12,13-diHOME ameliorates MASLD by regulating Sestrin2-mediated AMPK/ULK1/Lipophagy in obese mice.

Obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic lipid accumulation and impaired lipid metabolism. Enhancing lipophagy, the autophagic degradation of lipid droplets, represents a promising therapeutic strategy. Sestrin2, a stress-responsive protein, promotes lipophagy via the AMPK/ULK1 pathway. Here, we investigated the role of 12,13-diHOME, a brown adipose tissue-derived lipid, in modulating MASLD via Sestrin2. Male Sesn2 knockout and wild-type mice were fed a high-fat diet (HFD) and treated with 12,13-diHOME. Metabolic parameters, liver histology, and lipophagy-related protein expression were analyzed. 12,13-diHOME improved insulin sensitivity, reduced plasma triglycerides and free fatty acids, and alleviated hepatic steatosis and fibrosis by enhancing lipophagy in wild-type mice. Mechanistically, 12,13-diHOME increased Sestrin2 expression, activated AMPK/ULK1 signaling, inhibited mTOR phosphorylation, and enhanced lipophagic degradation of lipid droplets. These effects were abolished in Sesn2-deficient mice and cells, demonstrating that Sestrin2 is essential for 12,13-diHOME's protective actions. Our findings identify 12,13-diHOME as a potential therapeutic agent for MASLD via Sestrin2-mediated lipophagy.