Natural modulators of epithelial-immune signaling in atopic dermatitis: Molecular immunological mechanisms and...

Atopic dermatitis (AD) is a self-reinforcing epithelial-immune disorder in which barrier failure, alarmin release, type 2 cytokines, oxidative stress and dysbiosis converge on interconnected signaling circuits. This review critically evaluates natural products by mode of action rather than by pathway name alone. The available evidence supports coordinated suppression of NF-kB/MAPK-driven inflammatory cascades, indirect attenuation of JAK/STAT amplification, activation of Nrf2/HO-1 and AHR-dependent barrier programs, and upstream modulation of microbiota-metabolite-immune signaling. We distinguish system-level upstream processes (barrier injury, dysbiosis and epithelial alarmins), inflammatory convergence hubs (NF-kB/MAPKs), cytokine amplifiers (JAK/STAT), and counter-regulatory nodes (Nrf2/AHR). Importantly, most natural-product studies rely on endpoint assays in immortalized keratinocytes or hapten-induced murine models; direct target engagement, kinetic selectivity and achievable skin exposure are rarely established. Translation therefore requires chemical standardization, human-relevant models, pharmacokinetic-pharmacodynamic analysis, sensitization testing, and evaluation under the altered pH and microbial conditions of AD skin. Rational adjunctive use with biologics or JAK inhibitors also demands formal assessment of CYP-mediated interactions and combined safety rather than an assumption that natural origin confers tolerability.