USP14 modulates cell pyroptosis and ameliorates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing SIRT3.

This study investigates the role of the deubiquitinating enzyme USP14 in alleviating doxorubicin (DOX)-induced cardiotoxicity (DIC), particularly concerning its mechanism of regulating pyroptosis through the stabilization of the mitochondrial protein SIRT3. Using in vivo and in vitro models, the research demonstrated that USP14 overexpression protects against DOX-induced cardiac damage by modulating pyroptosis. Silencing SIRT3 via siRNA revealed that SIRT3 is a key intermediary molecule in USP14-mediated regulation of pyroptosis. Notably, DOX exposure resulted in decreased USP14 expression, while its overexpression preserved mitochondrial function and reduced oxidative stress by stabilizing SIRT3. Immunoprecipitation confirmed that USP14 stabilizes SIRT3 through deubiquitination. These findings position USP14 as a promising therapeutic target for mitigating DOX-induced cardiotoxicity by stabilizing SIRT3 and maintaining mitochondrial integrity, suggesting potential novel strategies for cardio-protection in chemotherapy.