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

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 E₂ (PGE₂) 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 PGE₂ 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.