Background: Forkhead box proteins (FOXs) play important roles in multiple biological processes; while little is known regarding the role of FOX members in pancreatic adenocarcinoma (PAAD). This study aimed to comprehensively investigate the function of FOX family members in PAAD.

Methods: Expression and prognostic value of FOXs were analyzed by R language and GEPIA. Genetic alteration and promoter methylation level were analyzed using CBioPortal and UALCAN. Protein-protein interactions and gene functions were analyzed using STRING and DAVID. TIMER and SENESCopedia were utilized to analyze the correlation of FOXs with immune cell infiltration or tumor senescence. Protein levels of FOXs were detected by immunohistochemistry.

Results: Expression of 15 of 50 FOXs were significantly elevated in PAAD. Among these 15 differentially expressed FOXs (DE-FOXs), 4 were significantly associated with the clinical cancer stage and 4 were negatively associated with overall survival. Functions of DE-FOXs were related to epithelial tube morphogenesis, nuclear chromatin, and DNA-binding. Promoter methylation and genomic alterations were not major causes of FOX dysregulation. Most DE-FOX was correlated with diverse immune infiltration cells. Seven of the DE-FOXs were positively related to tumor senescence. The protein levels of FOXM1, FOXP1, and FOXN3 were negatively correlated with OS in the collected PAAD patients.

Conclusions: FOXM1, FOXP1, and FOXN3 have prognostic value. Seven FOXs were related senescence, whereas most DE-FOXs were related to immune infiltration in PAAD. Our findings are instructive for future research on FOX family and provide novel insights into the selection of FOXs with potential prognostic or therapeutic target value.