NPC2 Regulates Glioblastoma Cholesterol Metabolism and Malignant Behavior via GPX4‐Linked Ferroptosis

ABSTRACT

Glioblastoma (GBM) is a highly aggressive intracranial malignancy originating from neuroepithelial glial progenitors. The prominent intra‐ and intertumoral heterogeneity of GBM is a major driver of therapeutic resistance and frequent tumor recurrence. Cholesterol is an essential structural component of mammalian cell membranes and plays crucial roles in membrane trafficking and transmembrane signal transduction. As a key intracellular cholesterol transporter, the Niemann‐Pick type C2 (NPC2) protein remains poorly characterized regarding its biological functions and clinical implications in GBM. In this study, immunohistochemical staining of clinical GBM specimens revealed that elevated NPC2 expression was significantly correlated with unfavorable patient prognosis. Consistent with clinical observations, genetic knockdown of NPC2 markedly suppressed the proliferation and invasion abilities of LN18 cells. Mechanistically, NPC2 silencing downregulated GPX4 expression at both transcriptional and translational levels, suggesting a potential regulatory relationship between NPC2 and the ferroptosis pathway. Collectively, these findings indicate that NPC2 may facilitate GBM malignant progression partially through modulating GPX4‐mediated ferroptosis, thereby representing a tentative prognostic biomarker and a potential therapeutic target for GBM that requires further validation.