Glucagon-like peptide-1(GLP-1) Prevents Doxorubicin-Induced Cardiotoxicity by Regulating Macrophage Polarization

Aims Anthracyclines, such as doxorubicin (DOX), are among the most potent chemotherapeutics for multiple malignancies. However, their clinical use has been limited by irreversible cardiotoxicity. Glucagon-like peptide-1 (GLP-1) has generated considerable interest as a novel therapeutic target in cardiovascular disease. This study aims to explore the potential role and mechanism of GLP-1 against DOX-induced cardiotoxicity in vivo and in vitro. Methods Tumor-bearing mice treated with or without DOX and GLP-1 were used to analyze their cardiac and cancer phenotype. High-throughput sequencing was performed to explore the underlying mechanism of GLP-1 treatment. Further, the downstream targets were verified at the cellular and animal levels. Results GLP-1 intervention significantly improved DOX-induced cardiac dysfunction, as evidenced by enhanced cardiac systolic function, reduced cardiac tissue fibrosis, and proper arrangement of cardiomyocytes. The mechanism was related to modulating macrophage polarization by regulating the PPAR-γ and NF-κB signaling pathways. Specifically, DOX treatment increased the M1 macrophage population while decreasing the M2 macrophage population in heart tissue. GLP-1 intervention reversed the imbalance of M1/M2 macrophages by promoting PPAR-γ translocation into the nucleus and suppressing active NF-κB translocation into the nucleus, thereby inhibiting pro-inflammatory cytokine production and reducing cardiac injury. This makes GLP-1 a potential strategy for treating cardiotoxicity induced by anti-cancer drugs. Conclusions Our results provide the first direct evidence that GLP-1 protects against DOX-induced cardiotoxicity by modulating macrophage polarization, offering new insights into potential therapeutic approaches for the clinical management of DOX-induced cardiomyopathy.