ZNF469 promotes extracellular matrix production in normal and keloid dermal fibroblasts

ABSTRACT: Aberrant production of extracellular matrix (ECM) from dermal fibroblasts drives fibrotic skin diseases, which significantly affect the quality of patients’ lives. Current treatment options for skin fibrosis remain limited or ineffective; therefore, new antifibrotic strategies are urgently needed. Gaining insights into molecular control of ECM production could lead to the identification of new therapeutic targets. Recent studies suggest Zinc Finger 469 (ZNF469) as a positive regulator for ECM production; however, its role in skin fibrosis has not been investigated. In this study, we found that knockdown of ZNF469 impaired proliferation, migration, and contraction in human dermal fibroblasts. More importantly, depletion of ZNF469 significantly caused a reduction in collagen production. RNA-sequence analysis of ZNF469-knockdown cells revealed significant suppression of several ECM genes and genes involved in the process of collagen biosynthesis, suggesting ZNF469 as a key regulator of ECM production. To find the clinical relevance, we examined expression of ZNF469 by reanalyzing public bulk and single-cell RNA-sequence data sets of hypertrophic scars and keloids as a representation of skin fibrosis. The RNA sequence of bulk tissues showed that hypertrophic scar and keloid tissues had higher levels of ZNF469 and that ZNF469 and ECM genes were positively correlated. Single-cell RNA sequence of keloid scars revealed restricted expression of ZNF469 in the fibroblast population. Further analysis of fibroblast subpopulations showed specific expression of ZNF469 in mesenchymal fibroblasts, a subpopulation that has been demonstrated to be crucial for collagen overexpression in keloids. Psuedotime analysis indicated ZNF469 as a pioneering factor to establish the mesenchymal fibroblast subpopulation. Supporting this finding, we observed downregulation of various mesenchymal fibroblast markers from our RNA sequence results of ZNF469-depleted dermal fibroblasts, suggesting ZNF469 as a crucial factor for maintaining mesenchymal phenotypes. Finally, to explore the therapeutic potential of ZNF469, we silenced it in human keloid fibroblasts and demonstrated that its depletion reduced proliferation, migration, contraction, and collagen production. Moreover, expression of key mesenchymal fibroblast markers was significantly downregulated in ZNF469-knockdown keloid fibroblasts. Together, we illustrated that ZNF469 promoted the ECM production in dermal fibroblasts and could serve as a novel target for treating skin fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290035 | GEO | 2025/11/13

REPOSITORIES: GEO