Cetirizine suppresses cancer-associated fibroblast-mediated fibrotic remodeling and epithelial–mesenchymal transition via histamine H1 receptor inverse agonism

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by high metastatic potential and limited therapeutic options. Cancer-associated fibroblasts (CAFs) promote epithelial–mesenchymal transition (EMT) and metastatic progression through extracellular matrix (ECM) remodeling and TGF-β signaling; however, the role of histamine H1 receptor (H1R) signaling in CAFs remains unclear. This study investigated whether cetirizine, a clinically approved second-generation H1R antagonist, modulates CAF function and suppresses metastasis in TNBC. Syngeneic 4T1 mouse models were used to evaluate the effects of cetirizine on tumor growth and metastasis. Bulk RNA sequencing and pathway analyses were performed on tumor tissues. Human breast cancer–derived CAFs were analyzed for H1R-dependent signaling, gene expression, and cytokine production. Non-contact co-culture assays were used to assess CAF-induced migration and EMT in 4T1 cells. Cetirizine improved survival in a subcutaneous TNBC model but had no effect in a lung colonization model, indicating suppression of early metastatic processes. Transcriptomic analyses revealed downregulation of ECM remodeling and fibrotic pathways. In CAFs, cetirizine inhibited H1R-dependent calcium signaling and suppressed expression of ECM genes (COL1A1, COL3A1, FN1, HSPG2) and TGFB1. These effects persisted under histamine-depleted conditions and were abolished by HRH1 knockdown, supporting inverse agonist activity. Functionally, cetirizine inhibited CAF-induced migration and EMT marker expression in 4T1 cells without direct effects on tumor cells in monoculture. Cetirizine suppresses CAF-mediated fibrotic remodeling and EMT through H1R-dependent mechanisms, likely via inverse agonism. By targeting stromal components of the tumor microenvironment, cetirizine may represent a practical repurposing strategy for preventing early metastatic progression in TNBC.