Inhibition of PKM2 by shikonin ameliorates ferroptosis in acute kidney injury by suppressing the mitochondrial DNA-triggered cGAS-STING pathway

Abstract Acute kidney injury (AKI) is a prevalent renal disorder that poses a significant risk to patient survival, yet current therapeutic strategies remain limited efficacy. Emerging evidence suggests that dysregulated glucose metabolism contributes to AKI progression. Here, we found that pyruvate kinase 2 (PKM2) expression was markedly increased in the kidneys of both I/R model mice and AKI patients. Correspondingly, the downstream metabolites pyruvate and lactate were elevated. Shikonin treatment alleviated renal injury in ischemia/reperfusion (I/R) model mice. Furthermore, shikonin markedly reduced ferroptosis in I/R model mouse kidneys, an effect further confirmed in cultured cells and shown to depend on PKM2 inhibition. Mechanistically, PKM2 upregulation led to lactate accumulation, which disrupted mitochondria integrity and function, leading to cytoplasmic accumulation of mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (ROS) production. Cytosolic mtDNA subsequently activated the cGAS-STING pathway, thereby increasing proinflammatory cytokine expression. Together with ROS, this cascade ultimately triggered ferroptosis in the kidney. Shikonin treatment effectively attenuated these detrimental effects. Our findings indicate that shikonin protects AKI-induced renal injury by repressing the PKM2-lactate-mtDNA-cGAS-STING axis. These results indicate that PKM2 may represent a viable target for future anti-AKI therapies.