Stanniocalcin 1 contributes to glioma stem cells phenotypic plasticity through NOTCH1/STAT3/GFPT2 axis

Glioma stem cells (GSCs) are key drivers of glioblastoma (GBM) tumorigenesis, invasion, therapy resistance, and recurrence and exhibit remarkable phenotypic plasticity. Stanniocalcin 1 (STC1) has been implicated in tumor progression and cancer stemness; however, its role and the molecular mechanisms through which it shapes GSC plasticity and malignant traits remain poorly understood. Here, transcriptomic RNA sequencing identified STC1 as a malignancy-associated gene enriched in GBM and mesenchymal (MES)-like GSCs. Comprehensive bioinformatic analyses further validated that STC1 was highly expressed in MES-like GBM/GSCs and closely associated with poor patient survival. Functional studies revealed that STC1 promoted multiple malignant properties of GSCs, including self-renewal, migration, invasion, tumorigenicity, and cellular plasticity. Conversely, STC1 silencing attenuated these effects. Mechanistically, STC1 activated the NOTCH1/STAT3 signaling cascade, leading to transcriptional upregulation of GFPT2, a key rate-limiting enzyme of the hexosamine biosynthetic pathway. This subsequently enhanced global O-GlcNAcylation, including modification of P65, thereby facilitating GSC plasticity and malignant progression. Genetic and pharmacological interventions targeting this signaling axis effectively mitigated the oncogenic effects driven by STC1. In conclusion, our study reveals that STC1 is a key regulator of GSC phenotypic plasticity and aggressiveness through the NOTCH1/STAT3/GFPT2/O-GlcNAcylation pathway. These results provide new mechanistic insights into GBM progression and suggest that targeting STC1-associated signaling networks may represent a potential therapeutic strategy for GBM.