Glioblastoma multiforme (GBM) is highly aggressive, invasive, and heterogenous primary brain cancer, contributing to poor prognosis. It is hypothesized that proton-sensing G protein-coupled receptor (GPCR), GPR68, plays a key role in tumor survival within the context of the acidic TME. Previously, a novel class of small molecule, Ogremorphin (OGM), were found to inhibit GPR68 producing robust cell death in a dose-dependent manner in vitro. Here, the findings suggest that acidic TME activates the extracellular proton-sensing receptor GPR68, which promotes pro-survival signals via inhibition of ferroptosis. Inhibiting GPR68 by OGM induces ferroptosis in GBM cells via ATF4 pathway, demonstrating that acidic TME is a promising therapeutic target for GBM.