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Cuproptosis, defined as cell death caused by intracellular copper accumulation, has not been thoroughly investigated in the context of IBD and MDD. This study aims to uncover the molecular mechanisms of cuproptosis-related genes (CRGs) in both conditions and to explore novel therapeutic strategies by the modulation of CRGs. Methods: In this study, we identified differentially expressed CRGs between normal and disease samples. We calculated the correlation among CRGs and between CRGs and immune cell infiltrations across various tissues. Four machine learning algorithms were employed to identify key CRGs associated with IBD and MDD. Additionally, drug sensitivity, molecular docking, and molecular dynamics simulations were conducted to predict therapeutic drugs for IBD and MDD. Results: We identified DLD, DLAT, DLST, PDHB, and DBT as common DE-CRGs, and DLD, LIAS, SLC31A1, SCO2, and CDKN2A as key CRGs associated with both IBD and MDD. Consequently, DLD was recognized as a shared biomarker in both diseases. A total of 37 potential therapeutic drugs were identified for IBD and MDD. Based on the molecular docking and molecular dynamics simulation analyses, barasertib and NTP-TAE684, which target DLAT, were predicted to be the most effective compounds. Conclusions: These findings have substantially enhanced our understanding of the similarities and differences in the regulatory mechanisms of CRGs within brain\u2013gut axis diseases. Key biomarkers have been identified, and potential therapeutic drugs have been predicted to effectively target IBD and MDD.<\/jats:p>","DOI":"10.3390\/genes16030339","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:07:51Z","timestamp":1741957671000},"page":"339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Common Regulatory Mechanisms Mediated by Cuproptosis Genes in Inflammatory Bowel Disease and Major Depressive Disorder"],"prefix":"10.3390","volume":"16","author":[{"given":"Jiyuan","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Sang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-820X","authenticated-orcid":false,"given":"Liming","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, China"},{"name":"Basic Medical Research Center, School of Medicine, Nantong University, Nantong 226019, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17562848231197509","DOI":"10.1177\/17562848231197509","article-title":"IBD Barriers across the Continents: A Continent-Specific Analysis\u2014Australasia","volume":"16","author":"Elford","year":"2023","journal-title":"Ther. 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