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Existing methods do not fully exploit higher-order collaborative information at the drug\u2013drug and disease\u2013disease levels, and their feature fusion strategies are often static, lacking adaptability to node-specific differences. To address these limitations, we propose ATSFCL-DR, an adaptive topology\u2013semantic fusion contrastive learning framework for drug repositioning. The method constructs a topology graph and a semantic graph, and introduces an adaptive fusion strategy to integrate node representations learned from these two views, thereby enabling more effective use of higher-order information. In addition, the framework designs a multiview fusion contrastive learning mechanism to enhance the consistency and discriminative ability of cross-view representations. To mitigate the noise introduced during higher-order neighborhood aggregation, the framework further incorporates a layer-level contrastive learning objective to improve the robustness of representation learning. Experiments using 10 repetitions of 10-fold cross-validation on three public benchmark data sets show that ATSFCL-DR outperforms representative baseline methods, achieving an average AUROC of 0.9093 and an average AUPR of 0.5362. Furthermore, by predicting previously unknown drug\u2013disease associations on the Gdata set and validating them against authoritative databases, ATSFCL-DR identifies pramipexole as a promising candidate drug for Alzheimer\u2019s disease. In summary, ATSFCL-DR provides an effective approach for drug\u2013disease association prediction and candidate drug screening by adaptively integrating topological and semantic information within a contrastive learning framework.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01393","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:56:26Z","timestamp":1788436586000},"page":"10635-10647","source":"Crossref","is-referenced-by-count":0,"title":["Adaptive Topology-Semantic\nFusion Contrastive Learning\nfor Drug Repositioning"],"prefix":"10.1021","volume":"66","author":[{"given":"Hao","family":"Zhang","sequence":"first","affiliation":[{"name":"Hainan Normal University , , ,","place":["Haikou, China, 570100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jincan","family":"Li","sequence":"additional","affiliation":[{"name":"Hainan Normal University , , ,","place":["Haikou, China, 570100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianfang","family":"Tang","sequence":"additional","affiliation":[{"name":"Wuhan Textile University , , ,","place":["Wuhan, China, 430200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Wuhan Textile University , , ,","place":["Wuhan, China, 430200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4934-1258","authenticated-orcid":true,"given":"Zilong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Haikou, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-3813","authenticated-orcid":true,"given":"Feifei","family":"Cui","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Haikou, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1057-1504","authenticated-orcid":true,"given":"Junlin","family":"Xu","sequence":"additional","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajie","family":"Meng","sequence":"additional","affiliation":[{"name":"Wuhan Textile University , , ,","place":["Wuhan, China, 430200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4689-8672","authenticated-orcid":true,"given":"Jialiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Genesis Beijing Co., Ltd. , ,","place":["Beijing, China, 100102"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6191-8770","authenticated-orcid":true,"given":"Yuhua","family":"Yao","sequence":"additional","affiliation":[{"name":"Hainan Normal University , , ,","place":["Haikou, China, 570100"]},{"name":"Hainan Normal University , , ,","place":["Haikou, China, 570100"]},{"name":"Hainan Normal University , , ,","place":["Haikou, China, 570100"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"2026091409075159100_cit1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/bib\/bbv020","article-title":"A survey of current trends in computational drug repositioning","volume":"17","author":"Li","year":"2016","journal-title":"Briefings Bioinf."},{"key":"2026091409075159100_cit2","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1001\/jama.2020.1166","article-title":"Estimated research and development\ninvestment needed to bring a new medicine to market, 2009\u20132018","volume":"323","author":"Wouters","year":"2020","journal-title":"Jama"},{"key":"2026091409075159100_cit3","first-page":"172","article-title":"The cost of new drug discovery and development","volume":"4","author":"Dickson","year":"2009","journal-title":"Discovery Med."},{"key":"2026091409075159100_cit4","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1111\/jphp.13273","article-title":"Drug repositioning:\na brief overview","volume":"72","author":"Jourdan","year":"2020","journal-title":"J. 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