iProXProteomicsGaozan TongHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0007032000s15869689556@163.comWenzhou Medical UniversityiProXHepatic 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.FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice.Tong Gaozan G, Chen Yiming Y, Chen Xixi X, Fan Junfu J, Zhu Kunxuan K, Hu ZiJing Z, Li Santie S, Zhu Junjie J, Feng Jianjun J, Wu Zhaohang Z, Hu Zhenyu Z, Zhou Bin B, Jin Litai L, Chen Hui H, Shen Jingling J, Cong Weitao W, Li XiaoKun XfalseTo explore potential proteins that bind to usp16HEK293T cells were transfected with FLag-USP16, and cells were performed with co-immunoprecipitation by Flag antibody or IgG with protein A/G beads.Fri Sep 01 00:00:00 BST 2023PXD045021960637777507