Inhibiting GPR68 by Small Molecule Induces Programed Cell Death Ferroptosis in Glioblastoma Multiforme

Abstract

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.