Dysfunctional tight junctions in psoriasis pathogenesis: mechanisms and therapeutic implications

Tight junctions (TJs) are essential intercellular adhesion structures in epidermal keratinocytes that govern the multicomponent epidermal barrier (paracellular permeability, keratinocyte polarity, and barrier homeostasis). Their disruption and dysregulation are early, consistent, and functionally important pathological features in psoriasis-a chronic inflammatory skin disorder driven by epidermal hyperproliferation, aberrant differentiation, and sustained immune activation. In psoriatic lesions, TJ proteins exhibit consistent abnormal expression, ectopic localization, and impaired assembly, which may act as upstream contributors to keratinocyte dysregulation and inflammatory amplification. Abnormally expressed or mislocalized TJ proteins increase epidermal paracellular permeability, which may facilitate the penetration of exogenous substances and further disturb skin homeostasis. Concurrently, psoriatic inflammatory cytokines-particularly the IL-23/IL-17 axis-further suppress TJ expression and assembly, establishing a self-reinforcing vicious cycle that sustains lesion chronicity. This review delineates epidermis-specific TJ structure and function in the context of the broader epidermal barrier system, systematically integrates the molecular links between TJ dysfunction and psoriasis pathogenesis, highlights the IL-23/IL-17 axis as a well-supported central regulator of TJ impairment, and discusses translational opportunities for TJ-targeted therapies. Where appropriate, we distinguish between well-established findings, strongly supported evidence, and remaining speculative mechanisms to ensure scientific rigor. By clarifying TJ-mediated mechanisms, we aim to inspire novel barrier-repair strategies for psoriasis.