Efficient Silencing of Androgen Receptor Gene via UTR-Targeting siRNAs for Androgenetic Alopecia Therapy

Androgenetic alopecia (AGA) is predominantly driven by excessive local activity of dihydrotestosterone (DHT), leading to follicular miniaturization and progressive hair loss. The need for novel treatment strategies for AGA is emphasized by the side effects and postoperative sequelae of current therapeutic approaches, including pharmacological interventions and surgical procedures. Small-interfering RNAs (siRNAs) have emerged as promising therapeutic candidates due to their target specificity, the enhanced efficacy, and long-term effect. Here, we screened a series of siRNA sequences targeting non-coding region of androgen receptor (AR) gene and identified a lead siRNA candidate (AR-27) conserved between Homo sapiens and Mus musculus . The chemically modified and cholesterol-conjugated candidate (AR-27 E-Chol) was evaluated in both cells and DHT-induced AGA mice model. AR-27 E-Chol effectively stimulated dorsal hair regrowth and significantly downregulated AR gene expression in skin tissues. These findings support the clinical potential of AR-27 E-Chol as an effective therapeutic candidate for AGA.