Artesunate Ameliorates APAP‐induced Liver Injury by Promoting NEDD4L‐Mediated Ubiquitination and Degradation of TXNIP

ABSTRACT Liver injury can lead to severe acute liver failure and even death in patients. Artesunate (ART), which is a derivative of artemisinin that has been approved by the FDA for the treatment of malaria, has significant regulatory effects on cell death and inflammation. In this study, we found that ART exerts a protective effect on various preclinical animal models of liver injury, including mouse models of liver injury induced by APAP, CCl ₄ , and Con A. Mechanistically, CETSA, DARTS and SPR indicate that ART directly binds to the LYS653 and ASP837 residues within the HECT domain of NEDD4L, and enhances the interaction between NEDD4L and the substrate TXNIP, promoting the ubiquitination and proteasomal degradation of TXNIP, ultimately alleviating APAP‐induced liver injury. Furthermore, the overexpression of TXNIP as well as the global knockout or liver‐specific knockdown of NEDD4L eliminates the effect of ART on alleviating liver injury. These data suggest that the NEDD4L‐TXNIP axis participates in the development of liver injury and highlight the potential of ART to be used in the clinical treatment of liver injury.