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Background and Aims  Hepatic ischemia‐reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5) is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear.    Approach and Results  RNF5 expression was significantly down‐regulated during HIR in mice and hepatocytes. Subsequently,  RNF5  knockdown and overexpression of cell lines were subjected to hypoxia‐reoxygenation challenge. Results showed that  RNF5  knockdown significantly increased hepatocyte inflammation and apoptosis, whereas  RNF5  overexpression had the opposite effect. Furthermore, hepatocyte‐specific  RNF5  knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage and cell apoptosis and activated hepatic inflammatory responses, whereas hepatic  RNF5  transgenic mice had the opposite effect compared with  RNF5  knockout mice. Mechanistically, RNF5 interacted with phosphoglycerate mutase family member 5 (PGAM5) and mediated the degradation of PGAM5 through K48‐linked ubiquitination, thereby inhibiting the activation of apoptosis‐regulating kinase 1 (ASK1) and its downstream c‐Jun N‐terminal kinase (JNK)/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR.    Conclusions  We revealed that RNF5 protected against HIR through its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5‐PGAM5 axis may be a promising therapeutic target for HIR.

hepatology

E3 ubiquitin ligase ring finger protein 5 protects against hepatic ischemia reperfusion injury by mediating phosphoglycerate mutase family member 5 ubiquitination