Gnetol significantly improved cardiac function, attenuated myocardial injury and fibrosis, and reduced oxidative stress in a mouse model of doxorubicin-induced cardiomyopathy.
Does gnetol improve cardiac function and attenuate ferroptosis in a mouse model of doxorubicin-induced cardiotoxicity?
Cysteine depletion is an early marker of doxorubicin cardiotoxicity, and gnetol is a promising cardioprotective agent that suppresses ferroptosis and improves cardiac function in preclinical models.
Doxorubicin (DOX)-induced cardiotoxicity remains a major limitation of cancer chemotherapy, largely due to the lack of sensitive approaches for early detection and effective cardioprotective interventions. This study investigated whether cysteine depletion represents an early redox event during DOX cardiotoxicity and evaluated a cysteine-activatable fluorescent probe, termed the cardiotoxicity-responsive cysteine probe (CCP), for in vivo redox imaging and therapeutic discovery. Cardiac imaging revealed a significant reduction in intracellular cysteine levels three weeks after DOX administration, preceding systolic dysfunction detected by echocardiography at four weeks. Mechanistically, cysteine depletion was accompanied by impaired glutathione-dependent antioxidant defense, iron accumulation, lipid peroxidation, and ferroptosis. Through probe-guided screening, gnetol (a naturally occurring polyphenolic stilbene) was identified as a potent regulator of intracellular cysteine homeostasis. Gnetol restored cysteine and glutathione levels, reduced lipid peroxidation, and suppressed ferroptosis by modulating the SMAD–hepcidin–FPN1 axis and preserving glutathione peroxidase 4 activity. In the mouse model of DOX-induced cardiomyopathy, gnetol significantly improved cardiac function, attenuated myocardial injury and fibrosis, and reduced oxidative stress without evident systemic toxicity. Collectively, these findings establish cysteine depletion as an early redox feature of DOX cardiotoxicity and demonstrate that cysteine-targeted redox imaging enables mechanism-guided discovery of cardioprotective agents. This study highlights gnetol as a promising ferroptosis-suppressing candidate and provides a mechanistic framework for early detection and intervention in redox-driven cardiac injury. • Cardiac cysteine depletion occurs early in doxorubicin cardiotoxicity. • Cysteine loss precedes systolic dysfunction in a mouse model. • Imaging-guided screening identifies gnetol as a cysteine homeostasis modulator. • Gnetol attenuates ferroptosis via SMAD–hepcidin–FPN1 and GPX4 pathways.
Chen et al. (Sun,) conducted a other in Doxorubicin-induced cardiotoxicity. Gnetol was evaluated on Cardiac function, myocardial injury, fibrosis, and oxidative stress. Gnetol significantly improved cardiac function, attenuated myocardial injury and fibrosis, and reduced oxidative stress in a mouse model of doxorubicin-induced cardiomyopathy.