YTHDF2 phase separation promotes arsenite-induced oxidative stress by facilitating YTHDF2-mediated PIK3R2 mRNA...

Oxidative stress is the major toxic mechanism of environmental pollutant arsenic, and elucidating the intracellular biomolecular interactions of arsenic-induced oxidative stress has been the focus of toxicology. Liquid-liquid phase separation (LLPS) of YTH N⁶-methyladenosine RNA-binding protein 2 (YTHDF2) may play a pivotal role in arsenic-induced oxidative stress. However, the mechanism of YTHDF2 phase separation is still poorly understood. In this study, we explored the function of YTHDF2 in arsenic-induced oxidative stress and the precise intermolecular interactions of YTHDF2 phase separation involved in arsenic-induced oxidative stress. The results showed that the level of YTHDF2 was increased in arsenic-induced oxidative stress in human keratinocytes (HaCaT cells), and knockdown of YTHDF2 significantly inhibited arsenic-induced oxidative stress, suggesting that YTHDF2 promoted arsenic-induced oxidative stress. Mechanistically, YTHDF2 was bound to the m⁶A-modified PIK3R2 mRNA (a key regulator of the PI3K-AKT signaling pathway) and underwent phase separation driven by m⁶A. YTHDF2 phase separation promoted YTHDF2-mediated degradation of PIK3R2 mRNA, thereby inhibiting the activity of the PI3K-AKT signaling pathway and ultimately leading to arsenite-induced oxidative stress. In conclusion, our study found that LLPS of YTHDF2 enhances arsenic-induced oxidative stress by facilitating YTHDF2-mediated degradation of m⁶A-modified PIK3R2 mRNA, which provides new insights into the mechanisms of arsenic toxicity.