放射治疗是食管鳞状细胞癌（ESCC）的主要治疗方式，但由于癌细胞对放射线的抵抗力，其疗效仍然受到限制。长链非编码 RNA (lncRNA) 和 N6-甲基腺苷 (m6A) 已被证明在肿瘤放射抗性中发挥重要作用。然而，m6A修饰的lncRNA在ESCC放射抵抗中的确切表现和作用仍不清楚。通过生物信息学分析来鉴定与ESCC放射抵抗有关的m6A修饰的lncRNA。进行了一系列功能实验来研究 LNCAROD 在 ESCC 中的功能。通过甲基化RNA免疫沉淀、RNA纯化-质谱法分离染色质、RNA免疫沉淀和免疫共沉淀实验，探讨m6A介导的LNCAROD表达上调的机制以及增强ESCC放射抗性的下游机制。使用小鼠异种移植模型评估 LNCAROD 的体内功效。在此，我们将 LNCAROD 鉴定为一种新型 METTL3 介导的 lncRNA，可增强 ESCC 细胞的放射抗性，并由 YTHDC1 进行转录后稳定。此外，我们证实LNCAROD通过促进PARP1-NPM1相互作用来阻止PARP1蛋白的泛素蛋白酶体降解，从而有助于同源重组介导的DNA双链断裂修复并增强ESCC细胞的抗辐射能力。在体内 ESCC 裸鼠模型中沉默 LNCAROD 会导致肿瘤生长减慢并增加放射敏感性。我们的研究结果增强了对 ESCC 放射抗性中 m6A 修饰的 lncRNA 驱动机制的理解，并强调了 LNCAROD 在此背景下的重要性，从而有助于为 ESCC 患者开发潜在的治疗靶点。© 2024 作者。约翰·威利出版的《临床与转化医学》

Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of cancer cells to radiation. Long non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A-modified lncRNAs in ESCC radioresistance remain unclear.Bioinformatics analysis was conducted to identify m6A-modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification-mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation experiments were performed to explore the mechanism of m6A-mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models.Herein, we identified LNCAROD as a novel METTL3-mediated lncRNA that enhanced radioresistance in ESCC cells and was post-transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin-proteasome degradation of PARP1 protein by facilitating PARP1-NPM1 interaction, thereby contributing to homologous recombination-mediated DNA double-strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity.Our findings enhance the understanding of m6A-modified lncRNA-driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.