DDX3X/MAVS alleviates doxorubicin‑induced cardiotoxicity by regulating stress granules

The specific mechanisms of doxorubicin (Dox)‑induced cardiotoxicity (DIC) remain unclear. In the present study, H9c2 cardiomyocytes were treated with Dox, and it was revealed that DEAD‑box RNA helicase 3 X‑linked (DDX3X), mitochondrial Antiviral signaling (MAVS) and stress granules (SGs) were present at lower levels in the treated H9c2 cardiomyocytes compared with those in the control cells. The present study further investigated the mechanisms through which DIC occurs. Pretreatment with arsenite, which pharmacologically accelerates SGs, alleviated the myocardial injury caused by Dox. By contrast, anisomycin, an SG inhibitor, increased cardiomyocyte Apoptosis induced by Dox. In addition, both DDX3X knockdown and pretreatment with RK‑33 (a DDX3X pharmacological inhibitor) decreased SG expression, whereas DDX3X overexpression promoted SG generation. These results indicated that DDX3X mitigated DIC through the regulation of SGs. In addition, MAVS knockdown inhibited SG assembly and reduced the expression of the anti‑apoptotic inhibitor Bcl2, and MAVS was influenced by DDX3X, thereby serving as a connector between DDX3X and SGs. The results from western blotting, reverse transcription‑quantitative PCR, immunofluorescence and flow cytometry analysis demonstrated that DDX3X, MAVS, and SGs may serve as key protective factors in DIC.

DEAD‑box RNA helicase 3 X‑linked; apoptosis; doxorubicin‑induced cardiotoxicity; mitochondrial antiviral signaling; stress granules.