DYRK2 drives renal fibrosis through CDK1-dependent G2/M phase dysregulation in tubular epithelial cells

Renal fibrosis is a common pathological characteristic of chronic kidney disease (CKD) and serves as a critical prognostic indicator for renal outcomes. However, current therapeutic strategies targeting renal fibrosis remain limited. Here, we identify dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) as a crucial driver of renal fibrosis. DYRK2 was significantly induced in the fibrotic mouse kidneys, particularly in proximal tubules, following unilateral ureter obstruction (UUO) or aristolochic acid nephropathy (AAN). Tubule-specific silencing of DYRK2 reduces the production of profibrotic cytokines and alleviates renal fibrosis in mice. In vitro, knockdown of DYRK2 reduces excessive reactive oxygen species (ROS) production, prevents the loss of epithelial phenotype in renal tubular epithelial cells (RTECs) and attenuates fibroblast activation by inhibiting G2/M arrest. Mechanistically, DYRK2 binds and phosphorylates CDK1 at Thr14, inducing G2/M arrest of RTECs and promoting tubulointerstitial fibrosis. Notably, DYRK2 upregulation was also observed in kidneys from various CKD patients, suggesting it may be a common pathogenic feature in human kidney diseases. Collectively, our studies indicate that DYRK2 could be a potential therapeutic target for renal fibrosis.