Neohesperidin Regulates Lipid Metabolism and Ameliorates <scp>MASLD</scp> by Targeting <scp>ECHS1</scp>

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver condition globally, closely linked to disrupted lipid metabolism, yet effective targeted therapies remain elusive. While we previously reported the efficacy of ShuGan-QieZhi Capsule against fatty liver disease, the therapeutic potential of its active component, Neohesperidin (NH), in MASLD was unknown. Here, we demonstrate that NH effectively alleviates lipid accumulation in high-fat diet (HFD)-induced mice and palmitic acid (PA)-treated hepatocytes. Mechanistically, NH directly binds to PHE248 of ECHS1, a key enzyme in fatty acid β-oxidation, and inhibits its ubiquitin-proteasome-mediated degradation, thereby stabilizing ECHS1 and promoting lipid catabolism. Additionally, NH modulates the PPARα signaling pathway, contributing to its overall therapeutic effect. Our findings not only identify ECHS1 as a promising therapeutic target for MASLD but also propose NH as a first-in-class small molecule that directly stabilizes ECHS1, providing a novel strategy against MASLD by targeting protein stability to restore lipid homeostasis.