DKK3-CKAP4 signaling drives fibroimmune remodeling and hair follicle miniaturization in androgenetic alopecia.

Authors

Seungchan An, Hyunju Kim, Mei Zheng, In Guk Park, Leegu Song, Jino Kim, Minsoo Noh, Jong-Hyuk Sung

Published in

Theranostics. Volume 16. Issue 13. Pages 7124-7138. Epub May 29, 2026.

Abstract

Androgenetic alopecia (AGA) is characterized by progressive hair follicle miniaturization driven by androgen signaling and alterations in the follicular microenvironment, including fibrosis and inflammation. Therefore, identifying key mediators of epithelial-mesenchymal crosstalk is essential for elucidating disease mechanisms and developing targeted therapeutic strategies. In this context, we investigated the role of the DKK3-CKAP4 signaling axis as a potential mediator of fibroimmune remodeling in AGA and evaluated its functional and therapeutic relevance.
We performed meta-analysis of human and mouse single-cell RNA sequencing datasets to identify candidate signaling pathways associated with AGA. Spatial expression of DKK3 and its receptor CKAP4 was validated by immunostaining. Functional roles were assessed using hair follicle organ culture and androgen-induced AGA mouse models, with pathway modulation by recombinant DKK3 and neutralizing antibodies. Single-cell transcriptomic analyses were conducted to characterize cellular and molecular changes following pathway inhibition.
DKK3 was expressed in epithelial and mesenchymal compartments of the hair follicle, whereas CKAP4 was enriched in dermal papilla cells and dermal fibroblasts. Recombinant DKK3 suppressed hair follicle growth in organ culture, while neutralization of DKK3 or CKAP4 restored hair elongation and promoted hair regeneration in androgen-driven models. Single-cell analysis revealed that androgen signaling induced fibroimmune transcriptional program in mesenchymal cells, characterized by extracellular matrix deposition and inflammatory pathway activation. Inhibition of DKK3 attenuated these responses and partially restored dermal papilla cell populations.
These findings identify the DKK3-CKAP4 axis that contributes to fibroimmune remodeling in AGA. Targeting this pathway restores a regenerative follicular microenvironment and represents a potential therapeutic strategy for reversing hair follicle miniaturization.

PMID:
42370170
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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