Elaidic acid drives cellular senescence and inflammation via lipid raft-mediated IL-1R signaling.

Fatty acids (TFAs) have been associated with various inflammatory diseases, including atherosclerosis and metabolic syndrome, such as metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanism remains unclear. Here, we show that in response to DNA damage, elaidic acid (EA), a most common TFA, amplifies interleukin-1 receptor (IL-1R) signaling, leading to the promotion of cellular senescence and senescence-associated secretory phenotype (SASP). Upon DNA damage, EA enhanced senescence-associated β-galactosidase activity and expressions of IL-1α/6/8 through the IL-1R-transforming growth factor-β-activated kinase 1 (TAK1)-nuclear factor (NF)-κB axis in a manner dependent on mammalian target of rapamycin (mTOR). Mechanistically, EA, incorporated into lipid rafts, enhances IL-1R activation and subsequent NF-κB signaling, creating a positive feedback loop. EA consumption elevated expressions of SASP factors and cellular senescence in the livers of high-fat diet mice. Our findings provide a mechanistic insight into TFA-related inflammation and disorders, including MASLD/MASH.