2. Academic Validation
  3. FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC

FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC

  • Nat Commun. 2024 Jun 4;15(1):4760. doi: 10.1038/s41467-024-49202-3.
Rong Li # 1,  Xijing Yan # 1 2,  Cuicui Xiao # 3,  Tingting Wang # 1 2,  Xuejiao Li # 1,  Zhongying Hu 1,  Jinliang Liang 1,  Jiebin Zhang 1 2,  Jianye Cai 1 2,  Xin Sui 4,  Qiuli Liu 5,  Manli Wu 6,  Jiaqi Xiao 1 2,  Haitian Chen 1 2,  Yasong Liu 1 2,  Chenhao Jiang 1 2,  Guo Lv 1,  Guihua Chen 1 2,  Yingcai Zhang 7 8,  Jia Yao 9 10,  Jun Zheng 11 12,  Yang Yang 13 14
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 2 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, 510630, China.
  • 3 Department of Anesthesiology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 4 Surgical ICU, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 5 The Biotherapy Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
  • 6 Department of ultrasound, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
  • 7 Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. zhangyc3@mail.sysu.edu.cn.
  • 8 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, 510630, China. zhangyc3@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. yaojia6@mail.sysu.edu.cn.
  • 10 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, 510630, China. yaojia6@mail.sysu.edu.cn.
  • 11 Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. zhengj67@mail2.sysu.edu.cn.
  • 12 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, 510630, China. zhengj67@mail2.sysu.edu.cn.
  • 13 Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. yysysu@163.com.
  • 14 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, 510630, China. yysysu@163.com.
  • # Contributed equally.
PMID: 38834654 DOI: 10.1038/s41467-024-49202-3
Abstract

Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation. The potential mechanism remains unclear. Here, we demonstrate older livers exhibit increased Ferroptosis during HIRI. Inhibiting Ferroptosis significantly attenuates older HIRI phenotypes. Mass spectrometry reveals that fat mass and obesity-associated gene (FTO) expression is downregulated in older livers, especially during HIRI. Overexpressing FTO improves older HIRI phenotypes by inhibiting Ferroptosis. Mechanistically, acyl-CoA synthetase long chain family 4 (ACSL4) and Transferrin Receptor protein 1 (TFRC), two key positive contributors to Ferroptosis, are FTO targets. For ameliorative effect, FTO requires the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrate nicotinamide mononucleotide can upregulate FTO demethylase activity, suppressing Ferroptosis and decreasing older HIRI. Collectively, these findings reveal an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO to improve graft function after older donor liver transplantation.

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