SFRP2 Editing Enhances Dermal Papilla Cell Function via Activation of the PI3K‐Akt Signaling Pathway

Secreted frizzled-related protein 2 (SFRP2) is an important molecule that regulates cell growth and development and participates in hair follicle (HF) development and homeostasis. The present study seeks to determine whether SFRP2 directly targets dermal papilla cells (DPCs), the pivotal functional cell population within HF, and characterize the intracellular signaling regulatory network triggered downstream. In this study, a CRISPR/Cas9-mediated SFRP2 gene editing DPC model was established in vitro. Multi-omics analyses, including transcriptomics and metabolomics, were performed alongside functional assays to investigate the regulatory mechanisms of SFRP2 in DPCs. Among three designed single guide RNAs (sgRNAs), sgRNA3 showed the highest editing efficiency (67.0%) without off-target effects. Genetic editing of SFRP2 markedly increased the transcript levels of pivotal hair follicle‑development‑related genes (LEF1, CCND1 and Wnt2). Meanwhile, it suppressed TGF‑β1 transcription, which resulted in elevated proliferation capacity and diminished apoptotic activity within DPCs. Transcriptomic profiling identified 2288 differentially expressed genes (DEGs) enriched in PI3K-Akt, MAPK and TNF signaling pathways, while metabolomic analysis identified 185 differential metabolites (DMs) associated with apoptosis, ABC transporters, and PI3K-Akt signaling. Integrated multi-omics analysis confirmed PI3K-Akt signaling as a central regulatory axis. Western blot analysis revealed increased phosphorylation of PI3K and Akt following SFRP2 editing, indicating pathway activation. Treatment of SFRP2-edited DPCs with the PI3K inhibitor LY294002 reduced the elevated phosphorylation and reversed the functional phenotypes, confirming PI3K-Akt pathway involvement. Collectively, these findings indicate that SFRP2 mediates DPC biological activities by means of PI3K‑Akt‑driven transcriptional‑metabolic networks, yielding novel perspectives on the molecular regulatory machinery controlling HF physiology.