HRH1-targeting mAb: a precision therapeutic strategy for Glioblastoma

Glioblastoma multiforme (GBM) remains one of the most aggressive primary brain tumors with limited therapeutic options. The efficacy of standard temozolomide chemotherapy is critically influenced by O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. While monoclonal antibody (mAb)-based biologics represent a promising therapeutic approach, current clinical trials have failed to demonstrate significant improvement in overall patient survival. In this study, systematic screening identified histamine H1 receptor (HRH1) as a potential therapeutic target. Genetic silencing of HRH1 significantly inhibited GBM cell proliferation, migration, and invasion both in vitro and in vivo. Pharmacological validation using the HRH1-specific antagonist terfenadine confirmed the anti-tumor effects of HRH1 targeting. Based on these findings, we developed an HRH1-targeting mAb that demonstrated potent anti-tumor activity in GBM xenograft models. Mechanistic investigations revealed that the therapeutic effect was mediated through protein kinase C (PKC)-dependent regulation of the RAF/MEK/ERK signaling pathway. In conclusion, we provided a new target, HRH1, for treating GBM and constructed an effective therapeutic mAb.