Prophylactic systemic low-dose pirfenidone attenuates intrauterine adhesion by inhibiting the TGF-β1/Smad3 pathway

Background: Intrauterine adhesion (IUA) is a severe fibrotic disorder lacking effective non-surgical treatments. This study explored pirfenidone (PFD), an antifibrotic drug approved for treating lung fibrosis, as a potential therapy for IUA.

Methods: Human endometrial stromal cells (HESCs) were treated with 10 ng/mL transforming growth factor-beta 1 (TGF-β1) ± PFD (0.2 or 0.5 mg/mL) for 48 h to assess fibrosis, proliferation, and migration. In vivo, IUA was induced in BALB/c mice via endometrial scraping and lipopolysaccharide (LPS) exposure, followed by oral PFD administration (150 or 300 mg·kg^-1·day^-1) for 14 days. Uterine tissues were subsequently analyzed for fibrosis, Collagen deposition, and inflammation.

Results: In vitro, PFD reduced TGF-β1-induced fibrosis, proliferation, and migration in HESCs by inhibiting the TGF-β1/SMAD3 signaling pathway. In the murine IUA model, PFD (150 mg·kg^-1·day^-1) significantly decreased fibrosis, restored endometrial structure, normalized Collagen ratios, increased matrix metalloproteinase-2, suppressed epithelial-mesenchymal transition and inflammation (interleukin-6, tumor necrosis factor-alpha, nuclear factor kappa-light-chain-enhancer of activated B cells), and balanced macrophage polarization. Notably, this low dose outperformed the 300 mg·kg^-1·day^-1 dose, which caused transient emesis.

Conclusion: PFD combats endometrial fibrosis and inflammation by inhibiting the TGF-β1/SMAD3 pathway, suppressing epithelial-mesenchymal and fibroblast-myofibroblast transition, and modulating immune responses. These findings highlight PFD as a promising pharmacological intervention for IUA.