Multifaceted Cardioprotective Potential of Reduced Glutathione Against Doxorubicin-Induced Cardiotoxicity via Modulating Inflammation–Oxidative Stress Axis

Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat many types of cancer. Its use is limited because of the reported accompanied cardiotoxicity, which is driven by oxidative stress and inflammation. Herin, we explored the cardioprotective impact of reduced glutathione (GSH) against DOX-induced cardiac damage in a mice model and highlighted the dynamic interplay between pro-inflammatory and antioxidant mechanisms, with tissue damage markers and oxidative byproducts. Mice were divided into four groups and administered DOX, GSH, or a combination, and the outcomes were compared to untreated controls. DOX administration caused significant mortality, weight loss, elevated serum markers of cardiac injury (CK-MB and LDH), oxidative stress (MDA and iron), pro-inflammatory cytokines (IL-6, IL-17, and IL-23), and upregulated pro-inflammatory gene expression of <i>STAT-3</i> and <i>NFκB</i> as well as downregulated gene expression of <i>NRF-2</i> and HO-1. Histological analysis showed myocardial fibrosis, vacuolization, and apoptosis, as confirmed by a TUNEL assay. Meanwhile, treatment with GSH improved survival rate, attenuated weight loss, and restored cardiac function markers. Furthermore, GSH suppressed oxidative stress and inflammation, modulated gene expression, and declined histopathological damage. These findings demonstrated the multifaceted cardioprotection of GSH through the restoration of redox homeostasis and modulation of the pro- and anti-inflammatory responses. GSH supplementation emerges as a promising adjunct therapy to mitigate DOX-induced cardiotoxicity, offering a strategy to improve cardiac health in cancer patients undergoing doxorubicin chemotherapy.