Abstract

The dose-cumulative cardiotoxicity of Doxorubicin (Dox) severely limits clinical anti-tumor treatment. Dual-specificity phosphatase 22 (DUSP22), which is expressed in various tissues, plays a key biological role in immune responses and tumor growth. However, the mechanism of DUSP22 on Dox-induced cardiotoxicity (DIC) remains unknown. Employing Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence analysis, we detected a notable decline in the expression of DUSP22 in the cardiac tissues of mice exposed to Dox. Cardiac-specific knockout of Dusp22 exacerbated Dox-induced deterioration of cardiac function and increased mortality in mice. In contrast, cardiac-specific overexpression of Dusp22 significantly improved Dox-induced deterioration of cardiac function and reduced mortality in mice. The mechanistic evidence we provided indicates that DUSP22 directly interacts with JNK, inhibits its phosphorylation, and then promotes mitophagy flux, improves mitochondrial quality, and reduces mitochondrial disorder-related apoptosis. The binding of DUSP22 to JNK and the dephosphorylation of JNK are crucial for DUSP22 to mitigate the process of DIC. Our findings ultimately identify DUSP22 as a key inhibitor of DIC and reveal that the DUSP22-JNK axis can serve as an important therapeutic target for the treatment of DIC. This finding may offer a novel cardioprotective strategy during Dox-based cancer chemotherapy, thereby enhancing treatment safety and patient prognosis.