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Here, this work establishes an in vitro assessment system for DbCM function using cardiomyocytes derived from human pluripotent stem cells and engineered heart tissue. This work finds high\u2010fat status in complex diabetes risk factors majorly contributes most to cardiomyocyte death and contractile dysfunction. Notably, PA induced early electrophysiological abnormalities, and lately is associated with cardiac fibrosis, mitochondrial fission, and systolic and diastolic dysfunction at tissue level. Using this in vitro assessment system, this work finds that empagliflozin (EMPA), a first\u2010line glucose\u2010lowering drug, effectively alleviated early PA\u2010induced cardiomyocyte injury. Treatment with EMPA enhanced abnormal diastolic and electrophysiological functions in the PA\u2010hEHT model and significantly reduced endoplasmic reticulum stress, and apoptosis. Furthermore, these promising results are confirmed in a type 2 diabetes mellitus mouse model, reinforcing the potential of EMPA as a therapeutic option to alleviate cardiomyocyte injury under diabetic conditions. These findings suggest that this work has developed an engineered model of diabetic cardiomyopathy that mimics the various stages of lipotoxic myocardial injury and support the use of EMPA as a potential therapeutic option for diabetic or lipotoxic cardiomyopathy.<\/jats:p>","DOI":"10.1002\/advs.202503173","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T06:02:44Z","timestamp":1748412164000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Human Engineered Heart Tissue\u2010Derived Lipotoxic Diabetic Cardiomyopathy Model Revealed Early Benefits of Empagliflozin"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3605-1429","authenticated-orcid":false,"given":"Lin","family":"Cai","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering Stem Cells and Tissue Engineering Manufacture Center School of Life Sciences Hubei University  Wuhan 430062 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering Stem Cells and Tissue Engineering Manufacture Center School of Life Sciences Hubei University  Wuhan 430062 China"},{"name":"Key Laboratory of Animal Biological Products &amp; Genetic Engineering Ministry of Agriculture and Rural Sinopharm Animal Health Corporation Ltd.  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