{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:21:15Z","timestamp":1774354875379,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["NSTC 112-2811-B-038-049"],"award-info":[{"award-number":["NSTC 112-2811-B-038-049"]}]},{"name":"National Science and Technology Council, Taiwan","award":["113-2314-B-038-063-MY3"],"award-info":[{"award-number":["113-2314-B-038-063-MY3"]}]},{"name":"Taipei Medical University\u2013Shuang Ho Hospital","award":["114TMU-SHH-21"],"award-info":[{"award-number":["114TMU-SHH-21"]}]},{"name":"Foundation for the Development of Internal Medicine in Okinawa, Japan","award":["4-02-003"],"award-info":[{"award-number":["4-02-003"]}]},{"name":"Foundation for the Development of Internal Medicine in Okinawa, Japan","award":["4-02-006"],"award-info":[{"award-number":["4-02-006"]}]},{"name":"Foundation for the Development of Internal Medicine in Okinawa, Japan","award":["5-02-007"],"award-info":[{"award-number":["5-02-007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic dysregulation in the heart plays a critical role in the pathogenesis of atrial fibrillation (AF), yet the underlying molecular mechanisms remain unclear. Loss-of-function variants in the zinc finger homeobox 3 gene (ZFHX3) increase AF risk by promoting structural and electrical remodeling. However, the role of ZFHX3 knockdown (KD) in cardiac metabolism has not been fully elucidated. This study investigated the impact of ZFHX3 KD on energy metabolism in atrial myocytes and assessed the therapeutic potential of trimetazidine (TMZ). Seahorse XFe24 extracellular flux analysis, bioluminescent assays, microplate enzyme activity assays, and Western blotting were used to study energy substrate (glucose and fatty acid) oxidation stress, intracellular lactate content, glucose uptake, pyruvate dehydrogenase (PDH) activity, and regulatory protein expression in control and ZFHX3 KD HL-1 cells with or without TMZ (10 \u03bcM) treatment. ZFHX3 KD cells exhibited a higher acute response in oxygen consumption after Etomoxir injection, upregulated CD36 and phosphorylated ACC expression, increased glucose uptake and lactate production, reduced PDH activity, and higher levels of PDK4 and LDHA. Furthermore, ZFHX3 KD cells showed mitochondrial Ca2+ overload and increased phosphorylated PDH and oxidized CaMKII proteins, all of which were significantly attenuated by TMZ. Additionally, TMZ improved mitochondrial dysfunction in ZFHX3 KD cells by decreasing basal and maximal respiration, spare capacity, and proton leak. These findings suggest that ZFHX3 downregulation shifts substrate preference toward fatty acid utilization at the expense of glucose oxidation, contributing to metabolic and mitochondrial calcium dysregulation. TMZ mitigates these effects, highlighting its therapeutic potential in AF associated with ZFHX3 deficiency.<\/jats:p>","DOI":"10.3390\/ijms26178576","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:18:57Z","timestamp":1756977537000},"page":"8576","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ZFHX3 Knockdown Enhances Metabolic Distress in Atrial Myocytes Through Mitochondrial and Calcium Dysregulation: Mitigation by Trimetazidine"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5206-9234","authenticated-orcid":false,"given":"Baigalmaa","family":"Lkhagva","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuen-Hsin","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5735-6249","authenticated-orcid":false,"given":"Satoshi","family":"Higa","sequence":"additional","affiliation":[{"name":"Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, 1199 Makiminato, Urasoe 901-2131, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Hsun","family":"Kao","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7224-4491","authenticated-orcid":false,"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"},{"name":"Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1177\/2047487317715769","article-title":"Atrial fibrillation and the risk for myocardial infarction, all-cause mortality and heart failure: A systematic review and meta-analysis","volume":"24","author":"Ruddox","year":"2017","journal-title":"Eur. 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