GAS-STING signaling plays an essential pathogenetic role in Doxorubicin-Induced Cardiotoxicity

Area of Science:

• Cardiology
• Immunology
• Pharmacology

Background:

• Doxorubicin (Dox) is a potent chemotherapy agent with severe cardiotoxic side effects, limiting its clinical use.
• The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is known to modulate inflammation and immune responses.
• The role of the cGAS-STING pathway in Doxorubicin-induced cardiomyopathy (DIC) remains uncharacterized.

Purpose of the Study:

• To investigate the role of the cGAS-STING pathway in Doxorubicin-induced cardiotoxicity.
• To determine if inhibiting the STING pathway can mitigate Doxorubicin-induced cardiotoxicity.

Main Methods:

• In vivo studies utilized wild-type and STING knockdown C57BL/6J mice treated with Doxorubicin.
• STING was silenced using adeno-associated virus 9 (AAV9).
• Cardiac function was assessed via echocardiography, histology, and molecular phenotyping. In vitro studies used HL-1 cardiomyocytes.

Main Results:

• Doxorubicin treatment significantly activated the cGAS-STING pathway in wild-type mice.
• STING silencing markedly improved survival rates and cardiac function in Doxorubicin-treated mice.
• STING inhibition reduced myocardial inflammatory cytokines and apoptosis, findings consistent in both in vivo and in vitro models.

Conclusions:

• The cGAS-STING pathway plays a critical role in mediating Doxorubicin-induced cardiotoxicity.
• Inhibition of STING effectively alleviates Doxorubicin-induced cardiotoxicity in a preclinical mouse model.
• Targeting STING in cardiomyocytes presents a promising therapeutic strategy for preventing Doxorubicin-induced heart damage.