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

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.