PGC-1α-Nrf2 Signaling Imbalance Mediates Doxorubicin-Induced Mitochondrial Dysfunction and Cardiac Injury.

摘要

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.