Pirfenidone attenuates urethral stricture after injury by inhibiting Gli2 mediated HAS2 expression in fibroblasts.

Activation of fibroblasts and excessive deposition of extracellular matrix are the primary causes of urethral stricture following injury. Pirfenidone (PFD) is an established antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, however, its potential role in preventing urethral stricture remains unclear. In this study, we investigated the effects of PFD on urethral stricture after injury and explored the underlying mechanisms both in vivo and in vitro. Our results demonstrated that PFD effectively attenuated urethral stricture and fibrosis in mice and suppressed fibroblast proliferation, migration, and invasion while promoting apoptosis. Mechanistically, RNA sequencing revealed that PFD significantly inhibited the expression of hyaluronan synthase 2 (HAS2), a key regulator of fibroblast activity. In addition, PFD suppressed GLI family zinc finger 2 (Gli2) expression in a Sonic hedgehog (Shh)–independent manner, which mediated the regulation of HAS2 by PFD. Furthermore, we found that Gli2 reduced HAS2 expression through the TGF-β1/Smad signaling pathway. Collectively, these findings indicate that PFD may serve as a promising therapeutic candidate for the prevention and treatment of urethral stricture.