Sunitinib induces cardiotoxicity through modulating oxidative stress and Nrf2-dependent ferroptosis in vitro and in...

Area of Science:

• Cardiology
• Toxicology
• Molecular Biology

Background:

• SUN is a tyrosine kinase inhibitor with known cardiotoxicity, limiting its clinical application.
• The precise molecular mechanisms underlying SUN-induced cardiotoxicity remain unclear.
• Investigating the role of ferroptosis, particularly Nrf2-dependent pathways, is crucial for understanding this toxicity.

Purpose of the Study:

• To elucidate the molecular mechanisms of SUN-induced cardiotoxicity.
• To determine if SUN-induced cardiotoxicity is associated with Nrf2-dependent ferroptosis.
• To evaluate the effects of SUN on cardiac function and ferroptosis markers in vitro and in vivo.

Main Methods:

• Utilized H9c2 cells (in vitro) and C57BL/6J mice (in vivo) to model SUN exposure.
• Administered SUN orally to mice at doses of 10, 20, and 40 mg/kg for 14 days.
• Assessed cardiac function via ECG, plasma enzyme activity, histology, and measured ferroptosis-related proteins using Western blot.

Main Results:

• SUN induced ferroptosis in H9c2 cells, evidenced by mitochondrial dysfunction, iron accumulation, and increased reactive oxygen species (ROS).
• In vivo, SUN impaired cardiac function, causing ECG abnormalities, elevated creatine kinase (CK) and lactate dehydrogenase (LDH) levels, and histological damage with fibrosis.
• SUN treatment decreased levels of glutathione (GSH), increased malondialdehyde (MDA) and Fe2+ content, and altered the expression of key proteins in the Nrf2/ferroptosis pathway (reduced Nrf2, HO-1, NQO1, GPX4, FTH1; increased TfR).

Conclusions:

• Oxidative stress and Nrf2-dependent ferroptosis are critical mechanisms underlying SUN-induced cardiotoxicity.
• SUN disrupts cellular defense systems, leading to iron dysregulation and ferroptotic cell death in cardiac tissue.
• Targeting the Nrf2 pathway and mitigating oxidative stress may offer therapeutic strategies against SUN cardiotoxicity.