Neohesperidin Regulates Lipid Metabolism and Ameliorates MASLD by Targeting ECHS1

ABSTRACT

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.