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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>CircRNAs are emerging regulators of human diseases, often functioning through miRNA-mediated regulatory networks. However, experimentally validated circRNA\u2013disease associations remain limited, hindering systematic investigation of circRNA functions and disease mechanisms. Here, we propose CSDPCDA, a miRNA-mediated cross-semantic regulatory network framework for predicting circRNA\u2013disease associations by integrating multi-layer molecular information. CSDPCDA constructs a heterogeneous regulatory network incorporating circRNA\u2013disease associations, circRNA\u2013miRNA interactions, miRNA\u2013disease associations, and molecular similarity information. Multiple biologically meaningful meta-paths are modeled to capture diverse regulatory patterns, and a cross-semantic attention mechanism is employed to integrate complementary molecular representations for association prediction. Comprehensive evaluations on the circR2Disease and circRNADisease datasets showed that CSDPCDA obtained higher AUC, AUPR, and F1-score than the representative existing methods under the same experimental settings. Ablation analyses demonstrated that incorporating miRNA-mediated regulatory information consistently improved the predictive performance across different datasets, while integrating complementary meta-path information further enhanced the characterization of complex molecular regulatory relationships. Moreover, case studies of breast cancer, colorectal cancer, and gastric cancer showed that many of the top-ranked predictions were consistent with previously reported disease-associated circRNAs, providing literature-based evidence for their potential biological relevance. CSDPCDA provides an interpretable framework for prioritizing potential disease-associated circRNAs and facilitating further biological investigation.<\/jats:p>","DOI":"10.3390\/ijms27188391","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CSDPCDA: A miRNA-Mediated Cross-Semantic Regulatory Network Framework for Predicting circRNA\u2013Disease Associations"],"prefix":"10.3390","volume":"27","author":[{"given":"Xin","family":"Wang","sequence":"first","affiliation":[{"name":"School of Computer Science and Engineering, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Intelligent Computing in Medical Image, Ministry of Education, Northeastern University, Shenyang 110189, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Mengyuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Northeastern University, Shenyang 110819, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yixuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Northeastern University, Shenyang 110819, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Sicheng","family":"Xiang","sequence":"additional","affiliation":[{"name":"School of Computer Science and Engineering, Northeastern University, Shenyang 110819, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2965-9920","authenticated-orcid":false,"given":"Chunyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Guohua","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Computing, Harbin Institute of Technology, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/MS9.0000000000002761","article-title":"Circular RNAs: History, metabolism, mechanisms of function, and regulatory roles at a glance","volume":"87","author":"Karimi","year":"2025","journal-title":"Ann. 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