Multi-omics analysis identified and confirmed TNF-α as a key initiator of the inflammatory response following spinal cord injury.

Spinal cord injury (SCI) is a complex central nervous system (CNS) trauma that triggers multifaceted immune responses. In recent years, zinc has garnered considerable attention for its beneficial roles in anti-apoptosis and the attenuation of oxidative stress. However, the regulatory mechanisms by which zinc influence post-SCI immune-inflammatory responses remain insufficiently understood. In this study, we employed a multi-omics approach, combining transcriptomics, metabolomics, and single-cell RNA sequencing, to elucidate the mechanisms through which zinc ions modulate immune responses in injured spinal cord tissues. Our results demonstrate that zinc ions significantly regulate the expression of TNF-α signaling molecules. By inhibiting the TNF-α signaling pathway, zinc ions effectively mitigate apoptosis and reduce immune-inflammatory responses following SCI. Furthermore, through the integration of human and murine immune cell atlases, we performed a cluster analysis of key immune cell populations and constructed an immunological landscape of spinal cord tissues post‑zinc ion treatment. Notably, we identified microglia, key CNS immune cells, as exerting a strong anti-inflammatory effect by suppressing their TNF-α signaling activity. This study not only sheds light on the pivotal immune-inflammatory regulatory mechanisms of TNF-α signaling in zinc ion-mediated SCI therapy but also provides valuable theoretical and experimental insights for advancing preclinical research on SCI.