Abstract

Psoriasis is a chronic immune-mediated inflammatory disorder with systemic implications. While transcobalamin 2 (TCN2) has been linked to several autoimmune diseases, its role in psoriasis remains unclear. Here, we investigated the contribution of TCN2 to psoriatic pathogenesis. TCN2 expression was significantly elevated in both lesional skin and peripheral blood mononuclear cells (PBMCs) from psoriasis patients, and its levels declined following biologic therapy. Similarly, increased TCN2 expression was observed in imiquimod (IMQ)-induced psoriatic lesions in mice. To further evaluate its function, we generated Tcn2-deficient (Tcn2−/−) mice and established an IMQ-induced psoriasis model. Compared with wild-type controls, Tcn2−/− mice developed attenuated skin lesions with reduced epidermal hyperplasia and inflammation. Transcriptomic analysis of lesional skin revealed downregulation of inflammatory mediators (S100A7, S100A8, S100A9, IL-1β, IL-6) and suppression of STAT3 signaling in Tcn2−/− mice. In parallel, TCN2-knockdown HaCaT cells exhibited impaired proliferation due to G1-phase arrest, along with reduced expression of proinflammatory factors. Together, these findings demonstrate that TCN2 promotes keratinocyte hyperproliferation and amplifies inflammatory responses in psoriasis. In conclusion, this study identifies TCN2 as a previously unrecognized regulator of psoriatic inflammation and keratinocyte biology, highlighting its potential as a novel therapeutic target. Graphical TCN2 is upregulated in psoriasis skin and PBMCs and decreases in PBMCs after secukinumab. In IMQ-induced dermatitis, Tcn2 deficiency attenuates epidermal hyperplasia and leukocyte infiltration, accompanied by reduced IL-1β readouts and STAT3 phosphorylation. In HaCaT cells, shTCN2 induces G1 arrest and dampens inflammatory outputs. M5 cytokines (IL-1α, IL-17A, IL-22, TNF-α, and OSM) increase TCN2, suggesting TCN2 is inflammation-responsive and associated with the IL-1β/STAT3 axis.