Integrative multi-omics identifies lyn-mediated microglial activation as a key driver of central post-stroke pain.

Abstract

Central post-stroke pain (CPSP) is a neuropathic pain condition that severely impairs patients' quality of life and recovery, yet its pathogenesis remains poorly understood. This study employed a multi-omics approach to investigate CPSP mechanisms in a mouse model generated by stereotaxic injection of collagenase IV into the thalamic ventral posterolateral nucleus (VPL). Pain-related behavioral tests confirmed successful model establishment and characterized associated behavioral deficits. Subsequent analyses using ELISA, qPCR, and immunofluorescence revealed elevated inflammatory cytokine levels and microglial activation in the VPL. Non-targeted metabolomics and transcriptomics further uncovered significant metabolic and gene expression changes in CPSP mice. Integrated multi-omics analysis identified the kinase Lyn as a key differentially expressed gene linked to these metabolic alterations, with its expression dynamically upregulated in CPSP mice. Lyn colocalized with activated microglia and promoted their shift toward a pro-inflammatory phenotype. Importantly, pharmacological inhibition of Lyn using Bafetinib attenuated pain hypersensitivity, suppressed microglial proliferation, and reduced inflammatory cytokine secretion in CPSP mice. These findings indicate that CPSP involves systemic metabolic and transcriptional dysregulation, and that Lyn-mediated microglial activation drives pain progression through enhanced neuroinflammation, highlighting Lyn as a potential therapeutic target for CPSP intervention.