Doxorubicin-Induced Cardiotoxicity: Comprehensive Pathway Insights and Advanced Preclinical Therapeutics

Area of Science:

• Cardiology
• Oncology
• Pharmacology

Background:

• Doxorubicin (DOX) is a key anthracycline chemotherapy agent.
• Its clinical use is limited by dose-dependent cardiotoxicity.
• Mechanisms include oxidative stress, ferroptosis, pyroptosis, and epigenetic alterations.

Purpose of the Study:

• To review the multifaceted mechanisms of doxorubicin-induced cardiotoxicity (DIC).
• To explore the role of autophagy, ferroptosis, pyroptosis, and epigenetic modifications in DIC.
• To highlight emerging therapeutic strategies, including gut microbiota modulation.

Main Methods:

• Literature review of studies on doxorubicin cardiotoxicity.
• Analysis of molecular pathways involved in DIC.
• Evaluation of potential interventions for mitigating cardiotoxicity.

Main Results:

• DOX induces cardiotoxicity via oxidative stress, lipid peroxidation, and disrupted iron homeostasis.
• Autophagy dysregulation, ferroptosis (GPX4 downregulation), and pyroptosis (NLRP3, GSDMD) contribute to cardiac damage.
• Epigenetic changes (DNMT1, miR-520h, HDAC inhibition) and gut dysbiosis exacerbate DIC.
• Interventions like probiotics, fecal microbiota transplantation, and compounds (glabridin, emodin) show protective effects.

Conclusions:

• DIC involves complex interplay of cellular stress pathways, epigenetic modifications, and gut microbiota.
• Targeting these pathways, particularly gut microbiota remodeling, offers promising therapeutic avenues.
• Further research is needed to develop effective strategies against DOX-induced cardiotoxicity.