{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T07:25:24Z","timestamp":1769066724943,"version":"3.49.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22176020"],"award-info":[{"award-number":["22176020"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32072262"],"award-info":[{"award-number":["32072262"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Graduate Research and Innovation Project of Chongqing Municipal Education Commission","award":["CYS23357"],"award-info":[{"award-number":["CYS23357"]}]},{"name":"CQMU Program for Youth Innovation in Future Medicine","award":["W0181"],"award-info":[{"award-number":["W0181"]}]},{"name":"Intelligent Medicine Research Project of Chongqing Medical University","award":["YJSZHYX202203"],"award-info":[{"award-number":["YJSZHYX202203"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Drug-induced hepatotoxicity (DIH), characterized by diverse phenotypes and complex mechanisms, remains a critical challenge in drug discovery. To systematically decode this diversity and complexity, we propose a multi-dimensional computational framework integrating molecular structure analysis with disease pathogenesis exploration, focusing on drug-induced intrahepatic cholestasis (DIIC) as a representative DIH subtype. First, a graph-based modularity maximization algorithm identified DIIC risk genes, forming a DIIC module and eight disease pathogenesis clusters. Network proximity values between drug targets and DIIC clusters were calculated to define drug\u2013disease relationships. Subsequently, a random forest model combining Mordred molecular descriptors, structural alerts (SAs), and network proximity achieved robust DIIC prediction: Accuracy(ACC)\u2009=\u20090.740\u2009\u00b1\u20090.014 and area under the curve (AUC)\u2009=\u20090.828\u2009\u00b1\u20090.008 (ntraining\u2009=\u2009342, nvalidation\u2009=\u2009114, nexternal test\u2009=\u2009295, randomly modeling 100 times). Notably, a K-nearest neighbors-graph convolutional network classified drugs into 8 clusters, with the Cluster 3 model demonstrating superior performance (ACC\u2009=\u20090.810\u2009\u00b1\u20090.024; AUC\u2009=\u20090.890\u2009\u00b1\u20090.014; ntraining\u2009=\u2009186, nvalidation\u2009=\u200963, nexternal test\u2009=\u2009172). Mechanistic analysis linked critical SAs to DIIC pathogenesis: (i) Furan (SA3) perturbed cytochrome P450-mediated metabolism and regulation of lipid metabolism by PPAR\u03b1; (ii) Nitrogen-sulfur heteroatom chains (SA7) disrupted metabolism of steroids; (iii) Phenylthio groups (SA12) and their CYP450 metabolites induced cholestasis. This multi-dimensional framework bridges molecular features and disease mechanisms, offering a generalizable strategy for toxicity prediction and pathway-centric drug safety evaluation, especial for complex disease.<\/jats:p>","DOI":"10.1093\/bib\/bbaf456","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T11:42:56Z","timestamp":1757331776000},"source":"Crossref","is-referenced-by-count":2,"title":["A multi-dimensional computational framework of drug-induced hepatotoxicity: integrating molecular structure features with disease pathogenesis"],"prefix":"10.1093","volume":"26","author":[{"given":"Huayu","family":"Zhong","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanji","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyun","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengcheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taiyan","family":"Zou","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]},{"name":"Chongqing Engineering Research Center for Clinical Big Data and Drug Evaluation, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 401331 ,","place":["P. R. China"]},{"name":"Medical Data Science Academy, College of Medical Informatics, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Han","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyun","family":"Mo","sequence":"additional","affiliation":[{"name":"The Guangxi Key Laboratory of Theory and Technology for Environmental Pollution Control, College of Environmental Science and Engineering, Guilin University of Technology , No. 12 Liutai Avenue, Xiufeng District, Guilin 541004 ,","place":["P. R. China"]},{"name":"Technical Innovation Center for Mine Geological Environment Restoration Engineering in Shishan Area of South China, Ministry of Natural Resources , No. 8 Minzu Road, Xingning District, Nanning 530028 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenling","family":"Qin","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chemical Biology Research Center, School of Pharmaceutical Sciences, Chongqing University , No. 174 Shazheng Street, Shapingba District, Chongqing 401331 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8574-9288","authenticated-orcid":false,"given":"Yonghong","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University , No. 1 Yixueyuan Road, Yuzhong District, Chongqing 400016 ,","place":["P. R. 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