Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated...

Area of Science:

• Biochemistry
• Cardiology
• Cell Biology

Background:

• Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a serious side effect of cancer therapy.
• Ferroptosis, characterized by iron accumulation and lipid peroxidation, is a key mechanism in DIC.
• The role of dioscin in chronic DIC and its mechanism in ferroptosis remain unclear.

Purpose of the Study:

• To investigate the protective effects of dioscin against chronic DIC.
• To elucidate the mechanism by which dioscin mitigates cardiac ferroptosis.

Main Methods:

• Chronic DIC rat models and H9c2 cells were utilized.
• Dioscin's effects on cardiac function, ferroptosis markers (Fe2+, lipid peroxidation, GPX4, ACSL4), and mitochondrial integrity were assessed.
• Transcriptomic analysis identified key regulatory pathways, including the Nrf2/GPX4 axis.

Main Results:

• Dioscin significantly improved cardiac function in chronic DIC models.
• Dioscin inhibited ferroptosis by reducing iron and lipid peroxidation, preserving mitochondrial integrity.
• Dioscin upregulated GPX4 and downregulated ACSL4 expression via the Nrf2/GPX4 pathway.
• Dioscin modulated NOX4, FXN, and ABCB8 expression to limit mitochondrial iron and lipid peroxide buildup.
• Nrf2 inhibition abolished dioscin's anti-ferroptotic effects.

Conclusions:

• Dioscin effectively mitigates chronic DIC by inhibiting ferroptosis.
• The protective mechanism involves modulating the Nrf2/GPX4 pathway and downstream iron metabolism genes.
• Dioscin represents a potential therapeutic agent for preventing or treating DOX-induced cardiotoxicity.