Abstract
Arsenic is a common environmental pollutant, typically affecting the skin most severely. Recent studies have shown that arsenic's toxicity may be linked to N6-methyladenosine (m6A), an abundant and dynamic epigenetic RNA modification. However, it is not completely understood how m6A contributes to arsenite-induced skin lesions. Herein, it is shown that methyltransferase-like 3 (METTL3) plays a crucial role in the involvement of arsenite-induced skin lesions in an m6A-dependent manner. Using bioinformatic analysis and experimental approaches, we demonstrate that arsenite induces METTL3 upregulation, represses suppressors of cytokine signaling 3 (SOCS3) expression in an m6A- YTH m6A RNA binding protein 2 (YTHDF2)-dependent manner, and leads to the aberrant activation of the Janus kinase (JAK)2/signal transducer and activator of transcription 3(STAT3) signaling pathway. We further found that the activated transcription factor STAT3 binds to the promoter regions of Krt1 and Krt10, promoting their transcription, which ultimately leads to arsenite-induced skin lesions. In conclusion, our study reveals the role of m6A in arsenite-induced skin lesions through the activation of the JAK2/STAT3/Krt signaling axis. The findings provide new insight into the potential molecular mechanisms underlying arsenic toxicity regulation through m6A modification.