Nociceptin-mediated SIRT6 downregulation drives cellular senescence in glioblastoma

Cellular senescence plays a crucial role in glioblastoma (GBM), influencing tumor progression and therapeutic resistance. Nociceptin (N/OFQ), an endogenous neuropeptide, and its receptor NOPr are implicated in various pathological processes, but their role in GBM remains unclear. This study investigated the effects of N/OFQ-NOPr signaling on cellular senescence in GBM. We found elevated plasma N/OFQ levels and increased NOPr expression in GBM tissues compared to normal controls. In U-251 GBM cells, N/OFQ upregulated NOPr expression, induced oxidative stress, and reduced telomerase activity and telomere length, leading to enhanced cellular senescence. Mechanistically, N/OFQ downregulated SIRT6 but not SIRT1 or HDAC, resulting in increased acetylation of p53, upregulation of p21, and suppression of p-Rb. Overexpression of SIRT6 reversed N/OFQ-induced senescence markers, restoring telomerase activity and reducing senescence-associated β-galactosidase. Notably, administration of the selective NOPr antagonist UFP-101 abolished N/OFQ-induced cellular senescence, indicating that this effect is NOPr-dependent. These findings suggest that N/OFQ-NOPr signaling promotes GBM senescence via SIRT6 downregulation, highlighting a potential therapeutic target for modulating senescence in GBM.