SLC22A17 affects the development of urethral stricture by promoting ferroptosis and inhibiting the activation of fibroblasts.

Urethral stricture is a common urological disorder associated with urethral fibroblasts, yet its pathogenesis remains poorly understood. This study aimed to elucidate the pathogenic mechanisms underlying the occurrence and development of this condition. The differentially expressed genes (DEGs) between urethral scar tissue and adjacent control urethral tissue in patients with urethral stricture were identified utilizing high-throughput mRNA sequencing, followed by Gene Ontology enrichment and the Kyoto Encyclopedia of Genes and Genomes pathway analysis. The expression of solute carrier family 22 member 17 (SLC22A17) was verified by quantitative real-time polymerase chain reaction and immunohistochemistry. Urethral scar fibroblasts were isolated from human urethral scar tissue and cultured in vitro. Ferroptosis was detected by measuring the levels of malondialdehyde, lipid reactive oxygen species, acyl-CoA synthetase long-chain family member 4, and glutathione peroxidase 4. The activation of fibroblasts was verified by measuring the expression levels of collagen I and α-smooth muscle actin. High-throughput mRNA sequencing revealed 201 up-regulated and 561 down-regulated DEGs in urethral scar tissues. Additionally, SLC22A17 levels were decreased in urethral scar tissue. SLC22A17 knockdown inhibited ferroptosis and promoted the activation of primary adjacent control urethral fibroblasts. Deferoxamine suppressed the SLC22A17 overexpression-mediated ferroptosis and the inactivation of primary urethral scar fibroblasts. Furthermore, the silencing of SLC22A17 inhibited the erastin-mediated ferroptosis and inactivation of primary urethral scar fibroblasts. These findings indicate that SLC22A17 may inhibit the fibrosis of urethral scar fibroblasts by promoting ferroptosis, thereby preventing the development of urethral stricture.