# DDX3X induces mesenchymal transition of endothelial cells by disrupting BMPR2 signaling

## TL;DR

This study shows that DDX3X promotes EndoMT by disrupting BMPR2 signaling, leading to endothelial dysfunction and inflammation.

## Contribution

DDX3X is identified as a novel regulator of EndoMT through its interaction and degradation of BMPR2.

## Key findings

- Elevated DDX3X levels promote EndoMT and endothelial dysfunction.
- DDX3X interacts with and degrades BMPR2, impairing its signaling.
- Downregulating DDX3X inhibits EndoMT in endothelial cells.

## Abstract

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.

Elevated DDX3X expression led to downregulation of BMPR2, a key regulator of endothelial homeostasis and function. Our co‐immunoprecipitation assays further demonstrated a molecular interaction between DDX3X and BMPR2. Notably, DDX3X promoted lysosomal degradation of BMPR2, thereby impairing its downstream signaling and facilitating endothelial‐to‐mesenchymal transition (EndoMT).