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Btg2 Inhibits the UFMylation of Fmo1 thus Restricting Taurine Synthesis and Exacerbating Ferroptosis in Hepatic Ischemia-Reperfusion Injury in Mice

ABSTRACT: Hepatic ischemia‒reperfusion (I/R) injury (HIRI) represents a frequently occurring pathological phenomenon during liver surgery, yet the mechanisms governing HIRI remain inadequately comprehended. This study intends to explore the role of B-cell translocation gene 2 (Btg2) in HIRI. We find that Btg2 expression is up-regulated following HIRI. We subsequently develop an HIRl model utilizing hepatocyte-specific Btg2 transgenic over-expression and systemic Btg2 knockout male mice, discovering that Btg2 deletion mitigates inflammation and apoptosis. Furthermore, cellular experiments confirm that Btg2 knockdown alleviates inflammation and mitochondrial stress generated by hypoxia/reoxygenation (H/R). Metabolomics reveals enrichment of taurine metabolism pathway in the Btg2-/- mice. Mechanistically, we demonstrate that Btg2 restricts the UFMylation of flavin-containing monooxygenase 1 (Fmo1), the essential enzyme for taurine synthesis, by the E3 ligase UFM1-specific ligase 1 (Ufl1), consequently facilitating the K48 ubiquitination-mediated degradation of Fmo1. Adeno-associated virus-mediated Fmo1 over-expression inhibits ferroptosis and HIRI significantly in vivo, while adenovirus-mediated Btg2 over-expression mitigates ferroptosis and hypoxia/reoxygenation damage in vitro. Moreover, virtual screening of natural compounds reveals that Daturataturin A inhibits Btg2 and attenuates ferroptosis and HIRI sufficiently. These results propose that Btg2 may constitute a promising therapeutics target for HIRI.

ORGANISM(S): Mus Musculus

SUBMITTER: Zhongjun Wu

PROVIDER: PXD066631 | iProX | Fri Jul 25 00:00:00 BST 2025

REPOSITORIES: iProX

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