Roles of m⁶A modification in regulating PPER pathway in cadmium-induced pancreatic β cell death

Cadmium can lead to the death of pancreatic β cells, thus affecting the synthesis and secretion of insulin. However, the specific mechanisms underlying the cadmium-induced pancreatic β cell death have not been fully understood. In this study, roles of m⁶A modification in regulating protein processing in endoplasmic reticulum (PPER) pathway in cadmium-induced pancreatic β cell death were explored. Our results demonstrated that cell viability and RNA m⁶A modification level were decreased, while apoptosis rates increased after CdSO₄ treatment in pancreatic β cells (NIT-1). In addition, expressions of Bcl-2, Xbp1, Col3a1, Bax, Chop, Dnajb1, and Hsp90aa1 were all significantly changed in CdSO₄ treatment cells. The m⁶A agonist entacapone (Ent) can prominently reverse the cytotoxicity effects of CdSO₄ and alleviate the changes of protein expression induced by CdSO₄ treatment. By contrast, m⁶A inhibitor 3-Deazaadenosine (DAA) can synergistically enhance the cytotoxicity of CdSO₄ and aggravate the disorder of protein levels caused by CdSO₄ treatment. Interestingly, the results of the immunoprecipitation experiment indicate that Ythdc2, one of m⁶A binding proteins, may regulate the PPER pathway molecules in an m⁶A-dependent manner. In summary, our findings provide new directions for the prevention and treatment of the impairment of pancreatic β cell function induced by cadmium.