Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor,and 95％ of patients die within 2 years after diagnosis.In this study,aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ),we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy.To accelerate the drug\'s clinical application,we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors.After screening a set of 93 FDA-approved drugs with simple structures,we identified pimavanserin tartrate (PIM),an effective 5-HT2A receptor inverse agonist used for the treatment of Parkinson\'s disease-associated psychiatric symptoms,as having the most potent inhibitory activity against the NFAT signaling pathway.Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity.In cellula,PIM significantly suppressed the proliferation,migration,division,and motility of U87 glioblastoma cells,induced G1/S phase arrest and promoted apoptosis.In vivo,the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM.Unbiased omics studies revealed the novel molecular mechanism of PIM\'s antitumor activity,which included suppression of the ATR/CDK2/E2F axis,MYC,and AuroraA/B signaling.Interestingly,the genes upregulated by PIM were largely associated with cholesterol homeostasis,which may contribute to PIM\'s side effects and should be given more attention.Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.