(−)-Epicatechin Protects against Fatty Liver Hemorrhagic Syndrome in Laying Hens by Integrating Multitarget Mechanisms via ERα Signaling

Abstract Fatty liver hemorrhagic syndrome (FLHS) is a common metabolic disorder in laying hens with limited preventive strategies. This study evaluated whether (−)-epicatechin (EC) protects against FLHS induced by a high-energy, low-protein diet. EC supplementation alleviated hepatic lipid accumulation, dyslipidemia, liver injury, oxidative stress, inflammation, and apoptosis. Network pharmacology identified estrogen receptor α (ERα) as a core target, and molecular docking predicted EC binding to the ERα ligand cavity. In vivo and in vitro validation confirmed an ERα-dependent mechanism: EC-activated ERα reprogrammed lipid metabolism, suppressed the HIF-1α pathway to enhance antioxidant capacity, and inhibited Src kinase to block NF-κB and MAPK signaling, thereby reducing inflammation and apoptosis. These findings demonstrate that EC counteracts FLHS through an ERα-centered multitarget mechanism, supporting its potential as a dietary supplement for managing FLHS in poultry.