ZNF469 promotes extracellular matrix production in normal and keloid dermal fibroblasts.

Aberrant extracellular matrix (ECM) production by dermal fibroblasts drives fibrotic skin diseases, which has an adverse impact on the lives of patients. Current treatments are limited; therefore, the development of new antifibrotic strategies is necessary. The aim of the present study was to investigate zinc finger 469 (ZNF469) as a potential ECM regulator in skin fibrosis. ZNF469 was knocked down in dermal fibroblasts using doxycycline‑induced short hairpin RNA. ZNF469 knockdown was found to impair proliferation, migration, contraction and collagen production in dermal fibroblasts. In addition, RNA sequencing revealed that ZNF469 knockdown suppressed the expression of genes associated with the ECM and collagen biosynthesis, indicating that ZNF469 plays a role in ECM regulation. Analysis of publicly available RNA‑sequencing data from hypertrophic scars and keloids revealed the upregulation of ZNF469 expression in these tissues and the positive correlation of ZNF469 expression with that of ECM‑related genes. Single‑cell analysis of keloids indicated that ZNF469 is localized in mesenchymal fibroblasts, a key collagen‑producing fibroblast subpopulation. Pseudotime analysis suggested that ZNF469 plays a role in the establishment of this phenotype. Consistent with this notion, the knockdown of ZNF469 in dermal fibroblasts was shown to downregulate the expression of mesenchymal markers. In addition, it reduced the proliferation, migration, contraction and collagen production of keloid fibroblasts. These findings indicate that ZNF469 is a crucial regulator of ECM production and the mesenchymal fibroblast phenotype, suggesting it may be a potential therapeutic target for skin fibrosis.