CXXC5 Mediates DHT-Induced Androgenetic Alopecia via PGD2

Abstract

The number of people suffering from hair loss is increasing, and hair loss occurs not only in older men but also in women and young people. Prostaglandin D2 (PGD2) is a well-known alopecia inducer. However, the mechanism by which PGD2 induces alopecia is poorly understood. In this study, we characterized CXXC5, a negative regulator of the Wnt/β-catenin pathway, as a mediator for hair loss by PGD2. The hair loss by PGD2 was restored by Cxxc5 knock-out or treatment of protein transduction domain–Dishevelled binding motif (PTD-DBM), a peptide activating the Wnt/β-catenin pathway via interference with the Dishevelled (Dvl) binding function of CXXC5. In addition, suppression of neogenic hair growth by PGD2 was also overcome by PTD-DBM treatment or Cxxc5 knock-out as shown by the wound-induced hair neogenesis (WIHN) model. Moreover, we found that CXXC5 also mediates DHT-induced hair loss via PGD2. DHT-induced hair loss was alleviated by inhibition of both GSK-3β and CXXC5 functions. Overall, CXXC5 mediates the hair loss by the DHT-PGD2 axis through suppression of Wnt/β-catenin signaling.

Nanodrug Delivery Strategies to Signaling Pathways in Alopecia

“…PGF 2α and PGE have positive effects on HF growth, while PGD has a negative impact. , A previous study showed that PGE 2 influences anti-inflammatory functions in wound repair and hair growth regulation . PGD 2 raises ROS levels in keratinocytes, and a recent report indicated that PGD 2 participates in DHT-induced alopecia via CXXC-type zinc finger protein 5 (CXXC5) as a mediator through inhibition of Wnt/β-catenin signaling . Furthermore, it enhances the formation of testosterone from androstenedione and mediates androgenic receptors-related proteins including transforming growth factor-β 1 (TGF-β 1 ), IGF-1, LEF1, and GSK3β in human DPCs, which is one of the critical negative feedback mechanisms. , …”

“…Representative drugs: minoxidil, − exosomes, ,− valproic acid, , lithium, necrostatins, and KY19382. , …”

“…Representative drugs: minoxidil, 33−35 exosomes, 21,36−46 valproic acid, 47,48 lithium, 49 necrostatins, 50 and KY19382. 51,52 2.2. Androgen Signaling Pathway.…”

“…144 PGD 2 raises ROS levels in keratinocytes, and a recent report indicated that PGD 2 participates in DHT-induced alopecia via CXXC-type zinc finger protein 5 (CXXC5) as a mediator through inhibition of Wnt/β-catenin signaling. 52 Furthermore, it enhances the formation of testosterone from androstenedione and mediates androgenic receptors-related proteins including transforming growth factor-β 1 (TGF-β 1 ), IGF-1, LEF1, and GSK3β in human DPCs, which is one of the critical negative feedback mechanisms. 147,148 Representative drugs: cetirizine, 146,149,150 bimatoprost, 148,151 and latanoprost.…”

Natural bioactive compounds as potential sources for alleviation and treatment of androgenetic alopecia: A research advance

“…With irregular habits and increasing stress, AGA occurs more frequently in young people, which seriously affects their health and brings great appearance anxiety (Farrant & Mchale, 2014; Hunt & McHale, 2005; Ryu et al, 2023). AGA is usually characterized by greasy hair, lack of luster, thinning, and soft hair on the forehead and crown of the head, and gradual loss (Alessandrini et al, 2021).…”