STING Drives Pyroptosis and Exacerbates Intestinal Ischemia-Reperfusion Injury

Abstract This study aimed to investigate the role of STING (Stimulator of Interferon Genes) in intestinal ischemia-reperfusion (IIR) injury, focusing on its impact on mitochondrial function, pyroptosis, and intestinal inflammation. The study utilized both in vivo and in vitro models, including a mouse model of IIR and intestinal organoids subjected to hypoxia-reoxygenation (HR). We assessed the effects of pharmacological STING inhibition using H.151 and STING knockout mouse on intestinal injury markers, including histological damage, pro-inflammatory cytokine levels, mitochondrial morphology and function, and pyroptosis markers. Our findings revealed that IIR significantly upregulated STING expression in the intestinal epithelium, coinciding with increased intestinal permeability, elevated pro-inflammatory cytokine production (IL-1β) (p < 0.05), and evidence of mitochondrial dysfunction, characterized by reduced ATP production and disrupted morphology (p < 0.01). Importantly, both H.151 treatment and STING knockout significantly attenuated IIR-induced intestinal damage (p < 0.01), reduced pro-inflammatory cytokine levels (p < 0.05), and preserved mitochondrial function (p < 0.01). Furthermore, we observed a significant reduction in pyroptosis, as evidenced by decreased cleaved gasdermin D levels, in both H.151-treated and STING knockout groups (p < 0.05). This study identifies STING as a critical mediator of IIR-induced intestinal injury, likely through the activation of pathways leading to mitochondrial dysfunction and pyroptosis. Our findings suggest that targeting STING represents a promising therapeutic strategy for mitigating intestinal damage following ischemia-reperfusion.