N ⁶ -methyladenosine promotes temozolomide resistance through non-canonical regulation of mRNA stability in glioblastoma cells

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 canonical m ⁶ A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming temozolomide resistance in glioblastoma.