A HRH1-YAP1 feedback loop drives pancreatic cancer progression and predicts therapeutic response

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a dismal prognosis, characterized by an immunosuppressive tumor microenvironment and rapid development of chemoresistance. The present study investigated the histamine receptor H1 (HRH1), a G protein-coupled receptor, and its functional interplay with the transcriptional coactivator YAP1, a known driver of PDAC progression. Through integrated multi-omics analysis of data from TCGA, ICGC and GEO cohorts, the present study found that HRH1 was consistently overexpressed in PDAC, and its expression correlated with poor prognosis. Mendelian randomization analysis further suggested a causal relationship between the use of fexofenadine, an HRH1 antagonist, and a reduced risk of PDAC. Mechanistically, the present study identified a positive feedback loop in which HRH1 stabilizes and activates YAP1 signaling, while YAP1 knockdown downregulates HRH1 transcription, potentially through direct binding to the HRH1 promoter region. The present study constructed a prognostic model based on the HRH1-YAP1 axis by integrating a panel of 101 machine learning algorithms. The model, which includes HRH1, YAP1, ECT2, ITGB5, SHCBP1, MAML2, YWHAZ and ITGA2, effectively stratified patients into groups with differential risk. Patients in the high-risk group exhibited characteristics associated with worse outcomes, including KRAS mutations, chemoresistance, an immunosuppressive microenvironment and reduced responsiveness to immunotherapy. The present study establishes HRH1 as a novel therapeutic target in PDAC and proposes the repurposing of fexofenadine as a promising strategy to disrupt the oncogenic HRH1-YAP1 feedback loop.