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Studies focusing on individual molecular markers have limitations in addressing the complex disease process. Methods: This study utilizes RNA-sequencing (RNA-seq) to investigate the differentially expressed genes (DEGs) in spinal cord tissue from a rat SCI model at 1 and 21 days post-injury (dpi). After data processing and analysis, a series of biological pathway enrichment analyses were performed using online tools DAVID and GSEA. Interactions among the enriched genes were studied using Cytoscape software to visualize protein\u2013protein interaction networks. Results: Our analysis identified 595 DEGs, with 399 genes significantly upregulated and 196 significantly downregulated at both time points. CD68 was the most upregulated gene at 21 dpi, with a significant fold change at 1 dpi. Conversely, MPZ was the most downregulated gene. Key immune response processes, including tumor necrosis factor (TNF) production, phagocytosis, and complement cascades, as well as systemic lupus erythematosus (SLE)-associated pathways, were enriched in the upregulated group. The enriched pathways in the downregulated group were related to the myelin sheath and neuronal synapse. Genes of interest from the most significantly downregulated DEGs were SCD, DHCR24, PRX, HHIP, and ZDHHC22. Upregulation of Fc-\u03b3 receptor genes, including FCGR2B and FCGR2A, points to potential autoimmune mechanisms. Conclusions: Our findings highlight complex immune and autoimmune responses that contribute to ongoing inflammation and tissue damage post-SCI, underscoring new avenues for therapeutic interventions targeting these molecular processes.<\/jats:p>","DOI":"10.3390\/genes16050514","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T11:00:54Z","timestamp":1745924454000},"page":"514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of Differentially Expressed Genes in Spinal Cord Injury"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6948-0034","authenticated-orcid":false,"given":"Andrew","family":"Chang","sequence":"first","affiliation":[{"name":"Medical School, The University of Western Australia, Perth, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9819-085X","authenticated-orcid":false,"given":"Shevanka","family":"Dias Abeyagunawardene","sequence":"additional","affiliation":[{"name":"Medical School, The University of Western Australia, Perth, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children\u2019s Hospital of Wenzhou Medical University, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children\u2019s Hospital of Wenzhou Medical University, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2021-8309","authenticated-orcid":false,"given":"Jiake","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Western Australia, Perth, WA 6009, Australia"},{"name":"Shenzhen Insitute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R950","DOI":"10.1016\/j.cub.2007.10.014","article-title":"Spinal cord","volume":"17","author":"Hochman","year":"2007","journal-title":"Curr. 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