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Transient receptor potential melastatin 2 (TRPM2) activity increases in diabetic oxidative stress state, and it is involved in myocardial damage and repair. We explore the protective effect of TRPM2 knockdown on the progression of DCM. A type 2 diabetes animal model was established in C57BL\/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100-mg\/kg streptozotocin (STZ). Genetic knockdown of\n                    <jats:italic>TRPM2<\/jats:italic>\n                    in heart was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 9 carrying\n                    <jats:italic>TRPM2<\/jats:italic>\n                    shRNA. Neonatal rat ventricular myocytes was exposed to 45\u00a0mM of high-glucose (HG) stimulation for 72\u00a0h in vitro to mimic the in vivo conditions. Western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry and fluorescence, electron, CCK-8, and flow cytometry were used to evaluate the phenotype of cardiac inflammation, fibrosis, apoptosis, and autophagy. Mice with HFD\/STZ-induced diabetes exhibited systolic and diastolic dysfunction, as demonstrated by increased myocardial apoptosis and autophagy inhibition in the heart. Compared to control group, the protein expression of TRPM2, bax, cleaved caspase-3, and P62 was significantly elevated, and the protein expression of bcl-2 and LC3-II was significantly decreased in the myocardial tissues of the HFD\/STZ-induced diabetes group. Knockdown of\n                    <jats:italic>TRPM2<\/jats:italic>\n                    significantly reversed the HFD\/STZ-induced myocardial apoptosis and autophagy inhibition.\n                    <jats:italic>TRPM2<\/jats:italic>\n                    silencing attenuated HG-induced apoptosis and autophagy inhibition in primary cardiomyocytes via regulating the MEK\/ERK mTORC1 signaling pathway. TRPM2 knockdown attenuates hyperglycemia-induced myocardial apoptosis and promotes autophagy in HFD\/STZ-induced diabetic mice or HG-stimulated cardiomyocytes via regulating the MEK\/ERK and mTORC1 signaling pathway.\n                  <\/jats:p>","DOI":"10.1007\/s11010-024-04926-0","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T22:01:56Z","timestamp":1706911316000},"page":"3307-3328","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["TRPM2 knockdown attenuates myocardial apoptosis and promotes autophagy in HFD\/STZ-induced diabetic mice via regulating the MEK\/ERK and mTORC1 signaling pathway"],"prefix":"10.1007","volume":"479","author":[{"given":"Feng","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"issue":"8","key":"4926_CR1","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.2337\/diacare.27.8.1879","volume":"27","author":"GA Nichols","year":"2004","unstructured":"Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB (2004) The incidence of congestive heart failure in type 2 diabetes: an update. 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