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Transcriptomic datasets from the GEO database related to diabetic cardiac dysfunction, heart failure, and cardiomyopathy-associated phenotypes were processed for differential expression analysis and WGCNA, with consideration of disease-definition and tissue-source heterogeneity. A two-sample Mendelian randomization analysis was used to evaluate genetically predicted associations between candidate gene expression and T2DM risk. External validation assessed diagnostic performance via ROC analysis. Multi-database screening and molecular docking identified candidate compounds. Streptozotocin-induced diabetic rats were treated with cynaropicrin for 8\u00a0weeks, with comprehensive cardiac and metabolic assessment. Analysis identified 30 candidate genes with functional enrichment in proteostasis and metabolism. Mendelian randomization prioritized three T2DM-associated genetically supported genes: PPIP5K2, RBM23, and IGF2BP2. Cynaropicrin significantly improved cardiac function, reduced fibrosis, and enhanced glycemic control in diabetic rats while suppressing pro-fibrotic signaling. PPIP5K2, RBM23, and IGF2BP2 represent T2DM-associated genetically supported biomarkers dysregulated in diabetic cardiac dysfunction-related datasets with diagnostic potential. Cynaropicrin demonstrates candidate cardioprotective and metabolic benefits in diabetic rats; however, its direct molecular targets and mechanism of action require further validation.<\/jats:p>","DOI":"10.1007\/s00210-026-05585-2","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:16:29Z","timestamp":1783656989000},"page":"20885-20902","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated transcriptomic and Mendelian randomization analysis identifies novel biomarkers for type 2 diabetes\u2013associated cardiac dysfunction: cynaropicrin as a candidate intervention"],"prefix":"10.1007","volume":"399","author":[{"given":"Lindong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonghua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"issue":"5","key":"5585_CR1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41569-019-0315-x","volume":"17","author":"L Adamo","year":"2020","unstructured":"Adamo L, Rocha-Resende C, Prabhu SD, Mann DL (2020) Reappraising the role of inflammation in heart failure. 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