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An ability to prioritize early-stage drug development programs toward those with a lower probability of causing clinical toxicity would improve drug development success rates. Here, we propose a target-centric framework that integrates network medicine principles with target biology features to predict operational target-level labels associated with safety-related drug attrition. From a set of 3,696 drugs with widely launched or safety-related termination outcomes, we curated 541 non-overlapping target labels, comprising 302 safety-liability-associated targets and 239 widely launched-associated targets. We engineered target-level features encoding both biological properties and human interactome (HI) topology and trained a gradient boosting classifier to predict the safety-liability-associated label. The model achieved a held-out test ROC AUC of 0.712. These results suggest that target biology and interactome context contain signal associated with safety-related clinical attrition and may support early target prioritization when used alongside compound-centric safety assessments.<\/jats:p>","DOI":"10.1038\/s41598-026-65633-y","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:04:11Z","timestamp":1787562251000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Target-biology and interactome-derived signatures predict target-level associations with safety-related drug attrition"],"prefix":"10.1038","volume":"16","author":[{"given":"Jordan","family":"Breffle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan D.","family":"Ghiassian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"65633_CR1","doi-asserted-by":"publisher","first-page":"3049","DOI":"10.1016\/j.apsb.2022.02.002","volume":"12","author":"D Sun","year":"2022","unstructured":"Sun, D., Gao, W., Hu, H. & Zhou, S. 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The study did not involve human participants or access to participant-level records, personally identifiable information, or human biospecimens. Accordingly, institutional ethics approval and informed consent were not required. All methods were carried out in accordance with relevant guidelines and regulations.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"25915"}}