{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:11:58Z","timestamp":1791987118100,"version":"4.4.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,3,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Imbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit \u03b2) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>GRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074700","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T10:01:23Z","timestamp":1767607283000},"page":"736-753","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["GRSF1 Protects Against Heart Failure by Maintaining BCAA Homeostasis"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6913-9514","authenticated-orcid":true,"given":"Hu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5902-1186","authenticated-orcid":true,"given":"Min","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."},{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (M.Z., H.C., J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0687-9234","authenticated-orcid":true,"given":"Ling","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-8980","authenticated-orcid":true,"given":"Hao","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (M.Z., H.C., J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8658-9247","authenticated-orcid":true,"given":"Cihang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China (C.L., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7878-2629","authenticated-orcid":true,"given":"Chenyu","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2108-0201","authenticated-orcid":true,"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8150-2923","authenticated-orcid":true,"given":"Jichun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China (J.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1173-0645","authenticated-orcid":true,"given":"Ming","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9488-7823","authenticated-orcid":true,"given":"Jiangping","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (M.Z., H.C., J.S.)."},{"name":"Department of Cardiac Surgery, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, China (J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1720-809X","authenticated-orcid":true,"given":"Wengong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China (C.L., W.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1680-3628","authenticated-orcid":true,"given":"Ming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China (H.W., J.W., M.Z., L.J., C.F., H.L., M.C., M.X.)."},{"name":"Research Unit of Medical Science Research Management\/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China 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