Lipidomics Reveals Potential Mechanisms of Intestinal-Targeted Astaxanthin in Ameliorating Metabolic Dysfunction-Associated Steatotic Liver Disease in ApoE–/– Mice

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health burden with an urgent need for effective interventions. Although astaxanthin (AST) exhibits hepatoprotective potential, its efficacy is limited by poor oral bioavailability. This study evaluated an intestine-targeted astaxanthin delivery system (AST-LPs) in HFHC-diet-induced MASLD mice. AST-LPs administration exhibited superior efficacy over free AST in attenuating hepatic steatosis, improving lipid profiles and glucose tolerance, and suppressing inflammation. Lipidomics analysis revealed that AST-LPs preferentially remodeled HFHC-disrupted lipid profiles, particularly cardiolipins, fatty acid esters of hydroxy fatty acids (FAHFAs), and sphingolipids. Mechanistically, AST-LPs modulated the peroxisome proliferator-activated receptor (PPAR) signaling pathway by upregulating PPARα while downregulating PPARγ and fatty acid-binding protein 1 (FABP1), shifting the metabolic balance toward lipid catabolism over storage. Molecular docking confirmed high binding affinities between AST and these core targets. Collectively, these findings suggest that intestinal-targeted AST delivery is a promising multitarget therapeutic strategy for MASLD.