{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T15:01:09Z","timestamp":1785164469231,"version":"3.55.0"},"reference-count":153,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The heart is a highly energy-demanding organ that depends on metabolic flexibility to adjust substrate utilization in response to changes in nutrient availability, endocrine signals, and energetic demands. Accumulating evidence demonstrates that dietary patterns are key determinants of myocardial metabolic homeostasis, affecting substrate selection, mitochondrial function, nutrient-sensing pathways, and long-term transcriptional and epigenetic regulation. This review analyzes the molecular mechanisms through which diet regulates cardiac metabolism and explores how chronic nutritional exposures influence the myocardial energetic phenotype. The physiological regulation of cardiac substrate utilization is described, with emphasis on fatty acids, glucose, ketone bodies, and branched-chain amino acids, underscoring the importance of metabolic flexibility in sustaining cardiac efficiency. The regulation of substrate transport and oxidation is examined, including the roles of the carnitine shuttle, insulin signaling, AMPK, mTOR, PPAR\u03b1\u2013PGC-1\u03b1, SIRT3, and other nutrient-sensing networks that coordinate mitochondrial ATP production. The effects of dietary composition and meal timing, such as caloric restriction and intermittent fasting, are discussed as modulators of myocardial metabolism. The adverse effects of chronic nutrient excess are reviewed, including lipotoxicity, glucotoxicity, insulin resistance, mitochondrial dysfunction, oxidative stress, pseudo-hypoxia, fetal metabolic reprogramming, and maladaptive cardiac remodeling. Recent findings on the gut\u2013heart axis, microbiota-derived metabolites, circadian regulation, and metabolic\u2013epigenetic interactions are also considered. Overall, current evidence supports the view that diet is an important and potentially modifiable regulator of the cardiac metabolic phenotype. Advancing the understanding of diet\u2013metabolism interactions may enable the development of targeted nutritional strategies to maintain metabolic flexibility, enhance cardiac bioenergetics, and prevent the progression of heart failure and other cardiometabolic diseases.<\/jats:p>","DOI":"10.3390\/nu18152451","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:08:14Z","timestamp":1785161294000},"page":"2451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diet-Associated Regulation of Cardiac Metabolism: Molecular Determinants and Pathophysiological Consequences"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-3721","authenticated-orcid":false,"given":"Gaetano","family":"Pacinella","sequence":"first","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4979-6399","authenticated-orcid":false,"given":"Anna Maria","family":"Ciaccio","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4868-9033","authenticated-orcid":false,"given":"Carlo Domenico","family":"Maida","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoriano","family":"Della Corte","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-2523","authenticated-orcid":false,"given":"Giuseppe","family":"Miceli","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1413-5945","authenticated-orcid":false,"given":"Mario","family":"Daidone","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosimo","family":"Quaranta","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Sebastian","family":"Soldano","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7318","authenticated-orcid":false,"given":"Antonino","family":"Tuttolomondo","sequence":"additional","affiliation":[{"name":"Department of Promoting Health, Maternal-Infant, Excellence, and Internal and Specialised Medicine (PROMISE) \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90127 Palermo, Italy"},{"name":"Internal Medicine and Stroke Care Ward, Policlinico \u201cP. 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