Furan fatty acids reprogram hepatic lipid metabolism via acyl-CoA conjugates in obesity.

Dietary fish oil (FO) and omega-3 fatty acids are associated with cardiometabolic benefits, yet their molecular mediators remain incompletely defined. Furan fatty acids (FuFAs), a distinct lipid class enriched in FO, have emerged as potential regulators of metabolic health. Here, we identify and quantify FuFA species in prescription omega-3 formulations and natural fish oils, and synthesize structurally engineered analogs designed to isolate antioxidant activity and β-oxidation susceptibility from FuFA bioactivity. In a diet-induced obesity mouse model, both natural and synthetic FuFAs reduced fat accumulation and inflammatory markers, while 11U3-2M additionally produced significant improvement in glucose tolerance, dyslipidemia, and hepatic steatosis. The superior activity of 11U3-2M reflects the stable accumulation of its acyl-CoA conjugate that activates peroxisome proliferator-activated receptor alpha (PPARα) signaling and allosterically inhibits acetyl-CoA carboxylases (ACCs) to reprogram hepatic lipid metabolism. These findings position FuFAs as functional dietary lipids contributing to fish oil's metabolic effects and define fatty acid structural determinants that govern hepatic metabolic activity.