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, cellular thermal shift assay, drug affinity responsive target stability assay, and 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.