Arsenic inducible islet β-cell dysfunction and ferroptosis through mA-YTHDF2-dependent CHAC1 enhancement.

Arsenic, recognized as an environmental and food contaminant, has been linked to the dysfunction of islet β-cells, the primary lesions in type 2 diabetes (T2D). Ferroptosis, a regulated cell death pathway dependent on GPX4, has been implicated in arsenic-induced β-cell dysfunction. However, the underlying molecular mechanisms remain unclear. GPX4 activity is significantly modulated by glutathione levels. In this study, we demonstrate that arsenic inhibits GPX4 expression by upregulating the expression of glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) (>2-fold in vivo and 1.5-fold in vitro). Conversely, arsenic does not affect the expression of the glutathione-cysteine ligase catalytic subunit (GCLC), which is crucial for glutathione synthesis. Notably, CHAC1 knockdown significantly ameliorated arsenic-induced β-cell dysfunction and ferroptosis. N6-methyladenosine (mA) plays a crucial role in the post-transcriptional modification of mRNA. Arsenic treatment downregulated the expression of methyltransferases METTL3/14 (approximately 0.5-fold), and overexpression of METTL3 alleviated arsenic-induced β-cell dysfunction and ferroptosis. The mA modification site on CHAC1 was identified, and RIP assays confirmed that arsenic treatment inhibited the interaction between METTL3/YTHDF2 and CHAC1. Furthermore, METTL3 overexpression reduced the half-life of CHAC1 mRNA (almost 0.5-fold). This study uncovers a novel mechanism by which arsenic modulates CHAC1 and ferroptosis through mA in β-cell dysfunction, highlighting potential therapeutic targets for arsenic-related T2D.