PGC‐1α–Nrf2 Signaling Imbalance Mediates Doxorubicin‐Induced Mitochondrial Dysfunction and Cardiac Injury

Doxorubicin (DOX)‐induced 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‐derived cardiomyocytes, and DOX‐induced murine models were used to investigate the functional interaction between peroxisome proliferator–activated receptor gamma coactivator‐1alpha (PGC‐1alpha) and nuclear factor erythroid 2–related 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‐mediated antioxidant responses, indicating functional uncoupling. PGC‐1alpha activation restored mitochondrial respiration and reduced oxidative stress, whereas its deficiency aggravated mitochondrial collapse. Notably, Nrf2‐mediated antioxidant protection was significantly attenuated under PGC‐1alpha deficiency, demonstrating dependence on mitochondrial integrity. In vivo, combined activation of PGC‐1alpha 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‐induced cardiotoxicity involves functional decoupling between antioxidant responses and mitochondrial metabolism. PGC‐1alpha maintains mitochondrial homeostasis and enables effective Nrf2‐mediated defense, suggesting that targeting the PGC‐1alpha/Nrf2 axis represents a promising therapeutic strategy for DOX‐induced cardiac injury.