LncRNA CCDC152 coordinates a tumor-associated selenoprotein P cycle that sustains selenium-dependent redox homeostasis in glioblastoma.

Selenium is essential for the synthesis of redox-active selenoproteins, including glutathione peroxidase 4 (GPX4), a central suppressor of ferroptosis. However, how malignant cells coordinate selenium acquisition and reutilization to maintain redox homeostasis remains poorly understood. Here, we identify a tumor-associated selenoprotein P (SELENOP) cycle in glioblastoma (GBM) that is coordinated by the long non-coding RNA (lncRNA) CCDC152. Highly proliferative GBM cells secrete SELENOP, recapture it through LRP8, and reutilize selenium to maintain intracellular selenoprotein abundance and cell proliferation. Disruption of SELENOP or LRP8 suppressed GBM cell proliferation, while LRP8 depletion reduced GPX1 and GPX4 abundance and its intracellular domain was required for growth-promoting activity. Unexpectedly, although CCDC152 suppresses SELENOP translation in hepatocyte-derived cells, it positively regulated SELENOP production, LRP8 expression, and intracellular GPX1 and GPX4 abundance in GBM cells. CCDC152 depletion also increased ferroptosis susceptibility. Clinical analyses further showed that elevated expression of SELENOP and CCDC152 was associated with poor prognosis in astrocytoma, IDH-mutant. Together, these findings identify the CCDC152- SELENOP-LRP8 axis as a tumor-adapted selenium utilization system that couples extracellular selenium transport to intracellular redox homeostasis, revealing selenium utilization as a redox vulnerability that may be exploited by ferroptosis-inducing therapies.