Background: Doxorubicin (DOX) treatment is a primary cause of chemotherapy-induced
cardiotoxicity. Antidiabetic sitagliptin (STG) has been shown to improve cardiovascular
functions through anti-inflammatory, antioxidant, and anti-apoptotic effects. Oxidative stress
plays a crucial role in the development of various cardiovascular diseases, especially those
related to endothelial dysfunction. The transcription factor nuclear factor erythroid-2-like 2
(Nrf2) is the main regulator of antioxidant defense mechanisms. Nrf2, along with its
suppressor protein Kelch-like ECH-associated protein 1 (Keap1), controls the levels of
reactive oxygen species (ROS). Objective: This study aimed to evaluate the role of the
Nrf2/caspase-3 signaling pathway in the cardiotoxic effect of DOX and the potential role of
sitagliptin (STG). Materials and Methods:Rats were divided into four groups, each
comprising eight animals (n=8): a control group, an STG group (receiving 10 mg/kg/day for
21 days), a DOX group (receiving 1mg/kg i.p per day for five injections week for 3 weeks)
and STG+DOX group (treated by STG and DOX as previously mentioned). Results: The
effect of DOX on cardiac tissue detected a significant reductionin ABP and deviated ST
segment, while STG improved DOX-induced cardiotoxicity markers, oxidative stress, and
inflammatory markers. Also, STG regulates cardiovascular hemodynamics and reduces both
cardiac caspase-3 and Keap-1 and upregulates NrF2 gene expression levels. Conclusion:
STG administration can exert protective effects against doxorubicin-induced cardiac toxicity
through anti-inflammatory, antioxidant, and anti-apoptotic properties, in addition to
promoting the Nrf2 signaling pathway.