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  • Title: Mu-opioid receptor alleviated ferroptosis in hepatic ischemia-reperfusion injury via the HIF-1α/KCNQ1OT1 axis.
    Author: Zou S, Sun H, Peng Y, Liang C, Zheng C, Wang L, Yang J.
    Journal: Am J Physiol Cell Physiol; 2023 Apr 01; 324(4):C927-C940. PubMed ID: 36717099.
    Abstract:
    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 KCNQ1OT1 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 KCNQ1OT1 in HIRI. Increases in HIF-1α and KCNQ1OT1 reversed the role of sufentanil in ferroptosis and HIRI. Subsequently, we determined that HIF-1α could activate the transcription of KCNQ1OT1 by binding to its promoter. In addition, KCNQ1OT1 was demonstrated to enhance ACSL4 stability by interacting with SRSF1. Finally, we observed that KCNQ1OT1 downregulation protected hepatocytes from hepatic I/R and inhibited ferroptosis. KCNQ1OT1 upregulation aggravated ferroptosis and hepatic injury during I/R. However, decreases in ACSL4 and SRSF1 reversed the harmful role of KCNQ1OT1 upregulation in HIRI. MOR alleviated ferroptosis in HIRI via the HIF-1α/KCNQ1OT1 axis.
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