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In cardiomyocytes, where approximately 70% of energy is derived from fatty acid oxidation, PPAR\u03b1 plays a central role in maintaining metabolic homeostasis. Moreover, the transcription factor is implicated in postnatal maturation of the heart and immune modulation. Dysregulation of PPAR\u03b1 signaling has profound consequences for cardiac energy balance, particularly under stress conditions. Accordingly, its role has been extensively investigated in cardiovascular diseases, including ischemia\/reperfusion, diabetic cardiomyopathy and sepsis-induced cardiomyopathy. Upon ischemia\/reperfusion and sepsis, cardiac PPAR\u03b1 expression is typically downregulated, contributing to impaired fatty acid breakdown and reduced metabolic flexibility. In contrast, diabetic cardiomyopathy is characterized by sustained PPAR\u03b1 activation, promoting excessive fatty acid oxidation, lipid accumulation and lipotoxicity. These context-dependent effects highlight a complex role of PPAR\u03b1 in cardiac diseases. PPAR\u03b1 has emerged as a promising therapeutic target, as its modulation can alleviate cardiac injury in preclinical models. However, further research is required to validate its efficacy in human disease, improve cardiomyocyte-specific targeting strategies to minimize systemic side effects, and better define optimal timing of intervention, as inappropriate or prolonged modulation may lead to detrimental outcomes.<\/jats:p>","DOI":"10.3390\/cells15100940","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PPAR\u03b1: Linking Cardiac Metabolism to Therapeutic Opportunities in Cardiovascular Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5246-1923","authenticated-orcid":false,"given":"Maxime","family":"Roes","sequence":"first","affiliation":[{"name":"Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-036X","authenticated-orcid":false,"given":"Claude","family":"Libert","sequence":"additional","affiliation":[{"name":"Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1844-6476","authenticated-orcid":false,"given":"Jolien","family":"Vandewalle","sequence":"additional","affiliation":[{"name":"Center for Inflammation Research, Vlaams Instituut voor Biotechnologie (VIB), 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1016\/j.jacc.2020.11.021","article-title":"The Global Burden of Cardiovascular Diseases and Risks","volume":"76","author":"Roth","year":"2020","journal-title":"J. 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