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This study aimed to elucidate the role and underlying molecular mechanisms of an FBP, F\u2010box and leucine\u2010rich repeat protein 4 (FBXL4), in pathological cardiac hypertrophy. Transcriptomic analysis of murine heart failure and human dilated cardiomyopathy samples revealed consistent downregulation of FBXL4. Similarly, FBXL4 expression was reduced in failing human hearts, hypertrophic mouse hearts, and angiotensin II (Ang II)\u2010treated neonatal mouse cardiomyocytes (NMCMs). Inducible ablation of FBXL4 in cardiomyocytes resulted in HF with reduced cardiac function, an enlarged heart chamber, increased fibrosis, and myofibrillar disorganization and sarcomere remodeling. Conversely, cardiac\u2010specific overexpression of FBXL4 attenuated pressure overload\u2013induced hypertrophy. Mechanistically, FBXL4 interacts with PFN1 and promotes its K48\u2010linked ubiquitination at lysine 70, leading to its proteasomal degradation and the preservation of sarcomeric integrity. Restoration of FBXL4 expression via AAV9 delivery ameliorated cardiac hypertrophy and dysfunction in FBXL4\u2010iCKO mice, while AAV9\u2010mediated PFN1 knockdown or pharmacological inhibition partially reversed these phenotypes. Furthermore, the transcription factor SP1 was found to repress FBXL4 expression during hypertrophy. FBXL4 deficiency also induced hypertrophic features in hiPSC\u2010derived cardiomyocytes. Together, these findings establish FBXL4 as a key regulator of sarcomere integrity and cardiac function through ubiquitin\u2010mediated degradation of PFN1.<\/jats:p>","DOI":"10.1002\/advs.202516702","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T12:57:52Z","timestamp":1769518672000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["F\u2010Box and Leucine\u2010Rich Repeat Protein 4 (FBXL4) Maintains Sarcomere Integrity and Cardiac Function by Enhancing K48\u2010Linked Ubiquitinated Degradation of Profilin\u20101 (PFN1)"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5275-9480","authenticated-orcid":false,"given":"Xingda","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacy the Second Affiliated Hospital of Harbin Medical University &amp; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqi","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy the Second Affiliated Hospital of Harbin Medical University &amp; 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State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenru","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy the Second Affiliated Hospital of Harbin Medical University &amp; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy the Second Affiliated Hospital of Harbin Medical University &amp; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongda","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy the Second Affiliated Hospital of Harbin Medical University &amp; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Cardiology the First Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy the Second Affiliated Hospital of Harbin Medical University &amp; State Key Laboratory of Frigid Zone Cardiovascular Disease, Harbin Medical University Harbin China"},{"name":"State Key Laboratory of Quality Research in Chinese Medicines Macau University of Science and Technology  Macau China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-1462","authenticated-orcid":false,"given":"Weijie","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD) Department of Pharmacology (State Key Laboratory \u2010Province Key Laboratories of Biomedicine\u2010Pharmaceutics of China, Key Laboratory of Cardiovascular Research, College of Pharmacy, Ministry of Education) Harbin Medical University  Harbin China"},{"name":"Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070) Chinese Academy of Medical Sciences  Harbin China"},{"name":"Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569\u2010022\u201000682\u20100"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-025-01150-1"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569\u2010018\u20100007\u2010y"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2024.102376"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13091319"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.09.008"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2015.09.008"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107514"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.07.017"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.07.016"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2274260"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112767"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103081"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00564a033"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2007.11.062"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.22.6516"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.249060"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013608"},{"key":"e_1_2_10_20_1","first-page":"1318","article-title":"Expression of Profilin\u20101 in Endothelial Cells of Rats with Acute Myocardial Infarction","volume":"21","author":"Hao P.","year":"2017","journal-title":"European Review for Medical and Pharmacological Sciences"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvw050"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.320080"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1715"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0320178"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000252345.80198.97"},{"key":"e_1_2_10_26_1","first-page":"882","article-title":"Endothelin\u20101 Mobilizes Profilin\u20101\u2013Bound PIP2 in Cardiac Muscle","volume":"231","author":"Evans N. 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