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This study employed an integrative multiomics strategy\u2014combining network toxicology, machine learning, Mendelian randomization (MR), and molecular docking\u2014to elucidate the biological basis of AZA\u2010induced AP. AZA\u2010associated genes were first identified through bioinformatics databases and analyzed using protein\u2013protein interaction networks and GO\/KEGG functional enrichment. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM\u2010RFE) were applied to prioritize key differentially expressed genes for diagnostic modeling. MR was then used to examine potential causal links between gene expression and AP risk, followed by molecular docking to assess AZA\u2013protein interactions. Sixty\u2010eight candidate genes related to AZA\u2010induced AP were identified. Enrichment analyses indicated involvement in lipid metabolic regulation, inflammatory pathways, and energy homeostasis. Machine learning highlighted seven key genes\u2014CES1, CTSK, JAK1, NR3C2, PLIN5, WEE1, and RORA\u2014as central to AP development. MR analysis further demonstrated that decreased expression of CES1 and CTSK may mediate AZA\u2010related AP susceptibility. Docking simulations revealed strong, specific binding between AZA and both CES1 and CTSK. Overall, this study identifies CES1 and CTSK as genetically protective factors and mechanistic mediators in AZA\u2010triggered AP. These findings offer new molecular insights into the genomic and biochemical pathways underlying this adverse drug reaction.<\/jats:p>","DOI":"10.1002\/psp4.70178","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T16:39:27Z","timestamp":1773592767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unraveling the Link Between Azathioprine and Acute Pancreatitis: Integrating Network Toxicology, Machine Learning, and Mendelian Randomization"],"prefix":"10.1002","volume":"15","author":[{"given":"Zhijun","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University  Lu Zhou Sichuan China"},{"name":"Department of West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University  Chengdu Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University  Chengdu Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University  Chengdu Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University  Lu Zhou Sichuan China"},{"name":"School of Integrated Traditional Chinese and Western Clinical Medicine, North Sichuan Medical College  Nanchong Sichuan Province China"},{"name":"The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University  Lu Zhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-6634","authenticated-orcid":false,"given":"Wenfu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University  Lu Zhou Sichuan China"},{"name":"Department of West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University  Chengdu Sichuan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61302-7"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-4642(19)30019-7"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-4642(18)30401-2"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjv188"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i25.7795"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.20317"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60107-5"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3139"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.07.016"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxics12120929"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz382"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2025.118132"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2024.114687"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2025.117966"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k601"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa971"},{"key":"e_1_2_11_18_1","first-page":"757","article-title":"Using ChEMBL Web Services for Building Applications and Data Processing Workflows Relevant to Drug Discovery","volume":"12","author":"Nowotka M. 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