Arsenic inducible islet β-cell dysfunction and ferroptosis through m⁶A-YTHDF2-dependent CHAC1 enhancement

Area of Science:

• Environmental toxicology
• Molecular biology
• Endocrinology

Background:

• Arsenic is an environmental contaminant linked to type 2 diabetes (T2D) by causing islet beta-cell dysfunction.
• Ferroptosis, a cell death pathway regulated by GPX4, is implicated in arsenic-induced beta-cell damage, but mechanisms are unclear.
• Glutathione levels critically influence GPX4 activity and ferroptosis.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying arsenic-induced beta-cell dysfunction and ferroptosis.
• To investigate the role of CHAC1 and N6-methyladenosine (m6A) modification in this process.
• To identify potential therapeutic targets for arsenic-related T2D.

Main Methods:

• Assessed arsenic's effect on GPX4, CHAC1, and GCLC expression in vivo and in vitro.
• Utilized CHAC1 knockdown and METTL3 overexpression to evaluate their impact on beta-cell function and ferroptosis.
• Identified m6A modification sites on CHAC1 and analyzed interactions using RIP assays.
• Measured CHAC1 mRNA half-life following METTL3 overexpression.

Main Results:

• Arsenic upregulates CHAC1 (>2-fold in vivo, 1.5-fold in vitro) and downregulates GPX4 expression, inhibiting glutathione-dependent ferroptosis.
• CHAC1 knockdown ameliorated arsenic-induced beta-cell dysfunction and ferroptosis.
• Arsenic treatment decreased METTL3/14 expression (~0.5-fold), while METTL3 overexpression protected beta-cells.
• METTL3 overexpression reduced CHAC1 mRNA half-life (~0.5-fold) by inhibiting METTL3/YTHDF2 interaction with CHAC1 mRNA.

Conclusions:

• Arsenic induces beta-cell dysfunction and ferroptosis by upregulating CHAC1 expression through inhibition of m6A modification mediated by METTL3.
• This study reveals a novel m6A-CHAC1-ferroptosis pathway in arsenic toxicity.
• Targeting the m6A pathway, particularly METTL3, offers a potential therapeutic strategy for T2D caused by arsenic exposure.