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Given the high cost of developing new drugs and running clinical trials for cardiovascular disease, repurposing of drugs with approved safety profiles is an attractive strategy for therapeutic development that can significantly reduce the time and cost investment before phase II clinical trials. In the era of \u201cOmics,\u201d various new methods and several large databases have been developed to enable the use of transcriptomics data for drug repurposing. This review summarizes the principles and workflow of signature mapping, which forms the foundation of statistical models used for transcriptome-based drug repurposing. We highlight the features of different analysis pipelines and databases that have been developed for signature mapping. These analysis pipelines prioritize genes that are statistically important, an approach that fundamentally differs from the pharmacological approach of identifying disease-driving and therapeutically targetable pathways. Outcomes of signature mapping pipelines are sensitive to the quality of input data, and results are not always reproducible. Moreover, all widely used RNA-seq databases are derived from cancer research and lack high-quality molecular data for cardiovascular disease. These unmet needs call for interdisciplinary collaboration and large networks of cardiovascular research-oriented biobanks to create the databases needed for transcriptomic-based signature mapping for drug repurposing efforts.<\/jats:p>","DOI":"10.1152\/ajpheart.00899.2025","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:10:27Z","timestamp":1774872627000},"page":"H1508-H1521","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Drug repurposing using transcriptomics: principles and unmet needs in cardiovascular disease"],"prefix":"10.1152","volume":"330","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3031-5888","authenticated-orcid":false,"given":"Samuel","family":"Leung","sequence":"first","affiliation":[{"name":"University of British Columbia","place":["Canada"]},{"name":"University of British Columbia","place":["Canada"]},{"name":"University of British 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