ARNT2 repression disrupts neuronal identity and promotes glioblastoma growth.

Tumor initiation and progression frequently involve oncogenic programs that favor proliferation at the expense of lineage commitment and differentiation. Here, we identify a MYC-driven mechanism that suppresses neuronal identity in glioblastoma (GBM) through repression of the transcription factor aryl hydrocarbon receptor nuclear translocator 2 (ARNT2). ARNT2 is highly expressed in the brain, cerebellum, and iPSC-derived neurons but is markedly reduced in GBM tumors and cell lines, where its loss correlates with higher tumor grade and poor survival. Mechanistically, MYC represses ARNT2 expression, and ARNT2 loss results in reduced expression of neuronal and glial identity genes. Although ARNT2 depletion does not alter GBM cell proliferation in vitro, it significantly enhances tumor growth and lipid metabolic remodeling in vivo. Conversely, ectopic ARNT2 expression suppresses tumor burden in both subcutaneous and orthotopic GBM xenograft models and promotes features of neuronal differentiation. Together, these findings identify ARNT2 as a tumor suppressor in GBM and establish MYC-mediated repression of ARNT2 as a critical mechanism by which GBM maintains a proliferative, undifferentiated, stem-like state.