PRMT1‐Mediated LDHA Methylation Drives STAT3 Lactylation to Orchestrate Intestinal Inflammation and Tumorigenesis

ABSTRACT Signal transducer and activator of transcription 3 (STAT3) activation is crucial in intestinal inflammation and tumorigenesis. However, its metabolic regulation is not well understood. Herein, we identified a macrophage‐dependent methionine‐S‐adenosylmethionine (SAM)‐protein arginine methyltransferase 1 (PRMT1)‐lactate dehydrogenase A (LDHA)‐lactate axis that controls intestinal inflammation through STAT3 regulation. Specifically, SAM promoted STAT3 Y705 phosphorylation and upregulated anti‐inflammatory interleukin‐10 expression in macrophages. Additionally, genetic ablation of PRMT1 in myeloid cells not only impairs STAT3 activation but also exacerbates colitis and promotes inflammation‐associated tumorigenesis. Mechanistically, PRMT1 directly methylates LDHA at R268/R269, thereby enhancing its activity and lactate production. Subsequently, the resulting lactate induces STAT3 lactylation at K709, stabilizing an open conformation that facilitates Y705 phosphorylation. Importantly, disruption of this modification through K709‐specific inhibition effectively blocks STAT3 activation and, consequently, exacerbates colitis progression. Overall, this study reveals STAT3 lactylation as a novel post‐translational modification that integrates methionine metabolism with glycolytic flux to regulate intestinal inflammation, highlighting the critical role of immunometabolism in colonic inflammation.