The PAR-score based on PANoptosis genes predicts the progression of ulcerative colitis and the response to anti-TNF-α treatment.

Background: Ulcerative colitis (UC), a chronic inflammatory bowel disease, carries an elevated risk of colitis-associated colorectal cancer (CAC). While PANoptosis-a coordinated cell death mechanism integrating pyroptosis, apoptosis, and necroptosis-has been linked to inflammatory disorders, its role in UC progression and CAC transformation remains undefined.

Objective: To delineate PANoptosis-related signatures and develop predictive models for the assessment of UC and CAC.

Methods: Transcriptomic data from UC patients, CAC cases, and controls (GEO database) were analyzed to identify PANoptosis-associated genes. Enrichment and immune infiltration analyses elucidated functional roles, while a dextran sulfate sodium (DSS)-induced murine colitis model validated candidate gene expression via Western blot. Single-cell sequencing dissected cellular heterogeneity, Mendelian randomization established causality, and molecular docking screened therapeutic agents.

Results: Four PANoptosis hub genes (CASP1, LCN2, STAT3, ZBP1) were identified as UC drivers. The PANoptosis-Associated Risk Score (PAR-Score) demonstrated robust diagnostic accuracy (AUC > 0.75) and stratified disease activity, anti-TNF-α responsiveness, and CAC risk. Molecular docking revealed strong binding affinity between epidermal growth factor receptor (EGFR) inhibitors and target proteins (binding energy: -6.0 to -8.4 kcal/mol), suggesting therapeutic potential.

Conclusion: The PAR-Score based on PANoptosis genes predicts the progression of UC and the response to anti-TNF-α treatment. EGFR inhibitors may serve as potential therapeutic agents for UC and CAC.