Work

Targeting noncanonical TGF-beta signaling: inhibition effects on the human keloid fibroblast transcriptome

Year: 2025

Type: article

Abstract: Keloids are benign fibrotic lesions that frequently cause persistent itch and pain, yet their underlying molecular mechanisms remain poorly defined. Aberrant transforming growth factor-beta (TGF-β) signaling, particularly through noncanonical pathways such as mitogen-activated protein kinase (MAPK), has been implicated in keloid pathogenesis. In this study, we investigated the effects of selective MEK1 inhibition in vitro using NL350-02 on human keloid fibroblasts via bulk RNA sequencing. Treatment with NL350-02 induced substantial transcriptomic reprogramming, including downregulation of TGF-β receptors, IL-6, IL-17 receptors, and proinflammatory chemokines, alongside the upregulation of proapoptotic genes and marked suppression of proliferation (eg, > 3000-fold reduction in Ki-67 expression). Pathway analyses revealed significant enrichment in processes related to apoptosis, cytokine signaling, and TGF-β regulation. Despite paradoxical increases in certain collagen transcripts, the concurrent induction of apoptosis suggests an indirect antifibrotic mechanism. Furthermore, transcriptomic overlap with pruritic conditions and the downregulation of itch-related cytokines highlight MEK1 as a potential target for modulating neuroinflammation in keloid-associated itch. These findings suggest that MEK1 inhibition may offer a dual therapeutic benefit, attenuating both fibrosis and pruritus, and warrant further validation in preclinical keloid models.

Source: Itch

DOI: 10.1097/itx.0000000000000084