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.