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Few of the first-line targeted drugs including sorafenib and lenvatinib are available, which often develop resistance. Drug combination therapy is crucial for improving the efficacy of cancer therapy and overcoming resistance. However, traditional methods for discovering drug synergy are costly and time consuming. In this study, we developed a novel predicting model PathSynergy by integrating drug feature data, cell line data, drug\u2013target interactions, and signaling pathways. PathSynergy combined the advantages of graph neural networks and pathway map mapping. Comparing with other baseline models, PathSynergy showed better performance in model classification, accuracy, and precision. Excitingly, six Food and Drug Administration (FDA)-approved drugs including pimecrolimus, topiramate, nandrolone_decanoate, fluticasone propionate, zanubrutinib, and levonorgestrel were predicted and validated to show synergistic effects with sorafenib or lenvatinib against liver cancer for the first time. In general, the PathSynergy model provides a new perspective to discover synergistic combinations of drugs and has broad application potential in the fields of drug discovery and personalized medicine.<\/jats:p>","DOI":"10.1093\/bib\/bbaf192","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T19:25:34Z","timestamp":1745522734000},"source":"Crossref","is-referenced-by-count":8,"title":["PathSynergy: a deep learning model for predicting drug synergy in liver cancer"],"prefix":"10.1093","volume":"26","author":[{"given":"Fengyue","family":"Zhang","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University , No. 100, East Daxue Road, Xixiangtang District, Nanning 530004, Guangxi ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuqi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University , No. 100, East Daxue Road, Xixiangtang District, Nanning 530004, Guangxi ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinrui","family":"Wei","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine , No. 13 Wuhe Avenue, Nanning 530200, Guangxi ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4059-4758","authenticated-orcid":false,"given":"Lichuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University , No. 100, East Daxue Road, Xixiangtang District, Nanning 530004, Guangxi 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