Targeting TRPV4 with sclareol ameliorates atopic dermatitis through by suppression of inflammatory response and oxidative stress.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune imbalance and excessive cytokine production, in which dysregulation of transient receptor potential vanilloid 4 (TRPV4) contributes to skin inflammation and itching. In this study, we screened a natural product library and identified sclareol as a preferential TRPV4 inhibitor. Molecular docking and calcium imaging in HaCaT cells confirmed that sclareol effectively blocks TRPV4 channel activation. With an MC903‑induced AD mouse model, we found that sclareol treatment significantly alleviated skin lesions, reduced epidermal thickening, decreased infiltration of CD4+ T cells, and lowered serum levels of immunoglobulin E (IgE), interleukin (IL)-1β, and IL-13. In an inflammatory cell model established by stimulating HaCaT cells with tumor necrosis factor (TNF)-α and interferon (IFN)-γ, sclareol attenuated the production of key inflammatory mediators, blocked activation of both NF‑κB and MAPK signaling pathways, and mitigated oxidative stress by reducing reactive oxygen species (ROS). To confirm target specificity, we used TRPV4‑knockout cells; notably, observed anti‑inflammatory and antioxidant effects were substantially attenuated in the absence of TRPV4. Collectively, this study establishes sclareol as a novel TRPV4 inhibitor that ameliorates AD pathology through a TRPV4‑dependent mechanism involving suppression of inflammatory signaling and oxidative stress.