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

  • Nat Commun. 2026 May 9;17(1):6270. doi: 10.1038/s41467-026-72455-z.
Dadi Peng  #  1 ,  Yihua Wang  #  2 ,  Dengliang Lei  #  1 ,  Kezhen Zong  #  1 ,  Shanshan Li  1 ,  Yunhai Luo  1 ,  Qiuying Li  1 ,  Liqing Jiang  1  3 ,  Weifeng Huang  1 ,  Yulin Ou  1 ,  Huarong Yu  4 ,  Jiayin Yang  5  6 ,  Zuotian Huang  7 ,  Zhongjun Wu  8
Affiliations
  • 1. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Department of Hepatobiliary Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 3. Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
  • 4. Research Center of Neuroscience, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China. [email protected].
  • 5. Department of Liver Transplantation Center & Institute of Organ Transplantation, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 6. Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • 7. Department of Hepatobiliary Surgery, Cancer Hospital of Chongqing University, Chongqing, China. [email protected].
  • 8. Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 42106354 DOI: 10.1038/s41467-026-72455-z
Abstract

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.

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