<scp>DDX3X</scp> induces mesenchymal transition of endothelial cells by disrupting <scp>BMPR2</scp> signaling

Endothelial-to-mesenchymal transition (EndoMT), a widely recognized biological process leading to abnormal endothelial function, has been implicated in various cardiovascular pathologies. DEAD-box proteins represent the largest family of RNA helicases associated with multiple physiological and pathophysiological processes; however, their role in the homeostasis of endothelial cells (ECs) remains largely unexplored. Here, we show that the levels of DEAD-box protein 3 X-linked (DDX3X), a DEAD-box RNA helicase protein, were significantly increased during EC transition in vivo and in vitro. DDX3X overexpression promoted EndoMT as well as endothelial dysfunction and inflammation, whereas its downregulation effectively inhibited this transition in ECs. Mechanistically, elevated DDX3X resulted in downregulation of bone morphogenetic protein receptor type 2 (BMPR2), a protein that is pivotal for maintaining endothelial homeostasis and function. Furthermore, our co-immunoprecipitation assays demonstrated a molecular interplay between DDX3X and BMPR2. Importantly, DDX3X was shown to promote the lysosomal degradation of BMPR2, thereby interrupting its downstream signal transduction. These findings identify DDX3X as a novel regulator of EndoMT by modulating BMPR2 signaling.