Mu-opioid receptor alleviated ferroptosis in hepatic ischemia-reperfusion injury via the HIF-1α/ KCNQ1OT1 axis

Ferroptosis is the ideal therapeutic target for hepatic ischemia and reperfusion injury (HIRI). The μ opioid receptor (MOR) is associated with ferroptosis in HIRI. We aimed to determine the ferroptosis-related therapeutic mechanism of MOR in HIRI. A model of HIRI was established in BALB/c mice. Primary hepatocytes isolated from mice were stimulated by hypoxia/reoxygenation (H/R). Changes in histopathology were determined by H&E staining. Alterations in ferroptosis were evaluated by malondialdehyde (MDA), iron, glutathione (GSH), ACSL4, GPX4, and mitochondrial morphology. ALT and AST were used to determine hepatic function. First, we found that hepatic ischemia/reperfusion (I/R) induced the destruction of hepatic tissue structure and dead hepatocytes and determined that ferroptosis occurred in vivo and in vitro. During HIRI, the expression levels of HIF-1α and were significantly upregulated. We demonstrated that sufentanil improved the damage in the liver and hepatocytes undergoing I/R. Importantly, sufentanil inhibited ferroptosis in HIRI. In addition, sufentanil downregulated the expression levels of HIF-1α and in HIRI. Increases in HIF-1α and reversed the role of sufentanil in ferroptosis and HIRI. Subsequently, we determined that could activate the transcription of by binding to its promoter. In addition, was demonstrated to enhance stability by interacting with SRSF1. Finally, we observed that downregulation protected hepatocytes from hepatic I/R and inhibited ferroptosis. upregulation aggravated ferroptosis and hepatic injury during I/R. However, decreases in ACSL4 and SRSF1 reversed the harmful role of upregulation in HIRI. MOR alleviated ferroptosis in HIRI via the HIF-1α/ axis.