β-Myrcene alleviates atopic dermatitis-like inflammation and is associated with ECM-FAK/Src-YAP signaling during epidermal barrier repair.

BACKGROUND: Atopic dermatitis (AD) is characterized by epidermal barrier impairment and immune-driven inflammation. Strategies that restore barrier architecture while constraining inflammation are of therapeutic interest. PURPOSE: To evaluate the barrier-reparative and anti-inflammatory effects of β-myrcene (MYR) in experimental atopic dermatitis and to investigate whether ECM-FAK/Src-YAP signaling is associated with these effects. METHODS: A 2,4-dinitrochlorobenzene (DNCB)-induced murine model of AD-like dermatitis was evaluated by transepidermal water loss (TEWL), histopathology, dermal collagen organization, filaggrin (FLG) immunofluorescence, and circulating inflammatory mediators. Integrated skin transcriptomic and proteomic analyses and public human AD transcriptomic datasets were used to identify MYR-associated pathways. In primary human keratinocytes stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), YAP localization, FAK Tyr397 and Src Tyr416 phosphorylation, YAP/TAZ target genes, barrier markers, and inflammatory outputs were assessed. Peptide 17 was used to examine the contribution of YAP-dependent transcription. RESULTS: MYR reduced dermatitis severity and epidermal hyperplasia, lowered TEWL, partially restored FLG immunofluorescence, and preserved dermal collagen organization in DNCB-challenged mice. Multi-omics profiling identified MYR-associated changes in extracellular matrix (ECM)-receptor interaction, focal adhesion, cytoskeletal remodeling, epidermal differentiation, and immune-related programs. In inflamed keratinocytes, MYR was associated with increased FAK and Src phosphorylation, YAP nuclear accumulation, CCN1/CCN2 expression, and barrier-marker expression, together with reduced inflammatory mediator production. Peptide 17 attenuated MYR-associated YAP nuclear accumulation and several downstream transcriptional responses. These findings support the participation of YAP-dependent signaling but do not establish MYR as a direct regulator of FAK, Src, or YAP or demonstrate a strictly linear signaling sequence. CONCLUSION: MYR produced barrier-restorative and anti-inflammatory effects in experimental atopic dermatitis. The results identify ECM-FAK/Src-YAP signaling as a candidate pathway associated with the MYR response, with pharmacological inhibition providing partial functional evidence for a YAP-dependent component.