The Interplay Between Cellular Senescence and Lipid Metabolism in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease worldwide. MASLD spans a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), and is linked to progressive fibrosis and ultimately hepatocellular carcinoma (HCC). Growing evidence implicates cellular senescence (CS) and lipid droplets (LD) dysregulation as key drivers of disease progression, although their interaction remains poorly characterized. This review synthe-sizes current mechanistic insights into how CS and LD regulation affect the transition from steatosis to MASH. Senescent hepatocytes display altered lipid metabolism, includ-ing upregulation of receptors such as cluster of differentiation (CD) 36, enhancing lipid uptake to meet increased energy demands. Initially, elevated free fatty acid influx can ac-tivate peroxisome-proliferator receptor alpha (PPARα), promoting fatty acid oxidation (FAO) as a compensatory response. Over time, persistent cellular senescence (CS) under steatotic conditions leads to mitochondrial dysfunction and suppression of fatty acid ox-idation (FAO), while the senescence-associated secretory phenotype (SASP), largely driven by nuclear factor – kappa B (NF-κB) signaling, promotes chronic hepatic inflammation. A comprehensive understanding of this dynamic crosstalk between CS and lipid metabo-lism could identify novel therapeutic targets to modulate the MASLD progression.