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RNA methylation is a prevalent post-transcriptional modification that regulates the splicing, stability, and translation of coding and non-coding RNAs, playing a critical role in tumor progression. Hypoxia/hypoxia-inducible factor 1α (HIF-1α) signaling and long noncoding RNAs (lncRNAs) participate in epigenetic regulation and tumor progression; however, the underlying mechanisms and roles of hypoxia/HIF-1α-induced methylation of specific RNAs/lncRNAs in tumorigenesis remain poorly understood. Our study revealed that hypoxia significantly induces 2′-O-methyladenosine (A_m) modification of total RNA, including a novel oncogenic lncRNA, MAHAC. A_m modification of MAHAC enhanced its interaction with a chromatin-modifying complex, increased RNA stability, and facilitated tumor progression. Notably, METTL25 was identified as a putative RNA methyltransferase (writer) associated with A_m modification. We aim to further investigate the role and molecular mechanisms underlying METTL25-mediated A_m modification of total RNA and MAHAC in epigenetic regulation and hypoxia-induced tumor progression. The biological functions and regulatory roles of METTL25 and A_m-modified RNAs will be evaluated, providing valuable insights into the fields of epigenetics and oncology. These findings may inform future strategies for tumor prognosis, prevention, diagnosis, and treatment.