STING deficiency alleviates ischemia-reperfusion injury via JAK2/STAT3-mediated macrophage polarization and autophagy

Intestinal ischemia-reperfusion (IIR) injury triggers severe inflammation and epithelial barrier damage, often leading to systemic complications. The stimulator of interferon genes (STING), a key regulator of innate immunity, has been implicated in inflammatory responses, but its role in IIR remains unclear. This study aimed to determine whether STING influences intestinal injury through macrophage polarization and autophagy regulation via the JAK2/STAT3 signaling pathway. Our results showed that IIR induced STING expression, promoted interferon-gamma (IFN-γ) production, activated JAK2/STAT3 signaling, and drove M1 macrophage polarization. Inhibition or deletion of STING suppressed JAK2/STAT3 activation, shifted macrophage polarization toward the anti-inflammatory M2 phenotype, enhanced autophagy, and alleviated epithelial damage. These effects were reproduced with JAK2 inhibition. Conversely, blocking autophagy reversed the protective effects, suggesting that autophagy plays a crucial role in this process. Our study indicates that STING aggravates IIR injury by promoting IFN-γ-mediated JAK2/STAT3 activation, M1 macrophage polarization, and autophagy dysregulation. Targeting STING may offer a novel therapeutic strategy for mitigating intestinal ischemia-reperfusion injury.