A novel antagonist of transient receptor potential vanilloid 3 (TRPV3): hydroxychloroquine alleviates TRPV3-dependent atopic dermatitis

Summary: Abstract Body: The transient receptor potential vanilloid 3 (TRPV3) channel is closely linked to skin inflammation, yet specific and effective antagonists for clinical use are scarce. In this study, we identified the antimalarial drug hydroxychloroquine (HCQ) as a selective antagonist of TRPV3 through network pharmacology analysis. Whole-cell patch-clamp recordings demonstrated that HCQ inhibited TRPV3 channel currents with an IC50 of 51.69±4.78 mM. At the single-channel level, HCQ decreased the open probability and conductance of TRPV3. Molecular docking and site-directed mutagenesis revealed that pore domain residues are crucial for HCQ's inhibitory effect. In a mouse model, HCQ reduced carvacrol-induced epidermal thickening, erythema, and desquamation. Additionally, serum immunoglobulin E levels and inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6, were significantly lower in the dorsal skin tissues of the HCQ-treated group compared to the model group. These results suggest that HCQ may serve as a potential therapeutic agent for alleviating skin inflammation by targeting TRPV3 channel. Bo Xie¹ 1. Dermatology, Hangzhou Third People's Hospital, Hangzhou, Zhejiang, China. Translational Studies: Cell and Molecular Biology