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

Abstract Hepatic ischemia-reperfusion injury (IRI) is a common complication that occurs during hepatic resection and liver transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aimed to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI and the underlying mechanisms. In this work, we found that FGF18 was upregulated in the livers of human and mice subjected to IRI. Hepatic stellate cells (HSCs) secreted FGF18 and protected against IRI-induced hepatocytes apoptosis, inflammation and oxidative stress. Liver-specific FGF18 overexpression effectively alleviated I/R-induced liver injury, while aggravated in mice with HSCs-specific FGF18 deletion. Mechanistically, FGF18 treatment reduced the mRNA and protein 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). In addition, USP16 interacted and deubiquitinated KEAP1 via K48-linked ubiquitination. More importantly, FGF18-induced Nrf2 directly bound to the promoter of USP16 and thus formed a negative feedback loop with USP16. Collectively, our results show that FGF18 alleviates hepatic IRI mainly by elevating the ubiquitination level of KEAP1 via downregulation of USP16 and thereby activating the Nrf2 signaling pathway, suggesting that FGF18 may represent a promising therapeutic approach for hepatic IRI.