Ogremorphin induces ferroptosis in primary human glioblastoma neurospheres
Recommended Citation
Wasserman AH, Tikaria B, Basrai HF, deCarvalho AC, Neitzel LR, Hong CC. Ogremorphin Induces Ferroptosis in Primary Human Glioblastoma Neurospheres. Biomed Pharmacother. 2026;204:119962.
Document Type
Article
Publication Date
11-1-2026
Publication Title
Biomedicine & pharmacotherapy
Keywords
Humans, Glioblastoma, Ferroptosis, Brain Neoplasms, Cell Line, Tumor, Animals, Spheroids, Cellular, Zebrafish, Receptors, G-Protein-Coupled, Cell Survival
Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults, with a median survival of only 15 months. While current treatment strategies combine surgery, radiation, and chemotherapy, the majority of cases recur with acquired resistance. Despite considerable heterogeneity within GBM tumors, one defining feature is an acidic tumor microenvironment, which provides growth advantages through an unknown mechanism. However, expression of GPR68 (OGR-1), an acid-sensing GPCR, increases in drug resistant GBM and radioresistant cell lines. Previous work utilized genetic and pharmacological GPR68 disruption to investigate the receptor-mediated cell survival mechanism. Immortalized GBM cell lines treated with Ogremorphin (OGM), a novel and highly specific small molecule GPR68 inhibitor, undergo ferroptosis, an iron-mediated cell death pathway. OGM also effectively treats larval zebrafish xenograft models of GBM without harming normal tissue. Here, we expand these findings to three primary human glioblastoma models. We observe dose-dependent cell death (LD(50) values of 0.297, 0.994, and 1.042 μM) and a decrease in three-dimensional spheroid size in response to OGM-mediated GPR68 inhibition, with some degree of heterogeneity between models. In addition, multiple hallmarks of ferroptosis are seen, such as reduced glutathione levels and increased expression of ferroptosis reporter genes. Notably, OGM displays synergistic trends with both the GBM frontline therapy temozolomide (TMZ) and ionizing radiation to induce cell death. This study complements existing research that OGM induces ferroptosis in GBM cell lines in vitro and in vivo and represents an important advancement of its translational potential.
Medical Subject Headings
Humans; Glioblastoma; Ferroptosis; Brain Neoplasms; Cell Line, Tumor; Animals; Spheroids, Cellular; Zebrafish; Receptors, G-Protein-Coupled; Cell Survival
PubMed ID
42815212
Volume
204
First Page
119962
Last Page
119962
