TRIM21 knockdown alleviates hemorrhage induced hepatic ischemia reperfusion injury by suppressing ferroptosis-induced NETs.

Hemorrhage-induced hepatic ischemia/reperfusion (I/R) injury is a severe complication of hemorrhagic shock, yet its molecular mechanisms remain unclear. The aim of this study was to investigate the potential mechanism of action of TRIM21 on hemorrhage-induced hepatic I/R injury. The role of TRIM21 in hepatic I/R injury was evaluated by establishing a mouse model of hemorrhage-induced hepatic I/R injury and an in vitro simulated oxygen-glucose deprivation/reoxygenation (OGD/R) hepatocyte injury model. A comprehensive analysis was conducted, including histopathological changes, serum biochemical indicators, inflammatory cytokine levels, markers of neutrophil extracellular trap (NETs) formation, and biomarkers related to ferroptosis, such as the expression of iron metabolism-related proteins SLC7A11 and FTH1, oxidative stress and antioxidant capacity, NETs formation markers (Cit-H3, PAD4, and MPO), and the expression levels of TRIM21.The study revealed that ferroptosis-induced NETs was involved in the process of hepatic I/R injury, concurrent with elevated serum ALT and AST levels and increased cell apoptosis. In the hemorrhage-induced hepatic I/R injury mouse model and OGD/R-induced hepatocyte injury, the expression of TRIM21 is significantly upregulated. Knockdown of TRIM21 can effectively inhibit the formation of ferroptosis-induced NETs, thereby alleviating hepatic I/R injury. In terms of the underlying mechanism, TRIM21 promotes the formation of ferroptosis-induced NETs by regulating the stability of the SLC7A11 protein, thus exacerbating hepatic I/R injury. The study discovered that silencing TRIM21 inhibits ferroptosis-mediated NETs formation by ubiquitinating SLC7A11, effectively alleviating hepatic I/R injury. This discovery may provide a potential therapeutic strategy for the treatment of hemorrhage-induced hepatic I/R injury.