Multi-omics integration reveals TIM-4 as a master regulatory hub of neuroinflammation and neuronal cell death.

Overview

1. Department of Emergency, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
2. Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China
3. Department of Gerontology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Abstract

Background: 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—particularly regarding its regulation of neuronal death.

Methods: 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.

Results: 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 < 0.001). Phosphoproteomics identified TIM-4 Y46 hyper-phosphorylation as a key post-translational regulatory event, and ATAC-seq/ChIP-seq revealed NF-κB-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.

Conclusion: 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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE214701, at NCBI GEO; found in the text, “Data acquisition and preprocessing”

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 4 authors, 8 keywords, 41 references.

Cite

This paper

Chen, L., Li, Y.-Y., Han, L., & Lu, S. (2026). Multi-omics integration reveals TIM-4 as a master regulatory hub of neuroinflammation and neuronal cell death. Frontiers in cell and developmental biology, 14, 1876873. https://doi.org/10.3389/fcell.2026.1876873

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