PGC-1alpha/Nrf2 signaling imbalance drives doxorubicin cardiotoxicity, restored by combined activation

Doxorubicin (DOX) is a potent chemotherapeutic, but its use is limited by severe cardiotoxicity, primarily driven by mitochondrial dysfunction and excessive oxidative stress. Current strategies often fall short in preventing this damage. While PGC-1alpha is crucial for mitochondrial biogenesis and function, and Nrf2 orchestrates antioxidant defenses, the precise interplay and functional coupling between these pathways in DOX-induced cardiac injury have remained unclear, representing a critical gap in therapeutic understanding.

Researchers employed transcriptomic analysis, human iPSC-derived cardiomyocytes, and doxorubicin (DOX)-induced murine models to dissect the functional interaction between peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and nuclear factor erythroid 2-related factor 2 (Nrf2). They used pharmacological activation and gene knockdown techniques to manipulate these pathways. The study investigated DOX's impact on mitochondrial metabolism and antioxidant responses, evaluating endpoints like mitochondrial respiration, oxidative stress markers, and cardiac structure/function through histological approaches and other assays.

DOX exposure significantly suppressed oxidative phosphorylation (OXPHOS), tricarboxylic acid cycle (TCA cycle), and mitochondrial biogenesis pathways, while concurrently activating Nrf2-mediated antioxidant responses, indicating a functional uncoupling. Activation of PGC-1alpha alone restored mitochondrial respiration and reduced oxidative stress. Conversely, PGC-1alpha deficiency severely aggravated mitochondrial collapse. Notably, Nrf2-mediated antioxidant protection was significantly attenuated under PGC-1alpha deficiency, demonstrating its 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.