N-methyladenosine promotes aberrant redox homeostasis required for arsenic carcinogenesis by controlling the adaptation of key antioxidant enzymes.

N-methyladenosine (mA), a high-profile RNA epigenetic modification, responds to oxidative stress and temporal-specifically mediates arsenic carcinogenesis. However, how mA affects aberrant redox homeostasis required for arsenic carcinogenesis is poorly understood. Here, we established arsenic-carcinogenic models of different stages, including As-treated, As-transformed, and As-tumorigenic cell models. We found that arsenic-induced reactive oxygen species (ROS) elevated mA levels, thus triggering mA-dependent antioxidant defenses. During arsenic-induced cell transformation, METTL3-upregulated mA on the mRNAs of SOD1, SOD2, CAT, TXN, and GPX1 promoted the mRNA translation and protein expressions of these antioxidant enzymes by increasing YTHDF1-mediated mRNA stability. Meanwhile, FTO-downregulated mA on PRDX5 mRNA increased PRDX5 translation and expression by reducing YTHDF2-mediated mRNA decay. After upregulated antioxidant defenses balanced with high levels of ROS induced by arsenic, the mA balance formed in mRNAs of six key antioxidant enzymes (SOD1, SOD2, CAT, TXN, GPX1, and PRDX5) and promoted high expressions of these antioxidant enzymes to maintain aberrant redox homeostasis. METTL3 inhibitor STM2457, FTO inhibitor FB23-2, or YTHDF1 knockdown disturbed the aberrant redox homeostasis by breaking the mA balance, causing cell death in arsenic-induced tumors. Our results demonstrated that mA promotes the formation and maintenance of aberrant redox homeostasis required for arsenic carcinogenesis by time-dependently orchestrating the adaptive expressions of six key mA-targeted antioxidant enzymes. This study advances our understanding of arsenic carcinogenicity from the novel aspect of mA-dependent adaptation to arsenic-induced oxidative stress.