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

Abstract

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.

Acknowledgments

This work was financially supported by grants from the National Key R&D Program of China (Grant No. 2022YFA0807200), the National Natural Science Foundation of China (Grant No. 32471201), the Natural Science Foundation of Jiangsu Province (Grant No. BK20220151), the Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University (no. SKLNMZZ2024JS34), the Open Research Fund of Yunnan Characteristic Plant Extraction Laboratory (Grant No. YKKF2024018), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and The National Innovation and Entrepreneurship Training Program for Undergraduates.

Ethical statements

All animal procedures in this study were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996), and the approved regulations set by the Laboratory Animal Care Committee at China Pharmaceutical University (LACUC Issue No: 2024-05-064, approval date: 2024-05-27).

Author contributions

The authors confirm contributions to the work as follows: study conception and design: Chen S, Zhang W; data collection: Zhang R, Li K, Zhao Z, Jiang X, Zhang R, Liu C; analysis and interpretation of results: Zhang R, Li K; draft manuscript preparation: Zhang R, Li K; manuscript revision and editing: Chen S, Zhang W. All authors reviewed the results and approved the final version of the manuscript.

Data availability

Data supporting this study are included in the article and supplementary files or available from the corresponding author on request.

Conflict of interest

The authors declare that there is no conflict of interest.

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