LDHA as a Potential Therapeutic Target for Lactylation Regulation in Spinal Cord Injury: Integrated Bioinformatics Analysis, Experimental Validation, and Drug Prediction.

Lactate metabolism and its epigenetic modification, lactylation, are emerging regulators in neurological disorders, yet their roles in spinal cord injury (SCI) remain unclear. Here, we mined SCI transcriptomes from GEO and identified 13 differentially expressed lactylation-related genes (DE-LRGs), with lactate dehydrogenase A (LDHA) significantly upregulated. Immune-infiltration analysis linked LDHA to T cells gamma delta, and Mfuzz time-series clustering showed dynamic LDHA upregulation during acute SCI, which was validated in GSE45006. Random forest and ROC analyses supported the diagnostic value of LDHA. PPI and GeneMANIA networks positioned LDHA at the intersection of lactate metabolism and immune regulation. Drug prediction with Enrichr/DSigDB and docking highlighted folic acid and quercetin dihydrate as candidate compounds. GSVA/GSEA indicated LDHA enrichment in immune activation, metabolic regulation, and stress-response pathways. Immunofluorescence in a rat SCI model confirmed sustained LDHA elevation from 1 to 3 days around the lesion. Importantly, Western blot validation (3 days post-injury) demonstrated increased nuclear HIF-1α and p-STAT3^Y705 (total STAT3 unchanged) together with elevated CXCL1, IL-6, and CCL2 and the infiltration marker MPO/CD68; these changes were attenuated by LDHA inhibition (FX11) and partially rescued by exogenous lactate, supporting an LDHA → lactate → HIF-1α/STAT3 → chemokine/infiltration axis in acute SCI. Collectively, our data identify LDHA as a key lactylation-related regulator in SCI that contributes to pathogenesis via metabolic reprogramming and immune modulation, highlighting its promise as a diagnostic biomarker and therapeutic target.