Btg2 inhibits Fmo1 UFMylation thus exacerbating ferroptosis and apoptosis in hepatic ischemia-reperfusion injury.

Hepatic ischemia‒reperfusion injury (HIRI) represents a frequently occurring pathological condition during liver surgery, yet the mechanisms governing HIRI remain inadequately comprehended. Here, we investigate the role of B-cell translocation gene 2 (Btg2) in HIRI. Btg2 is upregulated following HIRI. A 70% HIRI model using hepatocyte-specific Btg2 transgenic and systemic Btg2 knockout mice reveals that Btg2 deteriorates hepatic inflammation and apoptosis. In primary hepatocytes, Btg2 knockdown reduces hypoxia/reoxygenation (H/R)-induced inflammation and mitochondrial stress. Metabolomics indicates that taurine metabolism is significantly affected in the livers of Btg2-/- mice. Mechanistically, Btg2 suppresses UFMylation of flavin-containing monooxygenase 1 (Fmo1), a key taurine synthesis enzyme, promoting its K48-linked ubiquitination and degradation. Virus-mediated Fmo1 overexpression inhibits ferroptosis, apoptosis, and HIRI significantly both in vivo and in vitro. Virtual screening of natural compounds indicates that Daturataturin A (DTA) inhibits Btg2, thereby attenuating ferroptosis and HIRI. These results suggest that Btg2 may constitute a promising therapeutic target for HIRI.