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

Rong Li, Xijing Yan, Cuicui Xiao, Tingting Wang, Xuejiao Li, Zhongying Hu, Jinliang Liang, Jiebin Zhang, Jianye Cai, Xin Sui, Qiuli Liu, Manli Wu, Jiaqi Xiao, Haitian Chen, Yasong Liu, Chenhao Jiang, Guo Lv, Guihua Chen, Yingcai Zhang (), Jia Yao (), Jun Zheng () and Yang Yang ()
Additional contact information
Rong Li: Third Affiliated Hospital of Sun Yat-sen University
Xijing Yan: Third Affiliated Hospital of Sun Yat-sen University
Cuicui Xiao: the Third Affiliated Hospital of Sun Yat-sen University
Tingting Wang: Third Affiliated Hospital of Sun Yat-sen University
Xuejiao Li: Third Affiliated Hospital of Sun Yat-sen University
Zhongying Hu: Third Affiliated Hospital of Sun Yat-sen University
Jinliang Liang: Third Affiliated Hospital of Sun Yat-sen University
Jiebin Zhang: Third Affiliated Hospital of Sun Yat-sen University
Jianye Cai: Third Affiliated Hospital of Sun Yat-sen University
Xin Sui: the Third Affiliated Hospital of Sun Yat-sen University
Qiuli Liu: the Third Affiliated Hospital of Sun Yat-Sen University
Manli Wu: the Third Affiliated Hospital of Sun Yat-Sen University
Jiaqi Xiao: Third Affiliated Hospital of Sun Yat-sen University
Haitian Chen: Third Affiliated Hospital of Sun Yat-sen University
Yasong Liu: Third Affiliated Hospital of Sun Yat-sen University
Chenhao Jiang: Third Affiliated Hospital of Sun Yat-sen University
Guo Lv: Third Affiliated Hospital of Sun Yat-sen University
Guihua Chen: Third Affiliated Hospital of Sun Yat-sen University
Yingcai Zhang: Third Affiliated Hospital of Sun Yat-sen University
Jia Yao: Third Affiliated Hospital of Sun Yat-sen University
Jun Zheng: Third Affiliated Hospital of Sun Yat-sen University
Yang Yang: Third Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49202-3

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