Inhibition of COX‐2‐Mediated Arachidonic Acid Metabolism by FGF21‐PPARα Axis Alleviates Liver Steatosis

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is associated with disturbances in arachidonic acid (AA) metabolism; however, the role and regulation of cyclooxygenase‐2 (COX‐2), a key enzyme in AA metabolism, during disease progression remain incompletely understood. Here, we identify fibroblast growth factor 21 (FGF21) as a previously unrecognized suppressor of hepatic COX‐2 in MASLD. Although both FGF21 and COX‐2 were elevated in steatotic livers, FGF21 deficiency further augmented hepatic COX‐2 expression in mice fed with a high‐fat diet, leading to dysregulated AA metabolism, excessive prostaglandin E 2 (PGE 2 ) production, aggravated inflammation, oxidative stress, and fibrosis. Conversely, adeno‐associated virus (AAV)‐mediated restoration of FGF21 normalized COX‐derived AA metabolites, suppressed COX‐2 activation, and ameliorated hepatic injury. Pharmacological inhibition of COX‐2 partially recapitulated the protective effects of FGF21 but failed to reverse fibrosis, suggesting that COX‐2 contributes to disease progression but is not sufficient to account for fibrosis. Mechanistically, FGF21 suppressed COX‐2 through a PPARα‐dependent pathway, whereas ERK1/2 phosphorylation acted upstream of the FGF21/PPARα axis. In patients with MASLD, circulating PGE 2 was positively associated with liver injury after adjustment for body mass index and hepatic steatosis. Collectively, the FGF21‐PPARα‐COX‐2 axis represents a critical regulator of AA metabolic remodeling and a potential therapeutic target for MASLD.