PEMT ‐mediated phospholipid imbalance promotes age‐associated metabolic dysfunction‐associated steatotic liver disease progression

Metabolic dysfunction‐associated steatotic liver disease [MASLD; previously known as nonalcoholic fatty liver disease (NAFLD)] is a prevalent chronic liver disorder strongly associated with aging, yet the mechanisms underlying age‐related hepatic lipid dysregulation remain incompletely defined. This study investigates how aging alters hepatic phospholipid metabolism and the contribution of phosphatidylethanolamine N‐methyltransferase (PEMT) to MASLD progression. Here, lipid accumulation was characterized in the livers of 2‐, 6‐, 12‐, 18‐, and 24‐month‐old mice, revealing age‐dependent increases in hepatic triacylglycerol (TG), total cholesterol (TC), and lipid droplet formation. Lipidomic analysis revealed a marked imbalance in phospholipid composition, characterized by increased phosphatidylcholine (PC) and decreased phosphatidylethanolamine (PE), resulting in a 2.5‐fold increase in the PC/PE ratio in 24‐month‐old mice compared with 6‐month‐old controls. Mechanistically, PEMT, a key enzyme regulating PC and PE metabolism, exhibited significantly increased expression (~2.4‐fold at the protein level) in aged livers, suggesting a pivotal role in driving the observed phospholipid imbalance in vitro . PEMT inhibition significantly attenuated lipid droplet accumulation by ~30% and reduced intracellular TG levels by ~20% in D‐galactose‐induced senescent AML12 hepatocytes under lipid stress, compared with nonsilenced senescent controls. These findings suggest that aging‐driven PEMT overexpression promotes phospholipid remodeling and hepatic lipid accumulation. By leveraging a natural aging mouse model, our study provides the first evidence linking PEMT activity to age‐associated phospholipid dyshomeostasis, revealing a previously unknown mechanistic axis distinct from diet‐induced MASLD and offering new therapeutic insights.