Targeting astrocyte-monocyte-neuron crosstalk in spinal cord injury: therapeutic insights from methyl gallate.

Abstract

Integrative multi-omics cross-sectional study combining scRNA-seq, bulk transcriptomics, Mendelian randomization, and network pharmacology with molecular docking. To investigate the therapeutic mechanisms of methyl gallate (MG) in spinal cord injury (SCI) through the lens of cell-type-specific pathways and immune regulation. Publicly available SCI transcriptomic datasets and GWAS summary data were analyzed using established bioinformatics platforms. This study integrated single-cell RNA sequencing (scRNA-seq), transcriptomics, genome-wide association study (GWAS)-based Mendelian randomization (MR), and network pharmacology to explore MG's effects on SCI. Temporal scRNA-seq profiles were analyzed from mice with subacute SCI (days 3 to 14 post-injury) to identify changes in astrocyte dynamics and glia-neuron interactions. Differential gene expression and functional enrichment analyses were performed, followed by drug-target prediction and molecular docking. scRNA-seq revealed a significant reduction in astrocyte populations and disrupted astrocyte-monocyte-neuron communication post-SCI. A total of 959 astrocyte-specific and 1,459 SCI-related differentially expressed genes (DEGs) were identified. Enrichment analyses highlighted neuroimmune and inflammatory pathways. MR indicated a protective association between elevated monocyte count and reduced SCI risk. Network pharmacology and molecular docking demonstrated that MG targets overlapped with astrocyte DEGs, suggesting high binding affinities and regulatory effects on inflammation and neuron-glia signaling. MG may promote recovery from SCI by modulating neuroimmune interactions, particularly through astrocyte and monocyte-mediated pathways. The integrative multi-omics strategy supports MG's translational potential as a novel therapeutic candidate for SCI. Mechanism of SCI Repair and Neuronal Differentiation Mediated by MG (Created by BioRender).