<p>Liver ischemia reperfusion injury (IRI) is a major cause of postoperative liver dysfunction. RNF11, a conserved E3 ubiquitin ligase involved in inflammation, oxidative stress, and apoptosis, may be an important regulator of liver IRI. The role and mechanism of RNF11 in liver IRI were investigated using a mouse IRI model and AML12 hypoxia/reoxygenation (H/R) cells. RNF11 expressions were examined by RT-qPCR, Western blot, and immunohistochemistry. AAV- or lentivirus-mediated knockdown and overexpression were used to modulate RNF11. Liver injury was evaluated by serum biochemical parameters, histopathological changes, inflammatory cytokines, and apoptotic markers. RNA sequencing, KEGG analysis, co-immunoprecipitation, and ubiquitination assays were performed to explore mechanisms. RNF11 expression was markedly downregulated in IRI livers and H/R-treated AML12 cells. RNF11 knockdown aggravated liver damage, with higher ALT/AST levels, increased necrosis, enhanced inflammatory infiltration, and upregulated proinflammatory cytokines, whereas RNF11 overexpression alleviated liver IRI in vivo and in vitro. RNF11 interacted with histidine triad nucleotide-binding protein 1 (HINT1) and activated PI3K/AKT signaling. The PI3K/AKT inhibitor LY294002 abrogated the anti-inflammatory and anti-apoptotic effects of RNF11. RNF11 promoted K48-linked polyubiquitination and proteasomal degradation of HINT1. RNF11 is a critical regulator of liver IRI that protects against inflammation and apoptosis by targeting HINT1 for K48-linked polyubiquitination and activating PI3K/AKT signaling, suggesting a potential therapeutic target for liver IRI.</p>