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These conditions induce structural and functional alterations in the heart, including left ventricular dysfunction, fibrosis, and ultimately heart failure, particularly in the presence of coronary artery disease or hypertension. Autophagy, a critical cellular process for maintaining cardiac homeostasis, is frequently disrupted in metabolic cardiomyopathy. This review explores the role of autophagy in the pathogenesis of high-fat diet (HFD) and streptozotocin (STZ)-induced metabolic cardiomyopathy, focusing on non-selective and selective autophagy pathways, including mitophagy, ER-phagy, and ferritinophagy. Key proteins and genes such as PINK1, Parkin, ULK1, AMPK, mTOR, ATG7, ATG5, Beclin-1, and miR-34a are central to the regulation of autophagy in metabolic cardiomyopathy. Dysregulated autophagic flux impairs mitochondrial function, promotes oxidative stress, and drives fibrosis in the heart. Additionally, selective autophagy processes such as lipophagy, regulated by PNPLA8, and ferritinophagy, modulated by NCOA4, play pivotal roles in lipid metabolism and iron homeostasis. Emerging therapeutic strategies targeting autophagy, including plant extracts (e.g., curcumin, dihydromyricetin), endogenous compounds (e.g., sirtuin 3, LC3), and lipid\/glucose-lowering drugs, offer promising avenues for mitigating the effects of metabolic cardiomyopathy. Despite recent advances, the precise mechanisms underlying autophagy in this context remain poorly understood. A deeper understanding of autophagy\u2019s regulatory networks, particularly involving these critical genes and proteins, may lead to novel therapeutic approaches for treating metabolic cardiomyopathy.<\/jats:p>","DOI":"10.3390\/ijms26041668","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T03:41:47Z","timestamp":1739763707000},"page":"1668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Autophagy in High-Fat Diet and Streptozotocin-Induced Metabolic Cardiomyopathy: Mechanisms and Therapeutic Implications"],"prefix":"10.3390","volume":"26","author":[{"given":"Rong","family":"Zhou","sequence":"first","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zutong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjie","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinchun","family":"Duan","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanlin","family":"Miao","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mofei","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odell D.","family":"Jones","sequence":"additional","affiliation":[{"name":"University Laboratory Animal Resources (ULAR), University of Pennsylvania School of Medicine, Philadelphia, PA 19144, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingli","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehong","family":"Xu","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Genetics and Developmental Biology, Shaanxi Normal University College of Life Sciences, Xi\u2019an 710062, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1016\/j.jacc.2023.01.049","article-title":"Heart failure with preserved ejection fraction: JACC scientific statement","volume":"81","author":"Borlaug","year":"2023","journal-title":"J. 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