Polypharmacological targeting of atopic dermatitis by natural products: A mechanism-driven systematic review.

BACKGROUND

Atopic dermatitis (AD) involves interconnected disturbances in epidermal barrier function, immune regulation, microbial homeostasis, and neuroimmune itch. Natural products influence several of these processes, but their mechanistic and clinical evidence remains fragmented.

PURPOSE: To assess natural product-based interventions for AD within a polypharmacological framework and identify priorities for clinical translation.

STUDY

DESIGN

Mechanism-driven systematic review with qualitative narrative synthesis.

METHODS

PubMed and the Web of Science Core Collection were searched from inception to March 2026. Eligible studies evaluated isolated natural compounds, characterized extracts or formulations, natural lipids, or microbe-derived interventions in patients with AD or validated experimental models. Evidence was synthesized by chemotype, pathological axis, molecular target or pathway, study design, and translational relevance.

RESULTS

A total of 156 original studies were retained. Reported effects clustered around epidermal differentiation and lipid homeostasis, inflammatory signaling, host-microbial interactions, and pruriceptive pathways. Preclinical studies provided mechanistic evidence for barrier-restorative, immunomodulatory, microbiome-related, and antipruritic effects involving multiple pathways. Clinical studies reported improvements in disease severity, barrier-related measures, pruritus, and quality of life, although findings varied across interventions and study designs. Direct target engagement, exposure-response relationships, and contributions of individual constituents in multicomponent preparations remained incompletely resolved.

CONCLUSION

Natural products provide a pharmacologically diverse basis for intervention across interconnected AD pathways. Current evidence supports therapeutic potential and multitarget activity, although polypharmacological synergy, comparative efficacy, and long-term safety require further validation. Clinical translation requires reproducible product characterization, direct mechanistic validation, pharmacokinetic assessment, human-relevant models, and well-designed clinical studies.