{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T06:24:29Z","timestamp":1787293469387,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) is a leading cause of severe disability, frequently resulting in persistent cognitive dysfunction. Microglial M1\/M2 polarization is critically involved in TBI pathogenesis, yet its molecular regulatory mechanisms remain poorly understood. TIM-4, a TIM family member implicated in cerebral ischemia-reperfusion injury, has an unknown function in TBI\u2014particularly regarding its regulation of neuronal death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed a comprehensive multi-omics strategy integrating bulk RNA-seq, publicly available single-cell RNA sequencing (scRNA-seq; GEO: GSE101901), weighted gene co-expression network analysis (WGCNA), quantitative proteomics, phosphoproteomics, and epigenomic profiling (ATAC-seq and H3K27ac ChIP-seq) to systematically investigate TIM-4 in TBI. Functional validation included TIM-4 knockdown experiments, TUNEL apoptosis detection, Golgi staining for dendritic spine analysis, and behavioral assessments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TIM-4 was the most significantly upregulated gene and protein across all omics layers, with expression positively correlated with pro-inflammatory factors and negatively correlated with anti-inflammatory markers. ScRNA-seq revealed TIM-4 upregulation was restricted to activated M1-like microglia, and pseudotime trajectory analysis demonstrated TIM-4-driven M1 polarization. WGCNA identified a TIM-4-associated co-expression module strongly correlated with TBI severity and behavioral outcomes (r = 0.92, p &amp;lt; 0.001). Phosphoproteomics identified TIM-4 Y\n                      <jats:sup>46<\/jats:sup>\n                      hyper-phosphorylation as a key post-translational regulatory event, and ATAC-seq\/ChIP-seq revealed NF-\u03baB-driven chromatin remodeling at the TIM-4 locus. Multi-omics integration ranked TIM-4 as the master regulatory hub (composite evidence score = 0.89). Functionally, TIM-4 knockdown promoted microglial M2 polarization, reduced neuronal apoptosis and dendritic spine loss, and significantly improved spatial memory deficits and motor coordination following TBI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TIM-4 is established as a critical driver of neuroinflammation-associated neuronal death in TBI, representing a promising therapeutic target for TBI-related cognitive dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1876873","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:37:51Z","timestamp":1787290671000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics integration reveals TIM-4 as a master regulatory hub of neuroinflammation and neuronal cell death"],"prefix":"10.3389","volume":"14","author":[{"given":"Liang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Emergency, the First Affiliated Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency, Minhang Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Gerontology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Emergency, the First Affiliated Hospital of Soochow University","place":["Suzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"453","DOI":"10.3390\/medicina60030453","article-title":"Cognitive impairment following mild traumatic brain injury (mTBI): a review","volume":"60","author":"Alshareef","year":"2024","journal-title":"Med. 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