B-cell Translocation Gene 2 Inhibits UFMylation Modification of FMO1 thus Restricting Taurine Synthesis and Exacerbating Ferroptosis in Hepatic Ischemia-Reperfusion Injury

Hepatic ischemia-reperfusion (I/R) injury is a common complication occurs during liver transplantation. However, the mechanisms underlying hepatic I/R injury have not been fully elucidated. B-cell translocation gene 2 (Btg2) has been implicated in the development of various diseases. However, its involvement in hepatic I/R injury remains unclear. The present study aimed to explore the role of Btg2 in hepatic I/R injury. We observed that Btg2 expression was elevated alongside the progress of hepatic I/R injury in mice liver tissues and primary hepatocytes. Systemic Btg2 knock-out (KO) substantially alleviated inflammation and mitochondrial stress, while conditional hepatocyte Btg2 knock-in (KI) largely aggravated inflammation and mitochondrial oxidative stress in hepatic I/R injury. Metabolomics analysis revealed that taurine metabolism was significantly enriched in Btg2-KO mice after hepatic I/R injury. Mechanistically, Btg2 binds to FMO1 to restrict the UFMylation of FMO1 by the E3 ligase UFM1-specific ligase 1 (UFL1), which in turn promoting K48 ubiquitination-mediated degradation of FMO1. Our study results demonstrate that Btg2 exacerbates hepatic I/R injury by restricting the UFMylation and degradation of FMO1, which in turn aggravates ferroptosis. These results suggest that Btg2 may be a potential therapeutic target for hepatic I/R injury.