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This review synthesizes the core regulatory network governing cardiac lipid metabolism, encompassing lipid droplet dynamics mediated by perilipins (e.g., Plin5, Plin2), fatty acid uptake via CD36, systemic lipid modulation by apolipoproteins (e.g., APOC3), and the central energy\u2010sensing AMPK\/PGC\u20101\u03b1\/PPAR\u03b1 axis. Dysregulation of this network initiates a self\u2010perpetuating lipotoxic cycle, characterized by the accumulation of toxic lipid intermediates (e.g., diacylglycerols, ceramides), oxidative stress, and inflammatory activation, which serves as a common pathological mechanism across diverse cardiovascular diseases (CVDs), including atherosclerosis, heart failure, diabetic cardiomyopathy, and ischemic injury. Emerging from this mechanistic understanding is a promising landscape of biomarkers\u2014such as specific ceramide species, the ApoB\/ApoA\u20101 ratio, and circulating perilipins\u2014and targeted therapeutic strategies, including APOC3 inhibitors, SGLT2 inhibitors, and Plin5\u2010directed therapies. Future advances will depend on integrating multi\u2010omics technologies and precision medicine approaches to tailor interventions to specific metabolic phenotypes, thereby opening new avenues for the prevention and treatment of CVDs.<\/jats:p>","DOI":"10.1002\/jbt.71033","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T08:45:55Z","timestamp":1785141955000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Myocardial Lipid Metabolism Imbalance: The Pathological Core and Novel Diagnostic\u2010Therapeutic Directions of Cardiovascular Diseases"],"prefix":"10.1002","volume":"40","author":[{"given":"Peiyun","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1164-4664","authenticated-orcid":false,"given":"Qun","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meihua","family":"She","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.59298\/INOSRES\/2024\/141.61000"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2025.1526494"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz388"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvad100"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.08.004"},{"issue":"3","key":"e_1_2_12_7_1","first-page":"9","article-title":"Lipid Droplets and Perilipins in Cardiovascular Diseases","volume":"44","author":"Dian Y. 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