{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:55:01Z","timestamp":1775130901721,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>\n                    Metabolic dysfunction\u2010associated 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\u2010related hepatic lipid dysregulation remain incompletely defined. This study investigates how aging alters hepatic phospholipid metabolism and the contribution of phosphatidylethanolamine N\u2010methyltransferase (PEMT) to MASLD progression. Here, lipid accumulation was characterized in the livers of 2\u2010, 6\u2010, 12\u2010, 18\u2010, and 24\u2010month\u2010old mice, revealing age\u2010dependent 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\u2010fold increase in the PC\/PE ratio in 24\u2010month\u2010old mice compared with 6\u2010month\u2010old controls. Mechanistically, PEMT, a key enzyme regulating PC and PE metabolism, exhibited significantly increased expression (~2.4\u2010fold at the protein level) in aged livers, suggesting a pivotal role in driving the observed phospholipid imbalance\n                    <jats:italic>in vitro<\/jats:italic>\n                    . PEMT inhibition significantly attenuated lipid droplet accumulation by ~30% and reduced intracellular TG levels by ~20% in D\u2010galactose\u2010induced senescent AML12 hepatocytes under lipid stress, compared with nonsilenced senescent controls. These findings suggest that aging\u2010driven 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\u2010associated phospholipid dyshomeostasis, revealing a previously unknown mechanistic axis distinct from diet\u2010induced MASLD and offering new therapeutic insights.\n                  <\/jats:p>","DOI":"10.1111\/febs.70349","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:27:53Z","timestamp":1764311273000},"page":"2022-2041","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>PEMT<\/scp>\n                    \u2010mediated phospholipid imbalance promotes age\u2010associated metabolic dysfunction\u2010associated steatotic liver disease progression"],"prefix":"10.1111","volume":"293","author":[{"given":"Xilong","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Nutrition and Health, Key Laboratory of Functional Dairy China Agricultural 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