Crocin II alleviates metabolic dysfunction-associated steatotic liver disease by enhancing autophagic degradation of ANGPTL8

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a severe public health crisis, affecting more than a quarter of the adult population. ANGPTL8 is a potential therapeutic target for MASLD owing to its dual roles in lipid and inflammatory regulation. However, current targeting strategies are inadequate, particularly in the realm of natural compound-driven protein degradation inducers. In this study, we utilize molecular docking analysis, a cellular thermal shift assay, a drug affinity responsive target stability assay, and a surface plasmon resonance assay to identify Crocin II as a potential candidate for targeting ANGPTL8. We demonstrate that Crocin II can facilitate the degradation of ANGPTL8 protein via the autophagosome-lysosome pathway. Pharmacodynamically, Crocin II ameliorates HFD-induced MASLD by targeting ANGPTL8, with no overt adverse effects in murine kidneys, hearts, and spleens. In conclusion, our study demonstrates that Crocin II has a favorable therapeutic effect on MASLD by targeting ANGPTL8 and promoting its protein degradation, indicating that Crocin II is a promising candidate for MASLD therapy.