m⁶A-Methylated Taurine Transporter SLC6A6 Promotes Arsenic-Induced Malignant Transformation of Keratinocytes while Enhancing Sensitivity to Cuproptosis

Despite extensive studies on arsenic's carcinogenic effects, the epigenetic mechanisms underlying arsenic-induced malignant transformation at the metabolic level remain poorly understood. In this study, we explored epitranscriptomic-driven metabolic reprogramming using keratinocyte transformation models established by environmentally relevant arsenite exposure. Our results identified an elevated intracellular taurine concentration as a metabolic reprogramming hallmark of arsenite-induced transformation of keratinocytes, which was validated in mouse models and human samples. Upregulated taurine transporter SLC6A6 facilitated taurine uptake, promoting the arsenic-induced transformation. Mechanically, SLC6A6-mediated taurine uptake enhanced oxidative phosphorylation by upregulating mitochondrial cytochrome <i>c</i> oxidase II (MT-CO2), supporting the energy requirements of the arsenic-induced transformation. Notably, this taurine uptake also enhanced MT-CO2-dependent copper utilization, thereby sensitizing arsenite-transformed keratinocytes to copper-dependent and oxidative-phosphorylation-driven metabolic cell death, known as cuproptosis. Furthermore, <i>N</i>⁶-methyladenosine (m⁶A) methyltransferase METTL3 catalyzed m⁶A modifications at multiple sites on SLC6A6 mRNA, promoting the stability and translation of SLC6A6 mRNA by recruiting m⁶A binding protein YTHDF1 during arsenite-induced transformation. In conclusion, our results suggest that taurine uptake, mediated by m⁶A-methylated SLC6A6, promotes arsenite-induced malignant transformation while enhancing sensitivity to cuproptosis in arsenite-transformed keratinocytes. This study reveals novel RNA epigenetic mechanisms driving arsenic-induced transformation through metabolic reprogramming, offering valuable insights for environmental health risk assessment and potential intervention strategies.