胶质母细胞瘤（GBM）抗辐射的分子机制仍知之甚少。本研究的目的是阐明亲黑素 (MLPH) O-GlcNAcNA 酰化的潜在作用及其调节 GBM 放疗抵抗的具体机制。我们发现电离辐射（IR）后复发性 GBM 肿瘤组织中 MLPH 显着上调。 MLPH 通过调节 NF-κB 通路诱导 GBM 细胞和异种移植人类肿瘤的放疗抵抗。 MLPH 在保守丝氨酸 510 处被 O-GlcNAc 酰化，并且抗辐射 GBM 细胞表现出更高水平的 MLPH O-GlcNAc 酰化。 MLPH 的 O-GlcNAc 酰化保护了其蛋白质稳定性，含有 21（TRIM21）的三联基序被鉴定为促进 MLPH 降解的 E3 泛素连接酶，其与 MLPH 的相互作用受到 O-GlcNAc 酰化的影响。我们的数据表明，MLPH 通过促进 NF-κB 信号通路在 GBM 辐射抗性中发挥调节功能，并且 MLPH 的 O-GlcNA 酰化既可以稳定并保护其免受 TRIM21 介导的泛素化。这些结果确定了 GBM 辐射抵抗的潜在机制，并提出了 GBM 治疗的潜在治疗策略。© 2023。作者，获得 Springer Nature Limited 的独家许可。

The molecular mechanism of glioblastoma (GBM) radiation resistance remains poorly understood. The aim of this study was to elucidate the potential role of Melanophilin (MLPH) O-GlcNAcylation and the specific mechanism through which it regulates GBM radiotherapy resistance. We found that MLPH was significantly upregulated in recurrent GBM tumor tissues after ionizing radiation (IR). MLPH induced radiotherapy resistance in GBM cells and xenotransplanted human tumors through regulating the NF-κB pathway. MLPH was O-GlcNAcylated at the conserved serine 510, and radiation-resistant GBM cells showed higher levels of O-GlcNAcylation of MLPH. O-GlcNAcylation of MLPH protected its protein stability and tripartite motif containing 21(TRIM21) was identified as an E3 ubiquitin ligase promoting MLPH degradation whose interaction with MLPH was affected by O-GlcNAcylation. Our data demonstrate that MLPH exerts regulatory functions in GBM radiation resistance by promoting the NF-κB signaling pathway and that O-GlcNAcylation of MLPH both stabilizes and protects it from TRIM21-mediated ubiquitination. These results identify a potential mechanism of GBM radiation resistance and suggest a potential therapeutic strategy for GBM treatment.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.