Therapeutic Effect and Mechanism of Pirfenidone in Bladder Fibrosis After Spinal Cord Injury

Pirfenidone alleviates spinal cord injury-induced bladder fibrosis. • Ferroptosis is involved in bladder fibrosis. • Pirfenidone can modulate ferroptosis pathway. • This work supports Pirfenidone's clinical translation for bladder fibrosis. Pirfenidone (PFD), a broad-spectrum anti-fibrotic agent, shows therapeutic potential in various fibrotic diseases. However, its effect on neurogenic bladder fibrosis following spinal cord injury (SCI) and its association with ferroptosis remain unclear. This study aimed to investigate the therapeutic efficacy of PFD against bladder fibrosis after SCI and to preliminarily analyze its potential link with ferroptosis using a rat SCI model and a Transforming Growth Factor-β1 (TGF-β1)-induced fibrotic model in Simian Virus 40-Transformed Human Urothelial Cells (SV-HUC-1). In SCI rats, PFD treatment significantly improved urodynamic parameters, while markedly reducing collagen deposition, inflammatory infiltration, and the progression of epithelial–mesenchymal transition (EMT) in bladder tissue. In the cellular model, PFD effectively attenuated TGF-β1-induced fibrotic responses. Mechanistically, network pharmacology analysis predicted that PFD could modulate the TGF-β1 signaling and lipid peroxidation pathways. In vivo experiments confirmed that PFD reversed the dysregulation of key ferroptosis-related molecules, and in vitro studies demonstrated that PFD antagonized Erastin-induced ferroptosis, an effect comparable to the ferroptosis inhibitor Ferrostatin-1 (Fer-1). However, in the TGF-β1-induced fibrotic model, inhibition of ferroptosis alone only partially ameliorated the fibrotic phenotype, and its effect was weaker than that of PFD. This study demonstrates that PFD can effectively alleviate bladder fibrosis after SCI, and its therapeutic effect may be associated with the ferroptosis pathway. These findings suggest that PFD likely exerts its anti-fibrotic action through multi-pathway synergy, with ferroptosis inhibition representing an important contributing pathway supported by the current data, providing a new theoretical basis for treating neurogenic bladder fibrosis.