Vactosertib, a Novel, Orally Bioavailable Activin Receptor-Like Kinase 5 Inhibitor, Promotes Regression of Fibrotic Plaques in a Rat Model of Peyronie’s Disease

Abstract
Purpose:
This study aimed to evaluate the therapeutic effects of Vactosertib, a small molecule inhibitor of the transforming growth factor-β (TGF-β) type I receptor (activin receptor-like kinase-5, ALK5), in an experimental model of Peyronie’s disease (PD), and to investigate the anti-fibrotic mechanisms of Vactosertib in primary fibroblasts derived from human PD plaques.

Materials and Methods:
Male rats were randomly assigned to three groups (n=6 per group): untreated controls, PD rats receiving vehicle treatment, and PD rats treated with Vactosertib (10 mg/kg). PD-like plaques were induced by injecting 100 μL each of human fibrin and thrombin solutions into the tunica albuginea on days 0 and 5. Vactosertib was administered orally five times per week for two weeks. On day 30, erectile function was assessed via electrical stimulation of the cavernous nerve, and penile tissue was collected for histological analysis. Additionally, fibroblasts isolated from human PD plaques were used to study the anti-fibrotic effects of Vactosertib in vitro.

Results:
Vactosertib significantly reduced fibrotic plaque formation in vivo by decreasing inflammatory cell infiltration and downregulating phospho-Smad2 expression, leading to improved erectile function. In vitro, Vactosertib inhibited TGF-β1-induced production of extracellular matrix proteins and hydroxyproline content in PD fibroblasts by blocking Smad2/3 phosphorylation, nuclear translocation, and fibroblast-to-myofibroblast differentiation.

Conclusions:
Given the pivotal role of the TGF-β/Smad signaling pathway in the development of PD, targeting this pathway with an ALK5 inhibitor like Vactosertib offers a promising, targeted therapeutic strategy for Peyronie’s disease.