替莫唑胺（TMZ）是一种常用的烷化化学治疗药物，用于治疗脑肿瘤，如胶质母细胞瘤（GBM）和畸形星形胶质细胞瘤。GBM患者对该药物产生耐药性，其分子机制尚不清楚且复杂。竞争性内源性RNA（ceRNAs）在癌症的肿瘤发生、耐药性和复发中起着关键作用。本研究旨在预测ceRNAs，在TMZ抗药性中可能涉及的分子机制。因此，我们分析TMZ耐药GBM样本与敏感GBM样本中编码和非编码RNA表达水平，并对TMZ耐药样本中基因表达差异表达（DE）mRNAs进行通路分析。接下来，我们对950个DE长链非编码RNA（lncRNAs）、116个微小RNA（miRNAs）和7977个mRNAs应用数学模型，并获得10个与lncRNA关联的可能调控TMZ耐药GBM中与癌症相关通路相关的潜在靶基因，并通过吸附25个miRNAs来调控。其中，两个名为ARFRP1和RUSC2的lncRNAs调控了5个靶基因（IRS1，FOXG1，GNG2，RUNX2和CACNA1E），这些基因涉及AMPK、AKT、mTOR和TGF-β信号通路，激活或抑制自噬，导致TMZ耐药。在GBM中预测的新型lncRNA关联的ceRNA网络提供了对TMZ耐药性的新视角，可能有助于治疗这种恶性肿瘤。© 2023 John Wiley＆Sons Ltd.

Temozolomide (TMZ) is a common alkylating chemotherapeutic agent used to treat brain tumors such as glioblastoma multiforme (GBM) and anaplastic astrocytoma. GBM patients develop resistance to this drug, which has an unclear and complicated molecular mechanism. The competing endogenous RNAs (ceRNAs) play critical roles in tumorigenesis, drug resistance, and tumor recurrence in cancers. This study aims to predict ceRNAs, their possible involvement, and underlying molecular mechanisms in TMZ resistance. Therefore, we analyzed coding and non-coding RNA expression levels in TMZ-resistant GBM samples compared to sensitive GBM samples and performed pathway analysis of mRNAs differentially expressed (DE) in TMZ-resistant samples. We next applied a mathematical model on 950 DE long non-coding RNAs (lncRNAs), 116 microRNAs (miRNAs), and 7977 mRNAs and obtained 10 lncRNA-associated ceRNAs that may be regulating potential target genes involved in cancer-related pathways by sponging 25 miRNAs in TMZ-resistant GBM. Among these, two lncRNAs named ARFRP1 and RUSC2 regulate five target genes (IRS1, FOXG1, GNG2, RUNX2, and CACNA1E) involved in AMPK, AKT, mTOR, and TGF-β signaling pathways that activate or inhibit autophagy causing TMZ resistance. The novel lncRNA-associated ceRNA network predicted in GBM offers a fresh viewpoint on TMZ resistance, which might contribute to treating this malignancy.© 2023 John Wiley & Sons Ltd.