Doxorubicin (DOX) is a potent chemotherapeutic agent widely used to treat various malignancies; however, its dose-dependent cardiotoxicity severely limits long-term clinical application. Loss of Dual Specificity Phosphatase 4 (DUSP4) has been reported in multiple cancer types and is associated with aberrant activation of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, which regulates chemotherapy-induced apoptosis. Nevertheless, the role of DUSP4 in DOX-induced myocardial injury remains poorly understood. In this study, we explored the function of DUSP4 in DOX-induced cardiotoxicity using HL-1 cardiomyocytes and a DOX-treated C57BL/6 mouse model. DUSP4 expression was markedly decreased in both in vitro and in vivo settings. Concurrently, apoptosis- and autophagy-related proteins-including cleaved Caspase-3, Bax, LC3B II/LC3B I, and Beclin-1-were significantly upregulated, whereas Bcl-2 and P62 were downregulated. Overexpression of DUSP4 attenuated DOX-induced cardiotoxicity, while DUSP4 knockdown exacerbated apoptosis and autophagy. Mechanistically, activation of the p38 Mitogen-Activated Protein Kinase (p38 MAPK) and its downstream target MAPK-activated protein kinase 2 (MK2) was observed in both models. Pharmacological activation of the p38 MAPK/MK2 pathway abolished the cardioprotective effects mediated by DUSP4 overexpression. Collectively, these findings demonstrate that DUSP4 alleviates DOX-induced cardiotoxicity by suppressing the p38 MAPK/MK2 signaling cascade, highlighting the DUSP4 axis as a potential therapeutic target to improve cardiac safety during DOX-based chemotherapy.
