SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway

Area of Science:

• Cardiology
• Oncology
• Molecular Biology

Background:

• Doxorubicin (DOX) is a vital chemotherapy drug, but its use is limited by severe cardiotoxicity (DIC).
• DIC involves reactive oxygen species (ROS), impaired autophagy, and cell death, significantly impacting patient outcomes.
• SIRT4's role in cardiac metabolism and cell death suggests a potential link to DIC, but this remains unconfirmed.

Purpose of the Study:

• To investigate the role of SIRT4 in Doxorubicin-induced cardiotoxicity (DIC).
• To elucidate the molecular mechanisms by which SIRT4 influences DIC, particularly its interaction with autophagy and the Akt/mTOR pathway.

Main Methods:

• In vivo and in vitro experiments were conducted to assess the effects of SIRT4 overexpression on DIC.
• Cardiac function, cardiomyocyte apoptosis, and autophagy levels were measured.
• The involvement of the Akt/mTOR signaling pathway and autophagy activation (using rapamycin) was examined.

Main Results:

• SIRT4 overexpression significantly improved cardiac function and reduced cardiomyocyte apoptosis and autophagy in the context of DOX treatment.
• Activating autophagy with rapamycin negated the protective effects of SIRT4 overexpression against DIC.
• SIRT4 overexpression activated the Akt/mTOR signaling pathway, leading to the inhibition of autophagy.

Conclusions:

• SIRT4 overexpression confers protection against Doxorubicin-induced cardiotoxicity (DIC).
• This protective effect is mediated by the inhibition of autophagy through the Akt/mTOR signaling pathway.
• SIRT4 represents a promising therapeutic target for managing and preventing chemotherapy-induced heart damage.