The miR-221-3p/SESN2 axis mediates the protective effect of sevoflurane against hepatic ischemia-reperfusion injury

This is the authors' abstract. We don't add key points for this paper.

Hepatic ischaemia-reperfusion injury (HIRI) impairs graft function after liver transplantation. miR-221-3p is abnormally expressed during HIRI, but its mechanism and whether sevoflurane (sevo) exerts protection via miR-221-3p remain unclear. Serum miR-221-3p was measured in healthy controls and liver transplant recipients. L-02 cells were subjected to hypoxia/reoxygenation (H/R) to mimic hepatic I/R injury in vitro, and then treated with sevo, miR-221-3p mimic, or SESN2 overexpression construct as per experimental design. Cell viability, apoptosis, inflammatory factors (TNF-α, IL-6, IL-1β), oxidative stress (ROS, MDA, SOD), and ferroptosis markers (GPX4, SLC7A11, Fe²⁺) were assessed. Dual-luciferase reporter assay validated the miR-221-3p–SESN2 target relationship. miR-221-3p was most highly expressed in the HIRI group and showed significant positive correlations with AST, ALT and the MELD score ( r = 0.740, 0.781, 0.881); the AUC for diagnosing HIRI was 0.966 (HC vs. HIR), and miR-221-3p may serve as a candidate independent risk factor for HIRI. In the H/R model, miR-221-3p was significantly up-regulated; treatment with sevo reduced its expression, increased cell viability, reduced apoptosis, and inhibited inflammation and oxidative stress, whilst simultaneously up-regulating GPX4 and SLC7A11 and reducing Fe²⁺ levels; overexpression of miR-221-3p partially reversed these effects. Dual-luciferase assays confirmed that SESN2 is a direct target gene of miR-221-3p, and rescue experiments demonstrated that SESN2 overexpression reverses the damage induced by the miR-221-3p mimic. miR-221-3p is up-regulated in HIRI and serves as a potential diagnostic marker and risk factor. Sevo may alleviate H/R injury by down-regulating miR-221-3p to activate SESN2, thereby inhibiting inflammation, oxidative stress, and ferroptosis.