Abstract
Psoriatic disease (PsD) is a chronic inflammatory disease, with significant challenges in early risk stratification and drug development. Integration of proteomic and genomic data provides an unprecedented opportunity to identify predictive biomarkers and therapeutic targets for PsD. Here, through systemic genetic analyses, expression validation, and prospective cohort study, CDSN and PRSS8 were identified as candidate biomarkers and potential therapeutic targets for PsD. Individuals with higher levels of CDSN and PRSS8 were nearly three times more likely to develop PsD compared to the general population. It develops prediction models in adults without PsD at baseline from the UK Biobank. Combining CDSN and PRSS8 with demographics produced desirable predictions for PsD (area under the curve (AUC) = 0.80) and exhibited high specificity. Moreover, PRSS8 and CDSN were both predominantly localized in keratinocytes, and in vivo gene silencing of these proteins significantly reduced PsD-like skin lesions and systemic inflammatory markers. The findings strongly suggested that CDSN and PRSS8 are promising biomarkers for PsD onset and progression, providing a 12-year risk assessment window and potential as novel therapeutic targets. These results had important implications for screening high-risk populations and facilitating early intervention for PsD.