{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T07:01:40Z","timestamp":1784962900199,"version":"3.55.0"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":204,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Spinal cord injury (SCI) leads to a complex cascade of cellular events, among which necroptosis plays a critical role in exacerbating neuronal injury and inflammation. In this study, we aimed to identify and validate key genes associated with necroptosis in SCI using bulk RNA\u2010seq data, followed by differential analysis and weighted gene coexpression network analysis (WGCNA). We identified several candidate necroptosis\u2010related genes, and further least absolute shrinkage and selection operator (LASSO) regression highlighted five SCI\u2010necroptosis differentially expressed genes (DEGs): toll\u2010like receptor 4 (\n                    <jats:italic>Tlr4<\/jats:italic>\n                    ),\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    ,\n                    <jats:italic>Il1b<\/jats:italic>\n                    ,\n                    <jats:italic>Tnfaip3<\/jats:italic>\n                    , and\n                    <jats:italic>Stat4<\/jats:italic>\n                    . These genes were validated using RT\u2010qPCR and western blot experiments. Our analysis revealed that necroptosis scores were significantly elevated following SCI. Single\u2010cell RNA sequencing (scRNA\u2010seq) and spatial transcriptomics (ST) analysis revealed that\n                    <jats:italic>Tlr4<\/jats:italic>\n                    was upregulated in myeloid cells (microglia and macrophages) and played a pivotal role in triggering downstream necroptosis, which was confirmed by protein levels. In vitro and in vivo experiments confirmed that\n                    <jats:italic>Tlr4<\/jats:italic>\n                    inhibition attenuated necroptosis and inflammation. This study is the first to establish\n                    <jats:italic>Tlr4<\/jats:italic>\n                    as a direct upstream regulator of the pRIPK1\/pRIPK3\/pMLKL necroptotic axis in SCI, distinct from its role as a general inflammatory mediator, suggesting\n                    <jats:italic>Tlr4<\/jats:italic>\n                    as a promising therapeutic target for functional recovery.\n                  <\/jats:p>","DOI":"10.1155\/mi\/7306884","type":"journal-article","created":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T06:26:14Z","timestamp":1784960774000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiomics Profiling Identifies\n                    <i>Tlr4<\/i>\n                    as a Therapeutic Target of Necroptosis in Spinal Cord 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