Inhibition of transient receptor potential vanilloid 3 channels by antimalarial hydroxychloroquine alleviates...

Transient receptor potential vanilloid 3 channel (TRPV3) is closely associated with skin inflammation, but there is a lack of effective and specific inhibitors for clinical use. In this study, we identified antimalarial hydroxychloroquine (HCQ) as a selective TRPV3 inhibitor following the prediction by network pharmacology data analysis. In whole-cell patch-clamp recordings, HCQ inhibited the current of the TRPV3 channel, with an IC50 of 51.69 ± 4.78 μM. At the single-channel level, HCQ reduced the open probability of TRPV3 and decreased single-channel conductance. Molecular docking and site-directed mutagenesis confirmed that residues in the pore domain were critical for the activity of HCQ. In vivo, HCQ effectively reduced carvacrol-induced epidermal thickening, erythema, and desquamation. Additionally, the serum immunoglobulin E and inflammatory factors such as tumor necrosis factor-α and interleukin-6 were markedly decreased in the dorsal skin tissues in the HCQ treatment group, as compared to the model group. Our results suggested the antimalarial HCQ may represent a potential alleviator for treating skin inflammation by inhibiting TRPV3 channels.