Sodium butyrate inhibits ferroptosis and ameliorates intestinal ischemia-reperfusion injury by modulating the NRF2/SLC7A11/GPX4 pathway

Abstract

Abstract Purpose Sodium butyrate, a short-chain fatty acid produced by the metabolism of intestinal flora, has been shown to have a protective effect against intestinal ischemia reperfusion injury (IRI), but its effect on intestinal IRI-associated ferroptosis has not yet been demonstrated. Methods In this experiment, we used a model of superior mesenteric artery occlusion in mice to examine the effects and principles of sodium butyrate on ferroptosis related to intestinal IRI. We assessed the role of sodium butyrate by constructing mice intestinal IRI models and determining the extent of intestinal tissue damage and changes in ferroptosis-related factors. Results Results show that Intestinal IRI mice showed increased tissue damage, massive infiltration of inflammatory cells, severe destruction of villus structure, and elevated MDA. In addition, intestinal IRI led to downregulation of GSH, GPX4, FTH1 and SLC7A11, regulators of ferroptosis, and a rise in Fe2+, as well as downregulation of NRF2 by intestinal IRI. Sodium butyrate had an attenuating effect on intestinal IRI, whereas mice exogenously supplemented with sodium butyrate showed less tissue damage, some restoration of villus structure and decreased MDA, up-regulation of GSH, GSH/GSSG, GPX4, FTH1, SLC7A11, and NRF2, and decreased Fe2+. Conclusion This experiment demonstrates that sodium butyrate regulates the SLC7A11/GPX4 pathway by up-regulating NRF2, thereby inhibiting ferroptosis and attenuating intestinal IRI.