Synergistic cardioprotection by liraglutide and deferoxamine against doxorubicin-induced cardiotoxicity via modulation of ACSL-4/Nrf-2/GPX-4 signaling.
Monir Nada, Galal Omneya, Awad Azza S, Zaki Hala F, Saber Mona M
Abstract
Doxorubicin (Dox) is a highly effective chemotherapeutic agent whose clinical utility is limited by dose-dependent cardiotoxicity, largely driven by iron overload-dependent cell death (ferroptosis) and excessive reactive oxygen species (ROS). Targeting ferroptosis represents a promising strategy for cardioprotection. This study investigated the cardioprotective potential of liraglutide (Lira), deferoxamine (DFO), and their combination in a rat model of Dox-induced cardiotoxicity. Male Wistar rats received Dox (20 mg/kg, i.p.) following pretreatment with Lira (200 μg/kg/day), DFO (50 mg/kg/week), or their combination for 3 weeks. Cardiac injury markers, iron homeostasis, oxidative stress indices, ferroptosis-related gene expression, and histopathological alterations were evaluated. Dox administration induced marked cardiac dysfunction, elevated CK-MB and troponin-T, disrupted iron regulation, increased lipid peroxidation, suppressed Nrf-2/GPX-4 signaling, and triggered ferroptosis. Both Lira and DFO significantly attenuated these alterations; however, combined therapy produced superior restoration of ventricular function, normalization of iron parameters, enhancement of antioxidant defenses, and preservation of myocardial architecture. These findings demonstrate that simultaneous targeting of iron overload and antioxidant signaling confers enhanced cardioprotection against Dox-induced injury. The Lira-DFO combination may represent a promising adjunct strategy to mitigate anthracycline-associated cardiotoxicity.
Key Findings
- Doxorubicin induces cardiotoxicity via iron overload-dependent ferroptosis and suppression of Nrf-2/GPX-4 antioxidant signaling.
- Liraglutide and deferoxamine individually attenuate cardiac injury, oxidative stress, and ferroptosis markers in a rat model of doxorubicin cardiotoxicity.
- Combined liraglutide and deferoxamine treatment produces superior cardioprotection by restoring ventricular function, normalizing iron homeostasis, and enhancing antioxidant defenses.
Clinical Significance
The combination of liraglutide and deferoxamine offers a promising therapeutic strategy to mitigate doxorubicin-induced cardiotoxicity by targeting ferroptosis and oxidative stress pathways, potentially improving the safety of anthracycline chemotherapy.
Citation
Monir Nada, Galal Omneya, Awad Azza Set al.. Synergistic cardioprotection by liraglutide and deferoxamine against doxorubicin-induced cardiotoxicity via modulation of ACSL-4/Nrf-2/GPX-4 signaling. Naunyn-Schmiedeberg's archives of pharmacology. 2026-Jul-18.