DRP1 lysine 616 lactylation exacerbates cerebral ischemia-reperfusion injury by activating the STING inflammatory pathway

Ischemia-hypoxia-induced inflammation and glycolysis are linked to the severity of cerebral ischemia-reperfusion injury (CIRI), but the mechanisms are unclear. Current research suggests that the inflammatory response of immune cells activated by STING is a key regulatory molecule in cellular inflammatory damage. However, the specific mechanisms underlying STING-mediated CIRI inflammatory responses remain unclear. This study found that STING expression was specifically elevated in microglia in the damaged side of the hippocampus in CIRI model mice, and this elevation was positively correlated with the severity of CIRI. Our previous research indicated that the dynamic process of mitochondrial fusion and fission is closely associated with CIRI. Building on this, we integrated glycolysis, mitochondrial fission, and the STING inflammatory pathway. Mechanistically, our data suggest that DRP1 K616 is a critical candidate site involved in DRP1 lactylation-associated regulation, which promotes STING pathway activation and contributes to the progression of CIRI. In conclusion, our findings offer substantial evidence that lactate-driven DRP1-mediated mitochondrial fission facilitates the involvement of the STING inflammatory pathway in CIRI. These results suggest that modulating lactate metabolism may serve as a crucial upstream strategy for therapeutic intervention in CIRI.