From Barrier Disruption and Immune Dysregulation to Targeted Therapies in Atopic Dermatitis.

Atopic dermatitis (AD) is a heterogeneous inflammatory skin disorder characterized by recurrent eczematous lesions and persistent pruritus. Its pathogenesis involves epidermal barrier dysfunction, immune dysregulation, microbial dysbiosis, and altered neuroimmune signaling. Genetic defects in structural proteins, particularly filaggrin, and altered epidermal lipids increase allergen and microbial penetration, perpetuating itch, scratching, tissue injury, and inflammation. Molecular evidence further reveals AD endotypes beyond conventional clinical phenotypes, with heterogeneity in immune polarization, barrier dysfunction, microbial colonization, and pruritic pathways. This heterogeneity may underlie differences in clinical presentation and treatment response. Conventional treatments, including skin hydration, antihistamines, and topical anti-inflammatory agents, often provide incomplete or transient control. Mechanism-based therapies targeting IL-4/IL-13, OX40/OX40L, JAK, and PDE4, together with AhR agonists, have broadened treatment options. However, efficacy must be balanced against treatment-specific risks. Biologics require monitoring for ocular and injection-site reactions, whereas systemic JAK inhibitors require monitoring for infections and laboratory abnormalities and carry regulatory class warnings regarding major adverse cardiovascular events, venous thromboembolism, and malignancy; however, these warnings are largely extrapolated from studies in older patients with rheumatoid arthritis, and the magnitude of these risks in patients with AD remains uncertain. Long-term safety and real-world evidence remain limited for several emerging therapies. This review synthesizes current knowledge of barrier dysfunction, immune heterogeneity, molecular endotypes, microbiome imbalance, neuroimmune signaling, and mechanism-based therapies. Integrating clinical phenotypes with molecular endotypes, predictive biomarkers, efficacy, and individualized safety assessment may enable more precise treatment selection and durable disease control.