Targeting Runx1 Slows Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

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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.

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