circNLK restrains glioblastoma malignancy by binding to hnRNP L and destabilizing RGS16

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, underscoring the need to identify tumor-suppressive regulators for the development of more effective therapies. Circular RNAs (circRNAs) have emerged as important regulators in cancers, yet their roles in GBM remain incompletely understood. In this study, we identified circular NLK (circNLK; hsa_circ_0002103) as a tumor suppressor in GBM. circNLK expression was downregulated in GBM relative to non-neoplastic brain tissues, and higher circNLK expression associated with better patient outcomes. Ectopic circNLK overexpression inhibited GBM cell proliferation and motility while increasing apoptosis. Mechanistically, circNLK bound to the RNA-binding protein hnRNP L in an m6A-associated manner and partially competed with the RGS16 RNA transcript for hnRNP L binding, thereby reducing RGS16 stability and expression. In orthotopic mouse models of GBM, circNLK overexpression delayed tumor growth, prolonged survival, and reduced RGS16 expression in tumor tissues. Together, these findings expand our understanding of circRNAs as tumor suppressors and provide a rationale for exploring circNLK-based therapeutic strategies in GBM.