Targeting Runx1 Slows Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD), the most prevalent hereditary kidney disorder, is characterized by the progressive formation and expansion of kidney cysts that ultimately destroy normal renal parenchyma. Runt-related transcription factor 1 (Runx1), a highly conserved regulator of gene expression, orchestrates diverse cellular signaling pathways. Here, we identify Runx1 as a critical driver of cyst growth in ADPKD. Runx1 expression is markedly upregulated in Pkd1 mutant renal epithelial cells and kidney tissues through a cAMP-dependent mechanism. Pharmacological inhibition of Runx1 with its selective inhibitor, Ro5-3335, significantly attenuates cyst progression in both rapidly and slowly progressive Pkd1 mouse models. Mechanistically, Runx1 enhances proliferation of cyst-lining epithelial cells by activating the AKT-mTOR, MAPK, and STAT3 signaling cascades, while suppressing p53-mediated apoptosis. Moreover, Runx1 promotes macrophage infiltration and inflammatory responses via NF-κB activation and aggravates interstitial fibrosis through the TGF-β/Smad2 pathway. Collectively, these findings uncover Runx1 as a pivotal regulator of cystic disease progression and highlight it as a promising therapeutic target for ADPKD.