Chaoran Shi, Feifei Yuan, Xingyi Chen, Sheng Xu, Yinghe Ding, Haicheng Wen, Chunyue Duan, Tianding Wu, Hongbin Lu, Jianzhong Hu, Jiaqi Xu, Liyuan Jiang
Spinal cord injury (SCI) induces metabolic and immune disruptions that impede tissue repair. However, the underlying mechanisms are poorly understood. In this study, we identified lactate accumulation as a critical driver of macrophage-mediated inflammation through histone H3K9 lactylation (H3K9la). Targeted metabolomics revealed elevated serum lactate levels in SCI patients, which were linked to increased glycolysis and lactate dehydrogenase activity. In mice, lactate accumulation after SCI was found to drive histone H3K9la in lesion-infiltrating macrophages and circulating monocytes. Integrated CUT&Tag and RNA-seq analysis revealed that thioredoxin-interacting protein (TXNIP) is a direct H3K9la target that activates the TXNIP-NLRP3 pathway, exacerbating inflammation and impairing mitochondrial function. In vitro, glycolytic inhibition reversed lactate-induced inflammation and mitochondrial dysfunction. In vivo, a hypoxia-responsive peptide inhibitor (H3K9la-pe) selectively reduced macrophage lactylation and inflammation, restored mitochondrial integrity, promoted axon regeneration, and significantly improved functional recovery in SCI mouse model. These findings elucidate a subacute metabolic-epigenetic-inflammatory axis in SCI and highlight that blocking macrophage H3K9la is a promising therapeutic strategy.