Accumulation of polyunsaturated lipids fuels ferroptosis to promote liver failure after extended hepatectomy in mice

  • Free Radic Res. 2024 Nov;58(11):733-747. doi: 10.1080/10715762.2024.2423691.
Can Huang  1 ,  Jian Gan  1 ,  Xiangyue Mo  1 ,  Qingping Li  1 ,  Leyi Liao  1 ,  Biao Wang  1 ,  Xianqiu Wu  1 ,  Hanbiao Liang  1 ,  Chen Xie  1 ,  Tianzhou Peng  1 ,  Yang Lei  1 ,  Baoxiong Zhuang  2 ,  Minghui Zeng  3 ,  Yonghong Peng  4 ,  Yisi Chen  4 ,  Cuiting Liu  4 ,  Jie Zhou  1 ,  Kai Wang  1 ,  Chuanjiang Li  1
Affiliations
  • 1. Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2. Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • 3. Institute of Scientific Research, Southern Medical University, Guangzhou, China.
  • 4. Central Laboratory, Southern Medical University, Guangzhou, China.
PMID: 39514464 DOI: 10.1080/10715762.2024.2423691
Abstract

Background: Post-hepatectomy liver failure (PHLF) is a fatal complication of hepatectomy. However, the mechanism of hepatocyte injury in PHLF remains elusive.

Methods: PHLF was induced by extended 86% hepatectomy (eHx) in mice. Lipidomics was performed to investigate the eHx-induced lipid alteration in the residual liver. Ferroptosis was assessed to screen the hepatocyte injury induced by eHx. The therapeutic effects of ferrostatin-1 (Fer-1) on PHLF were evaluated.

Results: PHLF was induced by eHx with elevation in markers of hepatocyte injury and mortality in mice within 48 h after surgery. eHx-induced hepatocyte injury was manifested by hepatocyte enlargement and hepatocyte death with glycogen depletion and lipid accumulation. Lipidomics revealed that eHx induced the accumulation of ferroptosis-favored polyunsaturated lipids. Ferroptosis was found to mediate the eHx-induced hepatocyte death in the residual liver during the development of PHLF. Fer-1 could attenuate the eHx-induced ferroptotic hepatocyte death and PHLF in mice.

Conclusions: Ferroptosis partly mediates the eHx-induced hepatocyte injury during the development of PHLF. Accumulation of polyunsaturated lipids in hepatocytes may promote eHx-induced Ferroptosis, and targeting lipid peroxidation is a potential therapeutic strategy for PHLF.

Keywords
Post-hepatectomy liver failure; extended hepatectomy; ferroptosis; lipids; transient regeneration-associated steatosis.
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