Keratin 20 deficiency phenocopies human UAB and drives bladder fibrosis via a mechanotransduction-TGF-β axis

Lower urinary tract symptoms (LUTS) represent a spectrum of intractable and progressive disorders. A common pathological feature of LUTS is bladder fibrosis. Here, we established an original mouse model of urinary retention and underactive bladder by ablating urothelial keratin 20. Krt20 deficiency compromised the mechanical load-bearing capacity of umbrella cells, triggering their adaptive expansion and activation of the mechanosensitive protein Yap. Furthermore, loss of Krt20 alters mechanical homeostasis in bladder tissue, stimulating TGF-β/Tgfbr1 signaling activation and subsequently resulting bladder fibrosis. Utilizing this model, we demonstrated a promising therapeutic potential by targeting Tgfbr1-dependent signaling pathway. FFPE snRNA sequencing identified that Alk4/5/7 inhibitor SB-431542 treatment partially rescued the fibrotic bladder microenvironment by attenuating TGF-β signaling derived. Collectively, we present a genetically defined LUTS-fibrosis model and elucidate a mechanotransduction-dependent pathogenic axis, offering innovative avenues for mechanism and therapy exploration.