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Existing computational methods provide a cost-effective alternative to experimental method, but they tend to ignore biological attributes and complex feature interactions. To overcome these limitations, we propose ERFMTDA, an enhanced rotative factorization machine framework for predicting potential tsRNA-disease associations. ERFMTDA explicitly models complex interactions among heterogeneous biological features while integrating latent structural representations derived from the global association matrix. In addition, a biologically informed negative sampling strategy based on motif-level sequence similarity is introduced to improve the reliability of negative samples. Extensive experiments demonstrate that ERFMTDA consistently surpasses the other eleven state-of-the-art methods. Two case studies on diabetic retinopathy and hepatocellular carcinoma further corroborate the model\u2019s ability to prioritize biologically meaningful tsRNA\u2013disease associations.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1014594","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:34:52Z","timestamp":1787074492000},"page":"e1014594","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["ERFMTDA: Predicting tsRNA\u2013disease associations using an enhanced rotative factorization 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