Doxorubicin (DOX)-induced cardiotoxicity remains a major limitation of cancer therapy. Incretin-based therapies are established cardiometabolic agents with pleiotropic cardiovascular effects; however, their potential role in mitigating DOX-related cardiac injury has not been systematically synthesized. We conducted a PRISMA 2020-compliant systematic review to evaluate the effects of incretin-based therapies on DOX-induced cardiotoxicity, with a focus on functional, structural, biomarker, and mechanistic outcomes. PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched through 20 October 2025. Eligible studies included in vivo rodent models of DOX cardiotoxicity and any clinical studies directly evaluating incretin-based therapy during DOX exposure; in vitro studies, non-DOX models, combination-treatment studies, studies not focused on cardiotoxicity, gene therapy-based interventions, and reviews/editorials were excluded. Risk of bias and certainty of evidence were assessed using the SYRCLE tool and GRADE adapted for preclinical research. Thirteen rodent studies were included, and no eligible human study was identified. Investigated agents included liraglutide (n = 4), exenatide/exendin-4 (n = 4), semaglutide (n = 2), and tirzepatide (n = 3). In chronic cumulative-dose DOX models, incretin-based therapies were generally associated with preservation of left ventricular systolic function, with between-study improvements of approximately 7-20 percentage points in left ventricular ejection fraction, along with reductions in injury biomarkers. These effects were accompanied by attenuation of oxidative stress, inflammation, apoptosis, and, in some studies, ferroptosis. In contrast, findings were less consistent in acute single-dose models. Co-treatment during DOX exposure showed the most reproducible protective signal, whereas isolated pretreatment with liraglutide or tirzepatide and post-treatment with exenatide did not show a clear additional benefit. The evidence base is limited by exclusive reliance on small heterogeneous animal studies, predominantly male models, variable dosing/timing protocols, and low-to-very-low certainty of evidence. Overall, incretin-based therapies show biologically plausible cardioprotective effects in preclinical DOX cardiotoxicity, but these findings should be regarded as hypothesis-generating until confirmed in carefully designed clinical studies.
