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Lipodystrophy and recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.

ABSTRACT: Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20,000 people and are associated with metabolic comorbidities. Recently, we showed that fibrosis-associated lipodystrophy is dependent on sustained Wnt signaling, but the mechanisms remain unclear. Transcriptomic profiling of mature dermal adipocytes in vivo reveal that Wnt activation downregulates the de novolipogenesis (DNL) axis enzymes within 48 hours. We found that protein expression of Fatty Acid Synthase (FASN), a key DNL enzyme, is dependent on sustained Wnt activation in vitro and in vivo. In bleomycin model, human SSc (< 1year of disease) and keloids, FASN is significantly downregulated. Remarkably, FASN inhibition in mouse during reversal from Wnt induced fibrosis impeded recovery of DWAT lipid content and ECM topography. All together, we demonstrate that acquired lipodystrophy in the context of skin fibrosis is mediated by a new role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis, opening new avenues for therapeutic targets in skin fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE305616 | GEO | 2026/05/05

REPOSITORIES: GEO

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Project description: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.

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Lipodystrophy and recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.

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