{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:15:22Z","timestamp":1790079322949,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Doxorubicin (DOX)\u2010induced cardiotoxicity is characterized by mitochondrial dysfunction and oxidative stress; however, the mechanistic interplay between mitochondrial metabolic regulation and antioxidant defense remains unclear. In this study, Transcriptomic analysis, in vitro human iPSC\u2010derived cardiomyocytes, and DOX\u2010induced murine models were used to investigate the functional interaction between peroxisome proliferator\u2013activated receptor gamma coactivator\u20101alpha (PGC\u20101alpha) and nuclear factor erythroid 2\u2013related factor 2 (Nrf2). Pharmacological activation, gene knockdown, and histological approaches were employed to dissect pathway interdependence. DOX suppressed oxidative phosphorylation, tricarboxylic acid cycle, and mitochondrial biogenesis pathways while activating Nrf2\u2010mediated antioxidant responses, indicating functional uncoupling. PGC\u20101alpha activation restored mitochondrial respiration and reduced oxidative stress, whereas its deficiency aggravated mitochondrial collapse. Notably, Nrf2\u2010mediated antioxidant protection was significantly attenuated under PGC\u20101alpha deficiency, demonstrating dependence on mitochondrial integrity. In vivo, combined activation of PGC\u20101alpha and Nrf2 more effectively improved mitochondrial function, reduced oxidative injury, and preserved cardiac structure and function compared with single interventions. These findings indicate that DOX\u2010induced cardiotoxicity involves functional decoupling between antioxidant responses and mitochondrial metabolism. PGC\u20101alpha maintains mitochondrial homeostasis and enables effective Nrf2\u2010mediated defense, suggesting that targeting the PGC\u20101alpha\/Nrf2 axis represents a promising therapeutic strategy for DOX\u2010induced cardiac injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jbt.71013","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T06:57:33Z","timestamp":1782975453000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PGC\u20101\u03b1\u2013Nrf2 Signaling Imbalance Mediates Doxorubicin\u2010Induced Mitochondrial Dysfunction and Cardiac Injury"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4641-7851","authenticated-orcid":false,"given":"Shaohuan","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine The First Affiliated Hospital of Bengbu Medical University Bengbu Anhui 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