Update publication information. Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumor. Although alkylating agents (such as temozolomide (TMZ)) are widely used as first-line treatments for GBM, they often cause chemoresistance and are poorly effective for recurrent GBM. Therefore, anti-GBM drugs with novel mechanism are urgently needed clinically. Here, we report an effective Ca2 +-calcineurin-NFAT signaling pathway inhibitor (Pimavanserin), which exhibits effective anti-tumor activity against GBM. Pimavanserin induces GBM cell cycle arrest in G1/S, promotes cell apoptosis and inhibits tumor cell proliferation and metastasis. Through an in-depth study of the mechanism, it is found that Pimavanserin eliminates NFAT nuclear translocation by inhibiting the formation of puncta of STIM1. Subsequent transcriptomic and proteomic analysis unveiled that PIM can down-regulate E2F, MYC ATR and AuroraA/B signaling pathways to inhibit GBM cancer growth both in vitro and in vivo. In addition, the upregulated genes were mainly associated with cholesterol homeostasis and fatty acid synthesis, which may underlie the mechanism of PIM’s phospholipidosis side effect. This article is the first report of Pimavanserin as an anti- GBM drug.