{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T04:57:21Z","timestamp":1766120241231,"version":"3.48.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,11,18]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Heart failure is characterized by cardiac dysfunction, cardiac remodeling, and mitochondrial dysfunction. NR4a1 (nuclear receptor subfamily 4 group A member 1) plays a crucial role in regulating mitochondrial function and biological performance in various diseases. The main objective of this study was to investigate the influence of NR4a1 on cardiac hypertrophy and uncover its underlying mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">A mouse model was established by transverse aortic constriction surgery, and an in\u00a0vitro model was established by phenylephrine\u2010treated neonatal rat ventricular myocytes. Mice were transfected with adeno\u2010associated virus 9 to assess the role of NR4a1 in cardiac hypertrophy. We used PGC1\u03b1 (peroxisome proliferator\u2010activated receptor \u03b3 coactivator\u20101\u03b1) cardiac\u2010specific knockout mice for subsequent experiments to investigate the impact of NR4a1 on mitochondrial bioenergetics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p xml:lang=\"en\">NR4a1 overexpression significantly exacerbates transverse aortic constriction\u2010induced cardiac remodeling and cardiac dysfunction, and NR4a1 knockdown attenuates cardiac remodeling and cardiac dysfunction. Mechanistically, NR4a1 modulated cardiac remodeling and heart failure by impairing mitochondrial bioenergetics through PGC1\u03b1\/NRF1 (nuclear respiratory factor 1)\/TFAM (transcription factor A mitochondrial) axis. Inhibition of PGC1\u03b1 activation is critical for NR4a1 to impair mitochondrial bioenergetics in cardiac hypertrophy. Furthermore, cardiac\u2010specific PGC1\u03b1 knockdown counteracts heart failure and mitochondrial dysfunction ameliorated by NR4a1 knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Collectively, our findings demonstrate that NR4a1 drives pathological cardiac remodeling and heart failure progression by suppressing the PGC1\u03b1\/NRF1\/TFAM axis, leading to impaired mitochondrial function. Targeting NR4a1 and its interactions with PGC1\u03b1 may hold promise for the development of novel therapeutic strategies for treating cardiac hypertrophy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.042774","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T06:14:01Z","timestamp":1762928041000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Nuclear Receptor Subfamily 4 Group\u00a0A Member 1 Exacerbates Cardiac Remodeling by Inhibiting Mitochondrial Function Through the Peroxisome Proliferator\u2010Activated Receptor \u03b3 Coactivator\u20101\u03b1\/Nuclear Respiratory Factor 1\/Transcription Factor A Mitochondrial Axis"],"prefix":"10.1161","volume":"14","author":[{"given":"Chun\u2010yan","family":"Kong","sequence":"first","affiliation":[{"name":"Renmin Hospital of Wuhan University","place":["Wuhan, People\u2019s Republic of China"]},{"name":"Hubei Key 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