Liraglutide and deferoxamine combination synergistically protects against doxorubicin cardiotoxicity via `ACSL-4`/`Nrf-2`/`GPX-4`.
Background
Doxorubicin (Dox) is a potent chemotherapeutic, but its use is limited by severe, dose-dependent cardiotoxicity leading to irreversible heart failure. This damage is largely driven by iron overload-dependent cell death (ferroptosis) and excessive reactive oxygen species (ROS) production. Current cardioprotective strategies are often insufficient, leaving a critical need for novel approaches that can effectively mitigate Dox-induced cardiac injury without compromising its anticancer efficacy. Targeting the specific pathways of ferroptosis and oxidative stress offers a promising avenue to enhance cardiac resilience.
Study Design
Male Wistar rats were subjected to doxorubicin (Dox, 20 mg/kg, i.p.) to induce cardiotoxicity. Prior to Dox, rats received a 3-week pretreatment with Liraglutide (200 μg/kg/day), Deferoxamine (50 mg/kg/week), or their combination. A Dox-only group served as control. Researchers evaluated cardiac injury markers (CK-MB, troponin-T), iron homeostasis, oxidative stress indices, ferroptosis-related gene expression, and histopathological changes. Ventricular function was also assessed as a primary endpoint.
Results
Doxorubicin administration induced marked cardiac dysfunction, elevating CK-MB and troponin-T levels, disrupting iron regulation, and increasing lipid peroxidation. It also suppressed Nrf-2/GPX-4 signaling and triggered ferroptosis. Both Liraglutide and Deferoxamine monotherapies significantly attenuated these Dox-induced alterations, improving cardiac injury markers and oxidative stress.
However, the combined therapy of Liraglutide and Deferoxamine produced superior restoration of ventricular function, normalized iron parameters more effectively, and significantly enhanced antioxidant defenses. This combination also led to a more pronounced preservation of myocardial architecture compared to either agent alone, indicating a synergistic protective effect against Dox-induced injury.
Key Findings
- Doxorubicin induced severe cardiotoxicity, marked by cardiac dysfunction and elevated injury markers.
- Dox disrupted iron regulation, increased lipid peroxidation, and suppressed
Nrf-2/GPX-4signaling. - Both Liraglutide and Deferoxamine monotherapies significantly attenuated Dox-induced cardiac damage.
- Combined Liraglutide and Deferoxamine therapy offered superior restoration of ventricular function.
- The combination normalized iron parameters and enhanced antioxidant defenses more effectively than monotherapy.
Why It Matters
This study highlights a promising strategy to combat doxorubicin-induced cardiotoxicity, a major limitation in cancer treatment. The synergistic effect of Liraglutide and Deferoxamine suggests a novel adjunct therapy that could allow cancer patients to receive full therapeutic doses of Dox with reduced risk of heart damage. Combining a GLP-1 agonist with an iron chelator targets multiple pathways of Dox toxicity, specifically ferroptosis and oxidative stress, offering a more comprehensive cardioprotective approach than single-agent strategies. While preclinical, these findings pave the way for future clinical investigations into this combination, potentially improving long-term outcomes for cancer survivors.
liraglutide
deferoxamine
doxorubicin
cardiotoxicity
ferroptosis
oxidative-stress