Calcium signaling in psoriasis: from pathogenesis to therapeutic opportunities.

Psoriasis is a chronic inflammatory skin disease driven by the synergistic interplay between aberrant epidermal proliferation and immune imbalance, with its core pathological process centered on the IL-23/IL-17 inflammatory axis. In recent years, accumulating evidence has demonstrated that calcium (Ca2+) signaling not only participates in keratinocyte (KC) differentiation and the maintenance of skin barrier homeostasis but also serves as a critical upstream regulator of the maturation and activation of immune cells, including dendritic cells (DCs), Th17 cells, neutrophils, and mast cells. This review systematically summarizes the mechanistic roles of Ca2+ signaling dysregulation in psoriatic keratinocytes and multiple immune effector cells, with particular emphasis on the regulatory functions of SOCE within the DC-Th17 inflammatory axis. Current evidence indicates that the collapse of epidermal structural support systems, impaired Ca2+ sensing, and SOCE dysfunction collectively contribute to insufficient local Ca2+ signaling and defective KC differentiation. In contrast, persistently activated Ca2+-dependent signaling within the immune compartment promotes Th17 polarization, IL-17A release, and inflammatory cascade amplification through downstream pathways including Calcineurin-NFAT-RORγt. Based on these observations, this review further proposes that "compartment-specific bidirectional calcium dysregulation" may represent an underrecognized pathological pattern in psoriasis, characterized by the coexistence of impaired epidermal calcium signaling and persistent immune calcium hyperactivation. Furthermore, this review discusses therapeutic strategies targeting Ca2+ signaling and their translational challenges, including SOCE-targeted interventions and future combinatorial therapeutic approaches. Overall, this review reappraises the pathogenesis of psoriasis from the perspective of Ca2+ signaling with the aim of providing a novel theoretical basis for future precision immunomodulation and the development of innovative therapeutic strategies.