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Hepatocyte nuclear factor 4alpha (HNF4\u03b1) is closely associated with FAO in both cellular processes and disease conditions. Pellino 1 (Peli1), an E3 ligase containing a RING-like domain, plays a crucial role in catalyzing polyubiquitination of various substrates. In this study, we aimed to investigate the involvement of HNF4\u03b1 and its ubiquitination, facilitated by Peli1, in FAO during pressure overload-induced cardiac hypertrophy. Peli1 systemic knockout mice (Peli1<jats:sup>KO<\/jats:sup>) display improved myocardial hypertrophy and cardiac function following transverse aortic constriction (TAC). RNA-seq analysis revealed that changes in gene expression related to lipid metabolism caused by TAC were reversed in Peli1<jats:sup>KO<\/jats:sup> mice. Importantly, both HNF4\u03b1 and its downstream genes involved in FAO showed a significant increase in Peli1<jats:sup>KO<\/jats:sup> mice. We further used the antagonist BI6015 to inhibit HNF4\u03b1 and delivered rAAV9-HNF4\u03b1 to elevate myocardial HNF4\u03b1 level, and confirmed that HNF4\u03b1 inhibits the development of cardiac hypertrophy after TAC and is essential for the enhancement of FAO mediated by Peli1 knockout. In vitro experiments using BODIPY incorporation and FAO stress assay demonstrated that HNF4\u03b1 enhances FAO in cardiomyocytes stimulated with angiotension II (Ang II), while Peli1 suppresses the effect of HNF4\u03b1. Mechanistically, immunoprecipitation and mass spectrometry analyses confirmed that Peli1 binds to HNF4\u03b1 via its RING-like domain and promotes HNF4\u03b1 ubiquitination at residues K307 and K309. These findings shed light on the underlying mechanisms contributing to impaired FAO and offer valuable insights into a promising therapeutic strategy for addressing pathological cardiac hypertrophy.<\/jats:p>","DOI":"10.1038\/s41419-024-06470-7","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T18:02:43Z","timestamp":1707760963000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["HNF4\u03b1 ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy"],"prefix":"10.1038","volume":"15","author":[{"given":"Yuxing","family":"Hou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengxi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyang","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linli","family":"Que","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-9592","authenticated-orcid":false,"given":"Guoqing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5289-4910","authenticated-orcid":false,"given":"Qi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1224-4358","authenticated-orcid":false,"given":"Chuanfu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-6933","authenticated-orcid":false,"given":"Guoqiang","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1504-946X","authenticated-orcid":false,"given":"Yuehua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3487-7915","authenticated-orcid":false,"given":"Jiantao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,12]]},"reference":[{"key":"6470_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","volume":"15","author":"M Nakamura","year":"2018","unstructured":"Nakamura M, Sadoshima J. 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