biostudies-literatureUnknown16(1)Li YFibrosis, characterized by excessive extracellular matrix (ECM) accumulation and fibroblast proliferation, significantly contributes to global morbidity and mortality, affecting millions worldwide. Despite its prevalence, the mechanisms underlying fibrotic skin diseases remain poorly understood, and effective treatments are scarce. This study leverages single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of fibroblasts in fibrotic skin diseases, including normal skin, scar, keloid, and scleroderma. Through comprehensive analysis of scRNA-seq data from public repositories, we identified distinct fibroblast subpopulations specific to each fibrotic condition. Notably, pivotal regulators for each sub-fibroblast cluster were discovered: IRF4 for scar, CLOCK for keloid, RUNX3 for Scientific reports786https://www.ebi.ac.uk/biostudies/studies/S-EPMC12779643biostudies-literatureSingle‑cell RNA sequencing reveals fibroblast heterogeneity and identifies CLOCK as a key regulator in fibrotic skin diseases.PMC12779643Li YLi CYang LLi SLiu QTang RLiu WGao TfalseSingle‑cell RNA sequencing reveals fibroblast heterogeneity and identifies CLOCK as a key regulator in fibrotic skin diseases.Fibrosis, characterized by excessive extracellular matrix (ECM) accumulation and fibroblast proliferation, significantly contributes to global morbidity and mortality, affecting millions worldwide. Despite its prevalence, the mechanisms underlying fibrotic skin diseases remain poorly understood, and effective treatments are scarce. This study leverages single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of fibroblasts in fibrotic skin diseases, including normal skin, scar, keloid, and scleroderma. Through comprehensive analysis of scRNA-seq data from public repositories, we identified distinct fibroblast subpopulations specific to each fibrotic condition. Notably, pivotal regulators for each sub-fibroblast cluster were discovered: IRF4 for scar, CLOCK for keloid, RUNX3 for 2025-01-01T00:00:00Z2025 Dec2026-07-15T14:28:38.914Z2026-07-06T03:08:49.071ZS-EPMC127796434135056710.1038/s41598-025-30260-6