Transcriptome-guided development of a fibrosis-reversal compound reduces skin scarring and allows regeneration via mitochondrial uncoupling.

Abstract

Skin scarring impairs function and aesthetics. Current therapies show limited efficacy and cause iatrogenic dermal disruption (e.g., triamcinolone acetonide [TA], a first-line corticosteroid for keloids), with topical medications demonstrating inferior outcomes. Through transcriptome-guided evaluation, we develop FR-1 (fibrosis-reversal compound 1), a small molecule that reverses fibrosis in vitro by inhibiting fibroblast proliferation, suppressing α-smooth muscle actin (α-SMA), and remodeling the extracellular matrix (ECM) via collagen downregulation and matrix metalloproteinase-1 (MMP1) induction. In a murine linear excisional wound model, topical FR-1 application reduces scar area. Notably, unlike TA, FR-1 avoids skin atrophy and hair follicle damage. Comprehensive safety evaluations, druggability and skin permeation assessments, and studies utilizing patient-derived keloid ex vivo explants and in vivo xenografts demonstrate its translational potential. Mechanistically, FR-1 induces mitochondrial uncoupling, lowering ATP levels in profibrotic myofibroblasts. Other uncouplers similarly attenuate fibrosis. This work identifies a topical small molecule that attenuates scarring with translational potential, highlighting the therapeutic potential of mitochondrial uncouplers in resolving fibrosis.