Cysteine imaging reveals early redox dysregulation and identifies gnetol as a ferroptosis-modulating agent in doxorubicin cardiotoxicity - PubMed
5 hours ago
- #redox imaging
- #cardiotoxicity
- #ferroptosis
- Doxorubicin (DOX) causes cardiotoxicity with cysteine depletion as an early redox event, preceding systolic dysfunction.
- A cardiotoxicity-responsive cysteine probe (CCP) enabled in vivo imaging and identified cysteine loss three weeks after DOX treatment, linked to glutathione depletion, iron accumulation, and ferroptosis.
- Screening with the probe led to discovery of gnetol, a polyphenolic stilbene, which restored cysteine and glutathione, reduced lipid peroxidation, and suppressed ferroptosis via the SMAD-hepcidin-FPN1 axis and GPX4 activity.
- In a mouse model of DOX-induced cardiomyopathy, gnetol improved cardiac function, reduced myocardial injury and fibrosis, and lowered oxidative stress without systemic toxicity.
- Cysteine-targeted redox imaging facilitates mechanism-guided discovery of cardioprotective agents, positioning gnetol as a promising ferroptosis inhibitor for early intervention in redox-driven cardiac injury.