Nifuroxazide mitigates doxorubicin-induced cardiovascular injury: Insight into oxidative/NLRP3/GSDMD-mediated...

Area of Science:

• Cardiology
• Pharmacology
• Toxicology

Background:

• Doxorubicin (DOX) is a potent chemotherapy drug with dose-dependent cardiotoxicity, limiting its clinical application.
• Cardiomyopathy, vascular injury, and hematotoxicity are significant side effects of DOX treatment.
• Understanding the mechanisms underlying DOX-induced toxicity is crucial for developing cardioprotective strategies.

Purpose of the Study:

• To investigate the protective effects of nifuroxazide (NIFU) against DOX-induced cardiotoxicity, vascular injury, and hematotoxicity.
• To elucidate the underlying regulatory mechanisms of NIFU's cardioprotective actions.
• To evaluate NIFU's impact on oxidative stress, inflammation, and pyroptosis pathways.

Main Methods:

• In vivo studies involved administering DOX to induce cardiovascular injury, followed by NIFU treatment in rats.
• In vitro studies utilized neonatal rat cardiomyocytes to assess NIFU's effects on cell viability and pyroptosis.
• Evaluated parameters included electrocardiography (ECG), cardiac injury markers (CK-MB, LDH, AST), oxidative stress markers (ROS, MDA), inflammatory markers (IL-1β), and protein expression (TLR4, NF-kB, NLRP3 inflammasome).

Main Results:

• NIFU treatment restored blood cell counts and hemoglobin levels in vivo.
• NIFU normalized myocardial function, reduced cardiac injury markers, and improved the antioxidant-oxidant balance.
• NIFU significantly downregulated key inflammatory and pyroptosis markers, including TLR4, NF-kB, TXNIP, NLRP3, caspase-1, IL-1β, and GSDMD-N terminal, both in vivo and in vitro.
• In vitro, NIFU preserved cardiomyocyte architecture, enhanced cell viability, and inhibited NLRP3/IL-1β-mediated pyroptosis.

Conclusions:

• Nifuroxazide (NIFU) demonstrates significant cardioprotective effects against doxorubicin (DOX)-induced cardiotoxicity and vascular injury.
• NIFU mitigates DOX toxicity by restoring oxidant-antioxidant balance, inhibiting inflammatory pathways, and preventing pyroptosis.
• NIFU shows promise as a therapeutic agent to reduce the adverse cardiovascular effects of doxorubicin chemotherapy.