FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice

Gaozan Tong, Yiming Chen, Xixi Chen, Junfu Fan, Kunxuan Zhu, ZiJing Hu, Santie Li, Junjie Zhu, Jianjun Feng, Zhaohang Wu, Zhenyu Hu, Bin Zhou, Litai Jin, Hui Chen, Jingling Shen (), Weitao Cong () and XiaoKun Li ()
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Gaozan Tong: Wenzhou Medical University
Yiming Chen: The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University
Xixi Chen: Taizhou Central Hospital
Junfu Fan: Wenzhou Medical University
Kunxuan Zhu: Wenzhou Medical University
ZiJing Hu: Wenzhou Medical University
Santie Li: Wenzhou Medical University
Junjie Zhu: Wenzhou Medical University
Jianjun Feng: Wenzhou Medical University
Zhaohang Wu: Wenzhou Medical University
Zhenyu Hu: Wenzhou Medical University
Bin Zhou: Wenzhou Medical University
Litai Jin: Wenzhou Medical University
Hui Chen: Wenzhou Medical University
Jingling Shen: Wenzhou University
Weitao Cong: Wenzhou Medical University
XiaoKun Li: Wenzhou Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.

Date: 2023
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DOI: 10.1038/s41467-023-41800-x

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