Dexmedetomidine alleviates ferroptosis following hepatic ischemia-reperfusion injury by upregulating Nrf2/GPx4-dependent antioxidant responses

作者：Yongjun Zhang, Hua Wei, Mengmei Wang, Yang Yu, Mengyue Gu, Hui Zhong, Shuhua Dong · 发表于：Biomedicine & Pharmacotherapy · 年份：2023 · DOI：10.1016/j.biopha.2023.115915 · 被引用次数：48 · 研究领域：MicroRNA in disease regulation、Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research

Hepatic ischemia-reperfusion injury (HIRI) adversely affects liver transplant and resection outcomes. Recently, ferroptosis has been associated with HIRI. Dexmedetomidine (Dex), a potent sedative with anti-inflammatory, antioxidant, and anti-apoptotic properties, protects organs from hypoxic or ischemia-reperfusion (I/R) injuries. However, the mechanisms underlying this protective effect against I/R-induced liver injury remain unclear. This study evaluated the effect of Dex on HIRI in mouse models and the oxygen-glucose deprivation/reperfusion (OGD/R) AML12 cell model. We examined ferroptosis-related markers, including Fe2+ levels, reactive oxygen species (ROS) content, mitochondrial morphology, GPX4 protein expression, 4-hydroxynonenal (4-HNE), and Nrf2. The Nrf2 inhibitor ML385 was used in combination with Dex to treat HIRI mice and OGD/R-induced cellular models to explore the pathways by which Dex counteracts ferroptosis. Our results showed that Dex treatment significantly ameliorated OGD/R-induced ferroptosis in AML12 cells, including reduced Fe2+, ROS, malondialdehyde (MDA), and 4-HNE levels. Dex also ameliorated liver tissue damage and reduced serum AST, ALT, and inflammatory factor levels in HIRI mice. Additionally, Dex increased the levels of GSH, an antioxidative stress marker, and GPX4 expression in HIRI mice. Mechanistically, Nrf2 expression and nuclear translocation were significantly inhibited in both HIRI mice and OGD/R-treated AML12 cells. Dex treatment also re...