{"doi":"10.1101/2025.09.14.676126","title":"<i>N</i> <sup>6</sup> -methyladenosine promotes temozolomide resistance through mRNA stabilization in glioblastoma cells","abstract":"ABSTRACT N 6 -methyladenosine (m 6 A) is a critical regulator of mRNA processing and function, impacting nearly every step of the mRNA lifecycle. Changes in m 6 A status have been implicated in many different types of cancer, including glioblastoma where acquired resistance to temozolomide remains a major clinical challenge. We established glioblastoma cell culture models of acquired temozolomide resistance and analyzed the role of m 6 A in controlling resistance-associated pathways. We show that m 6 A stabilizes key genes and pathways promoting temozolomide resistance in glioblastoma, including MGMT , the enzyme that repairs primary temzolomide-induced DNA damage, and PI3K/Akt signaling, a major driver of chemoresistance. Pharmacological inhibition of the m 6 A methyltransferase METTL3 destabilizes MGMT and other critical mRNAs, restoring temozolomide sensitivity. Collectively, our results suggest that genes associated with temozolomide resistance are stabilized by m 6 A methylation, even as the majority of the transcriptome remains subject to m 6 A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming temozolomide resistance in glioblastoma.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574908,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9459,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":257385,"name":"Dorthy Fang","orcid":null,"position":1,"is_corresponding":false},{"id":1472936,"name":"Kyal Sin Htet","orcid":null,"position":2,"is_corresponding":false},{"id":1472937,"name":"Nicole S. Harry","orcid":null,"position":3,"is_corresponding":false},{"id":1482930,"name":"R. R. Pascoe","orcid":null,"position":4,"is_corresponding":false},{"id":1482532,"name":"Jiapeng Yang","orcid":"0009-0005-9856-2814","position":5,"is_corresponding":false},{"id":348288,"name":"Clara D. Wang","orcid":"0000-0002-7522-1719","position":6,"is_corresponding":false},{"id":87804,"name":"Sigrid Nachtergaele","orcid":"0000-0003-0231-580X","position":7,"is_corresponding":false},{"id":276006,"name":"Emily Dangelmaier","orcid":"0000-0002-4698-2500","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T02:57:44.572630Z","pmid":"41000782","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}