acyl-CoA species, as well as the activities of acyltransferases and deacylases, and can modulate metabolic enzyme activity, inflammatory signaling pathways, and gene transcription. This review summarizes the interplay between metabolic dysregulation and lysine acylation in MASLD, with particular emphasis on how gut-derived metabolites, disturbances in hepatic glycolipid metabolism, and alterations in subcellular metabolic environments influence the formation of distinct lysine acylation modifications. Furthermore, from the perspectives of hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells, we discuss the potential roles of lysine acylation in cellular injury, inflammatory responses, hepatic stellate cell activation, and liver fibrosis. In addition, we highlight the current progress regarding the potential of lysine acylation as a biomarker and therapeutic target, and propose that integrated approaches involving metabolic tracing, spatial omics, and site-specific genome editing may further elucidate the functional significance of key acylation events in MASLD. Overall, lysine acylation is closely associated with metabolic disturbances, hepatic inflammation, and fibrogenic processes in MASLD. A deeper understanding of cell type–specific regulatory acylation sites will facilitate the evaluation of their potential applications as biomarkers and therapeutic targets for MASLD.