The ectopic olfactory receptor OR7A17 regulates the proliferation and differentiation of human epidermal keratinocytes, and ginsenoside Rh3 acts as its antagonist

Abstract

Background

Olfactory receptors perform diverse functions in many cell types and are ectopically expressed in human epidermis.

Purpose

This study aimed to examine the role of OR7A17 in keratinocyte biology, its signaling pathway and the potential of ginsenosides as its antagonist.

Methods

OR7A17 function was examined in stably OR7A17-overexpressing HaCaT cells using western blots, image analysis, flow cytometric and qPCR.

Results

We found that OR7A17 overexpression promoted keratinocyte proliferation through MAPK signaling pathway, accompanied by elevated cAMP and cytosolic Ca²⁺ levels, which activated AP-1 and CRE. Moreover, blockade experiments showed that CNG, TRPV1, and TRPA1 channels mediated these Ca²⁺ signals. OR7A17 also promoted the PI3K/AKT pathway, activating NF-κB and driving G1/S cell cycle progression via GSK-3β inhibition and P70S6K activation. Conversely, OR7A17 overexpression repressed differentiation, as evidenced by reduced expression of early and late differentiation markers. Molecular docking and functional assays confirmed that ginsenoside Rh3 bound OR7A17 and antagonized its signaling, thereby inhibiting proliferation and restoring differentiation.

Conclusion

In summary, OR7A17 promoted keratinocyte proliferation by activating PKA/MAPK, Ca²⁺/CREB, and PI3K-AKT-NF-κB pathways, while repressing differentiation. In addition, ginsenoside Rh3 functioned as an antagonist of OR7A17, counteracting these effects. These findings suggest OR7A17 as a therapeutic target for proliferation- and differentiation-related skin disorders such as atopic dermatitis, with ginsenoside Rh3 as a potential regulator for epidermal homeostasis.