Regulatory role of AMPK/Nrf2 signaling pathway in sevoflurane-enhanced intestinal protection against ischemia-reperfusion injury

Intestinal ischemia-reperfusion (I/R) injury is common in clinical settings and is associated with high mortality. Sevoflurane, a widely used anesthetic, has long recognized for its protective effects against intestinal I/R injury, though the underlying mechanisms remain largely uncharacterized. In this study, using both in vivo and in vitro models, we uncovered a novel role of sevoflurane in preventing ferroptotic cell death during intestinal I/R injury. Sevoflurane treatment activated transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and upregulated its target genes involved in iron sequestration (FTL) and glutathione biosynthesis (SLC7A11 and GCLM). These changes reduced intracellular ferrous iron levels and alleviated iron-dependent oxidative stress and lipid peroxidation, a hallmark of ferroptosis. Importantly, through large-scale kinome screening, we revealed that sevoflurane-induced Nrf2 activation was mediated by AMP-activated protein kinase (AMPK). Sevoflurane treatment activated AMPK, which subsequently phosphorylated Nrf2 and prevented its degradation. Stabilized Nrf2 then entered nucleus, where it promoted the transcription of downstream targets. We concluded that sevoflurane exerts anti-ferroptoic function in intestinal I/R through the AMPK/Nrf2 signaling pathway. These results expand our knowledge about the pathogenesis of intestinal I/R injury, and provide novel insights for optimizing clinical treatments and developing novel therapeutic strategies.