心脏脂质过载是糖尿病心肌病的早期但被忽视的特征。目前尚无可用于治疗此病状的疗法。酪氨酸激酶抑制剂（TKIs）被用作不同类型癌症的一线或二线疗法。在癌症患者合并糖尿病的情况下，据报道TKIs改善了血糖控制，使胰岛素停用。它们还可减少非酒精性脂肪肝小鼠模型中的肝脏脂肪过载。本研究旨在确定二代TKI达沙替尼对肥胖型2型糖尿病小鼠的脂质积累和心脏功能的治疗效果，并评估该药物是否影响心外脂肪组织沉积。两项对21周龄的肥胖型瘦素受体突变BKS.Cg-+Leprdb/+Leprdb/OlaHsd（db/db）小鼠的研究比较了达沙替尼（5mg/kg）和载剂（10%二甲亚砜+90%聚乙二醇300）每隔三天一次进行一周或每周一次进行四周的治疗。通过超声心动图研究功能和容量指标。尸检分析包括组织学检查脂肪沉积和纤维化，并使用免疫组织化学和流式细胞术评估细胞衰老。还研究了达沙替尼对人骨髓（BM）来源的间充质干细胞（MSCs）的抗脂质生成作用。适当采用非配对参速或非参数检验比较两个或多个组。达沙替尼减少了糖尿病小鼠心脏的脂肪过载和纤维化。该药物还减少了BM脂肪堆积，但不影响其他脂肪沉积。这些结构变化与改善舒张功能指标，特别是E/A比值和非流动时间相关。此外，与载剂对照组相比，达沙替尼治疗小鼠心脏中p16水平较低，表明该药物对细胞衰老信号通路具有抑制作用。体外实验证明，达沙替尼抑制人BM-MSC的存活能力和脂肪生成承诺。我们的研究结果表明，达沙替尼对心脏和BM脂肪积聚和心脏纤维化具有逆作用。在心脏中，这与有利的功能后果相关，即舒张功能指数的改善。以TKI重新用途获得心脏益处，可解决糖尿病心脏脂质过载的未满足需求。©2023. BioMed Central Ltd., part of Springer Nature.

Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots.Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Unpaired parametric or non-parametric tests were used to compare two and multiple groups as appropriate.Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.© 2023. BioMed Central Ltd., part of Springer Nature.