The GLP-1 receptor agonist Semaglutide preserves cardiac function, reduces inflammation-driven cardiotoxicity with cardio–hepatic benefits in non-diabetic models exposed to anthracyclines and HER2 blockade

Background: Sequential anthracycline and HER2-targeted therapy remains a major cause of cancer therapy–related cardiovascular toxicity, characterized by early myocardial dysfunction, inflammatory activation, and multi-organ injury. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert pleiotropic cardiovascular and anti-inflammatory effects beyond glycemic control; however, their cardioprotective role in non-diabetic cardio-oncology settings remains insufficiently explored. Methods: A clinically relevant sequential cardiotoxicity model was established in female C57BL/6 mice receiving doxorubicin (2.17 mg/kg/day intraperitoneally, days 1–5) followed by trastuzumab (2.25 mg/kg/day intraperitoneally, days 6–10). Semaglutide (120 μg/kg/day subcutaneously) or vehicle was administered daily throughout the protocol starting one day before anthracycline exposure. Serial high-resolution transthoracic echocardiography was performed to assess left ventricular ejection fraction (LVEF), fractional shortening, and speckle-tracking–derived longitudinal and radial strain. Automated immunohistochemistry of cardiac and hepatic tissues quantified inflammatory and chemotactic signaling pathways, including IL-1β, IL-6, CXCR4, troponin I, and H-FABP expression. Circulating biomarkers of myocardial injury and stress (hs-cTnI, cTnT, NT-proBNP), inflammasome-related mediators (NLRP3, MyD-88, IL-1β, IL-6, IL-18 and CXCR4), hepatic injury markers AST, ALT, as well as glucose and pancreatic safety biomarkers (amylase and lipase) were quantified by selective ELISA. Results: Sequential doxorubicin/trastuzumab exposure induced significant systolic dysfunction and impaired myocardial deformation, evidenced by reductions in LVEF and strain parameters, together with myocardial fibrosis and hypertrophic remodeling. These changes were associated with marked activation of systemic inflammatory pathways and increased circulating biomarkers of cardiac injury and stress. Semaglutide significantly preserved ventricular systolic function and myocardial mechanics, attenuated structural remodeling, and reduced troponin release.. Immunohistochemical analyses demonstrated reduced myocardial and hepatic expression of IL-1, IL-6, CXCR4, and troponin I, together with preservation of H-FABP signaling, indicating attenuation of inflammation-driven tissue injury. Semaglutide additionally reduced inflammasome-related cytokines and mitigated hepatic injury biomarkers, supporting coordinated multi-organ protection without significant alterations in glycemic status or pancreatic safety biomarkers. Conclusions: In non-diabetic experimental models exposed to sequential anthracycline and HER2 blockade, semaglutide mitigates early chemotherapy-related cardiac dysfunction through modulation of inflammatory and chemotactic pathways while simultaneously preserving hepatic integrity. These findings provide mechanistic support for GLP-1 receptor agonists as potential preventive strategies in cardio-oncology and support future translational evaluation in high-risk patients receiving cardiotoxic anticancer therapies.