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Neuroinflammation is a common pathological hallmark of Coronavirus Disease 2019 (COVID-19) and epilepsy; however, their shared immunogenomic mechanisms remain poorly defined. This study explores shared immune-inflammatory transcriptomic signatures and identifies potential repositioning therapeutics. Methods: We integrated single-cell RNA-seq data from peripheral blood mononuclear cells (PBMCs) of COVID-19 patients and healthy donors (GSE149689), and bulk RNA-seq data from hippocampal tissue of patients with Temporal Lobe Epilepsy with Hippocampal Sclerosis (TLE-HS) and healthy controls (GSE256068). Common Differentially Expressed Genes (DEGs) were identified and subjected to GO\/KEGG enrichment, a PPI network, hub gene detection (cytoHubba), and transcriptional regulation analysis (ENCODE-based TF\/miRNA networks). Drug repositioning was performed using the LINCS L1000 database. Results: We identified 25 DEGs shared across datasets, including 22 upregulated genes enriched in cytokine\u2013cytokine receptor interaction, NF-\u03baB, and Toll-like receptor pathways. PPI analysis revealed a CX3CR1\u2013TLR4-centered immune module. Gabapentin emerged as a promising repositioning candidate with potential to downregulate CX3CR1, TLR4, and selectin P ligand (SELPLG). Receiver Operating Characteristic (ROC) analysis confirmed the diagnostic value of these targets (AUC &gt; 0.90 in epilepsy). A mechanistic model was proposed to illustrate Gabapentin\u2019s dual action on microglial polarization and cytokine suppression. Conclusions: Our results reveal a shared CX3CR1\u2013TLR4\u2013NF-\u03baB inflammatory axis in COVID-19 and epilepsy, supporting Gabapentin as a potential dual-action immunomodulator. These findings reveal a previously underappreciated immunomodulatory role for Gabapentin, providing mechanistic rationale for its repositioning in neuroinflammatory conditions beyond seizure control.<\/jats:p>","DOI":"10.3390\/biomedicines13092133","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T13:27:44Z","timestamp":1756733264000},"page":"2133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CX3CR1\u2013TLR4 Axis as a Shared Neuroimmune Target in COVID-19 and Epilepsy: Integrative Transcriptomics and Gabapentin Repositioning"],"prefix":"10.3390","volume":"13","author":[{"given":"Nannan","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Neurology, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penghui","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Chen","sequence":"additional","affiliation":[{"name":"Geriatric Neuroscience Center, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhen","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5727-2782","authenticated-orcid":false,"given":"Yuping","family":"Ning","sequence":"additional","affiliation":[{"name":"Geriatric Neuroscience Center, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 511436, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1001\/jama.2022.10594","article-title":"Review of Antiseizure Medications for Adults With Epilepsy","volume":"328","author":"Majeed","year":"2022","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/s41573-024-00981-w","article-title":"New epilepsy therapies in development","volume":"23","author":"Klein","year":"2024","journal-title":"Nat. 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