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

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

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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