TYMP upregulation mediated by the hyperactivated IL-17/NF-κB1 axis promotes psoriasis through enhancing aberrant keratinization and neutrophil-mediated inflammation.

Psoriasis is a common, chronic, and recurrent immune-mediated disorder with global prevalence, underscoring the need for novel biomarkers to improve diagnosis and treatment. In this study, differentially expressed genes (DEGs) in psoriatic tissues were comprehensively identified through integrated single-cell and bulk RNA-seq analyses. Thymidine phosphorylase (TYMP) emerged as one of the most significantly upregulated biomarkers in psoriasis. Multiplex immunohistochemistry (mIHC) and IHC assays jointly confirmed marked overexpression of TYMP in psoriatic keratinocytes. Mechanistically, we demonstrated that IL-17-mediated inflammatory signaling transcriptionally induces TYMP expression via NF-κB1. TYMP overexpression promotes keratinocyte proliferation and activates signaling pathways associated with keratinization and neutrophil degranulation in psoriasis. Immune infiltration analysis, blood routine tests, and ELISA verified that TYMP upregulation is closely correlated with neutrophil degranulation in psoriasis. In the imiquimod (IMQ)-induced psoriasis-like mouse model, pharmacological inhibition of TYMP by tipiracil partially reverses the pathological effects of TYMP overexpression, including accelerated keratinocyte proliferation, aberrant keratinization, and neutrophil-driven inflammation. In summary, TYMP is overexpressed in psoriasis due to hyperactivation of the IL-17/NF-κB1 signaling. Targeting TYMP by Tipiracil ameliorates psoriasis symptoms by suppressing abnormal keratinization and neutrophil degranulation, thereby highlighting its potential as a therapeutic target for psoriasis.