DEAD-box protein 21 promotes renal fibrosis via p21-dependent cell cycle arrest in proximal tubular epithelial cells.

Renal interstitial fibrosis is the final common outcome of various chronic kidney diseases (CKD). Renal tubular epithelial cells (TECs) G2/M cell cycle arrest play a pivotal role in renal fibrosis. Although RNA-binding proteins (RBPs) are implicated in organ fibrosis, the underlying mechanisms remain poorly understood. Here, we identify DEAD-box protein 21 (DDX21), a representative RBP, as highly expressed in fibrotic renal tissues, especially in TECs. Moreover, DDX21 expression is positively correlated with renal function decline in CKD patients, underscoring its role in disease progression. TECs-specific deletion of Ddx21 alleviates cell cycle arrest in G2/M, and attenuates fibrotic responses. Mechanistically, silencing DDX21 reduces p21 expression at both the mRNA and protein levels and decreases cell apoptosis, indicating that DDX21 promotes G2/M cell cycle arrest by regulating the p21 signaling pathway. This study suggests that DDX21 may serve as a promising therapeutic target for kidney fibrosis.