Work

Double Knockdown of the Androgen Receptor Target Genes DKK1 and SFRP1 Does Not Potentiate the Hair Growth-Promoting Effect of SFRP1 Silencing in Healthy Human Hair Follicles Ex Vivo

Year: 2026

Type: article

Abstract: Androgen receptor (AR) signaling plays a key role in male pattern baldness. We investigated whether targeting Dickkopf 1 (DKK1) and Secreted frizzled-related protein 1 (SFRP1), two AR-regulated genes, offers a novel therapeutic strategy for hair loss. AR expression was validated in freshly frozen human scalp hair follicles (HFs). AR knockdown was induced in human HFs using AR spherical nucleic acid (SNA). DKK1 and SFRP1 siRNA treatment were performed in HEK293 cells, human dermal papilla cells (hDPC), and human HFs ex vivo. Functional effects of single and combined DKK1 and SFRP1 knockdown were analyzed in human HFs ex vivo by quantitative (immuno)histomorphology. AR knockdown decreased SFRP1 and DKK1 expression. We found reciprocal mRNA upregulation between DKK1 and SFRP1 following their siRNA knockdown in HEK293 and hDPC. We therefore applied a single and combined treatment of DKK1 and SFRP1 siRNA in HFs ex vivo. SFRP1 knockdown prolonged anagen, increased hair matrix keratinocyte proliferation, reduced apoptosis, and increased DKK1 levels in HFs ex vivo, whereas DKK1 knockdown had no effect, and combined knockdown did not enhance SFRP1’s benefits. The culture-dependent compensatory regulation of SFRP1 and DKK1 underscores Wnt-signaling complexity in hair growth and strengthens the rationale for SFRP1 based therapies in anagen maintenance and hair loss.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27041815