Prolyl-tRNA synthetase inhibitor as a novel first-in-class keloid treatment: Downregulation of de novo collagen synthesis and inflammatory cascade

Abstract Background Keloids are severe dermal fibrotic disorders caused by excessive deposition of collagen. Current therapies have high recurrence rates, and there is a high clinical need for a new fundamental approach. We focused on inhibiting proline, an essential amino acid for collagen biosynthesis. We developed DWN12088, a drug that downregulates prolyl-tRNA synthetase (PRS), an enzyme involved in proline ligation with its tRNA. This study aims to evaluate the therapeutic efficacy of this drug on keloids. Objectives We investigated the anti-fibrotic activity of selective PRS inhibitors and elucidated the importance of DWN12088 as a first-in-class therapeutic agent for keloids. Methods Patient-derived keloid fibroblasts (KFs) and keloid tissues were obtained to observe the upregulation of PRS. In addition, the anti-fibrotic activity of selective PRS inhibitors was studied using KFs, and their treatment efficacy was further validated in vivo using a KF xenograft severe combined immune-deficient (SCID) mouse model. Histological and immunohistochemistry analyses were performed with human-derived keloid tissues. Additional experiments included immunocytochemistry, cell viability analysis, migration analysis, and western blotting on KFs. Human KFs were injected into SCID mice to study the nodule formation and histological characteristics. Results Compared to normal fibroblasts and normal skin tissues, PRS was overexpressed in both KF and keloid tissues. A selective PRS inhibitor downregulated fibrotic markers, reduced migration capacity, and lowered collagen production in KFs. In a KF xenograft SCID mouse model, a selective PRS inhibitor effectively suppressed keloid formation and mitigated inflammation and fibrosis. Conclusions DWN12088, a selective PRS inhibitor, may be a novel first-in-class treatment modality that effectively prevents keloid development. Further clinical trials are required to verify the safety and clinical efficacy of PRS inhibitors for keloids. We believe that our study has applicability across several fibrotic wound problems such as hypertrophic scars.