STING controls glycolysis and histone lactylation to drive macrophage metabolic reprogramming in postoperative ileus.

Postoperative ileus (POI) is characterized by dysregulated inflammation within the intestinal muscular layer, which significantly disrupts gastrointestinal motility and presents a major challenge to postoperative recovery. Although macrophages are known to contribute to inflammation through glycolytic bursts that support rapid energy production, the role of the stimulator of interferon genes (STING) in orchestrating macrophage glycolysis and modulating phenotypic polarization remains poorly defined. To address this gap, we examined the regulatory relationship between STING and macrophage metabolism. Here, we demonstrate that lipopolysaccharide (LPS)-stimulated RAW 264.7 cells display a pronounced enhancement of glycolysis, an effect that was markedly attenuated in STING knockout (STING KO) cells. Further analysis revealed that STING deletion reduces histone lactylation, consequently restricting chromatin accessibility at the hexokinase 2 (HK2) gene loci. Through CUT&Tag sequencing, we identified IRF3 as a transcription factor that directly binds to the promoter regions of HK2 and enhances its expression. Our results delineate a STING-regulated glycolytic feedback loop in macrophages: STING stabilizes hypoxia-inducible factor 1-alpha (HIF1α), thereby amplifying glycolysis and promoting histone lactylation at HK2 loci. This epigenetic modification facilitates IRF3 binding to the HK2 promoter, further boosting HK2 expression and sustaining glycolytic flux. Together, these findings elucidate a molecular mechanism through which STING modulates macrophage polarization via metabolic reprogramming, highlighting the therapeutic potential of targeting STING to regulate macrophage metabolism, alleviate inflammation, and improve outcomes in POI.