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

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.