{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:11:19Z","timestamp":1791216679623,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014Next Generation EU\u2014NRRP M6C2","award":["E83C24000750006"],"award-info":[{"award-number":["E83C24000750006"]}]},{"name":"Italian Ministry of Health","award":["E83C24000750006"],"award-info":[{"award-number":["E83C24000750006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The peroxisome proliferator-activated receptor family of lipid-activated nuclear receptors (PPARs) plays a critical role in the regulation of cellular lipid metabolism. In cardiac muscle, PPAR\u03b1 is highly expressed and regulates genes involved in fatty acid oxidation, but its activity is downregulated in hypertrophic hearts; however, the consequences of chronic PPAR\u03b1 deficiency on the cardiac contractile apparatus remain unclear. This study aimed to investigate the PPAR\u03b1 role in hypertrophic phenotype and to evaluate the potential effects of the antioxidant Ebselen (Ebs) treatment on changes associated with PPAR\u03b1 depletion. We thus generated an in vitro model of cardiac hypertrophy by stable silencing of the PPARA gene in H9c2 rat cardiomyoblasts. We observed that PPAR\u03b1 silencing induces a hypertrophic phenotype, characterized by increased NPPB and decreased FBXO32 expression, mitochondrial dysregulation, impaired lipid metabolism, oxidative stress, and ferroptosis-related alterations. Epigenetically, H3K27ac levels increased while H3K27me3 decreased. Moreover, miR-34a, miR-132, and miR-331 were downregulated, implicating a miRNA-mediated mechanism in PPAR\u03b1-linked cardiac hypertrophy. Treatment with Ebs, a redox-active compound with inhibitory effects on ferroptosis and epigenetics, reversed hypertrophic phenotype and restored miRNA levels. In conclusion, we found that PPAR\u03b1 depletion promotes oxidative stress and hypertrophic phenotype and that Ebs may act as a potential therapeutic agent.<\/jats:p>","DOI":"10.3390\/antiox14091059","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T08:01:01Z","timestamp":1756454461000},"page":"1059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-0754","authenticated-orcid":false,"given":"Marzia","family":"Bianchi","sequence":"first","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5365-3123","authenticated-orcid":false,"given":"Nadia","family":"Panera","sequence":"additional","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Petrillo","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3297-1592","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Cicolani","sequence":"additional","affiliation":[{"name":"Core Facilities, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5898-9518","authenticated-orcid":false,"given":"Cristiano","family":"De Stefanis","sequence":"additional","affiliation":[{"name":"Core Facilities, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Scarsella","sequence":"additional","affiliation":[{"name":"Core Facilities, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Ciavardelli","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University \u201cKore\u201d of Enna, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1825-9347","authenticated-orcid":false,"given":"Fiorella","family":"Piemonte","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-6329","authenticated-orcid":false,"given":"Anna","family":"Alisi","sequence":"additional","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-9419","authenticated-orcid":false,"given":"Anna","family":"Pastore","sequence":"additional","affiliation":[{"name":"Research Unit of Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. 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