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This study aims to identify cytokines mediating the effects of different lifestyles on RA subtypes and to discover new drugs for personalized treatment. Mendelian randomization revealed that three cytokines (MIP1b, SCGFb, and TRAIL) partially mediated the effects of different lifestyles on RA overall or its subtypes. The pretrained model, i.e., DrugBAN, predicted the probability of 723,000 small molecule drugs binding to these three targets. In molecules with high binding rates, we calculated the structural similarity between known drugs for RA and other drugs to screen for new drugs, followed by molecular docking and molecular dynamics simulations for validation. The results indicate that these targets had promising binding affinity with known drugs and other drugs with high similarity. Our findings may guide therapeutic approaches for heterogeneous RA patients with specific lifestyle habits.<\/jats:p>","DOI":"10.3390\/ijms26125686","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T09:51:24Z","timestamp":1749808284000},"page":"5686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Yuqing","family":"Yan","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Wu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0455-7318","authenticated-orcid":false,"given":"Yixuan","family":"Sun","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Wu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2983-2422","authenticated-orcid":false,"given":"Feiyang","family":"Xue","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanhui","family":"Yu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7217-4462","authenticated-orcid":false,"given":"Shichao","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6801-2030","authenticated-orcid":false,"given":"Xiaohui","family":"Niu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00281-017-0627-z","article-title":"The role of autoantibodies in the pathophysiology of rheumatoid arthritis","volume":"39","author":"Derksen","year":"2017","journal-title":"Semin. 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