Single-cell transcriptomic profiling identifies YY1 as a key regulator of fibroblast plasticity in hypertrophic scar formation.

Background: Hypertrophic scars (HTSs) are characterized by excessive extracellular matrix deposition and impaired scar remodelling. Fibroblasts are central to HTS pathogenesis, yet clinical strategies remain limited by an incomplete understanding of fibroblast heterogeneity and transcriptional regulation. This study aimed to identify a key fibroblast subpopulation and its regulatory transcription factors to address this translational gap. Methods: Single-cell RNA sequencing was performed on dermal cells from freshly excised human HTS and normal skin (NS) tissues. Fibroblast subsets and transcriptional regulators were identified using Seurat, pseudotime, transcription factor prediction, and cell-cell communication analyses. Functional validation involved lentiviral overexpression of Yin Yang 1 (YY1) in fibroblasts derived from patients with hypertrophic scars, followed by bulk RNA sequencing, western blotting, CUT&Tag, and immunofluorescence assays. Results: Clinical HTS specimens showed characteristic collagen overproduction and vascular hyperplasia. Single-cell analysis of 43 303 cells revealed disease-specific shifts in cellular composition, including pronounced pericyte expansion and reduced fibroblast abundance. Notably, fibroblast subcluster Fib_5 (ADAM12 Conclusion: This work establishes the Fib_5-YY1 axis as a central hub in HTS pathogenesis, with YY1-mediated fibroblast plasticity as a key transcriptional mechanism underlying skin fibrogenesis.