{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T09:46:57Z","timestamp":1764582417951,"version":"3.46.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Starting Up Foundation for PhD of Hunan University of Medicine","award":["202401"],"award-info":[{"award-number":["202401"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Exercise is a promising non-pharmacological intervention for cocaine addiction but molecular mechanisms of exercise-related genes in addiction remain unclear. This study aimed to identify exercise-related signature genes for cocaine addiction and to assess the potential causal relationship between exercise and cocaine addiction using two-sample Mendelian randomization (MR) analysis. Methods: Midbrain transcriptomic data were analyzed for differentially expressed genes (DEGs) and intersected with exercise-related genes. Functional enrichment, protein-protein interaction (PPI) and immune infiltration analyses explored their roles while signature genes were screened via LASSO\/Random Forest and validated by ROC curves. GSEA explored pathways and MR confirmed exercise\u2019s causal effect. Results: A total of 244 DEGs were identified, including 27 exercise-related, and six signature genes (CALM3, CCL2, CD44, CLIC1, JUN, VCAM1) showed AUC values between 0.714 and 0.868 in distinguishing cocaine-addicted individuals from controls. Functional analyses revealed enrichment in immune-inflammatory pathways, metabolic processes and neuro-immune interactions and immune infiltration analysis showed cocaine addicts had elevated pro-inflammatory cells, reduced regulatory cells and signature genes correlated with immune dysregulations. MR analysis suggested a statistically significant protective association between genetically proxied higher levels of exercise and cocaine addiction risk (p &lt; 0.05). Conclusions: These six genes may be potential biomarkers and therapeutic targets, and exercise may protect against cocaine addiction by regulating immune-inflammatory responses, metabolic pathways and neuroplasticity, although further validation in larger, independent cohorts and experimental models is required.<\/jats:p>","DOI":"10.3390\/genes16121414","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T16:31:52Z","timestamp":1764261112000},"page":"1414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Exercise-Related Signature Genes Potentially Associated with Cocaine Addiction by Integrating Bioinformatics and Mendelian Randomization Analysis"],"prefix":"10.3390","volume":"16","author":[{"given":"Jinke","family":"He","sequence":"first","affiliation":[{"name":"Hunan Provincial Key Laboratory of Dong Medicine, Biomedical Research Institute, Hunan University of Medicine, Huaihua 418000, China"},{"name":"School of Basic Medical Sciences, Xinjiang Second Medical College, Kelamayi 834000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Deng","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Dong Medicine, Biomedical Research Institute, Hunan University of Medicine, Huaihua 418000, China"},{"name":"School of Basic Medical Sciences, Hunan University of Medicine, Huaihua 418000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxuan","family":"Deng","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Dong Medicine, Biomedical Research Institute, Hunan University of Medicine, Huaihua 418000, China"},{"name":"School of Clinical Medical, Hunan University of Medicine, Huaihua 418000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0245-5271","authenticated-orcid":false,"given":"Xiao","family":"Huang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Dong Medicine, Biomedical Research Institute, Hunan University of Medicine, Huaihua 418000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/WNF.0b013e3181a9163c","article-title":"The neurobiology of addictive disorders","volume":"32","author":"Ross","year":"2009","journal-title":"Clin. 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