N6-methyladenosine mediated-NRF2 signaling pathway attenuates cadmium cytotoxicity by inhibiting oxidative damage in bronchial epithelial cells.

Abstract

Although N⁶-methyladenosine (m⁶A) and its regulatory proteins were involved in multiple cellular damage processes, the roles of m⁶A and its regulatory proteins in cadmium-induced pulmonary cell damage remain largely unknown. Our present data indicated that cadmium exposure caused serious damage in bronchial epithelial cells, as evidenced by reduction of cell viability and elevation of oxidative damage and apoptosis. These processes were accompanied by alterations of m⁶A modification and its regulatory proteins (FTO, ALKBH5, YTHDC2). It is noteworthy that pretreatment with the m⁶A agonist entacapone (ENT) markedly attenuated the detrimental effects of cadmium, including cell death, oxidative damage, and the activation of the nuclear factor erythroid 2-related factor 2 (NRF2）signalling pathway. Conversely, the detrimental effects of CdSO₄ were significantly exacerbated when m⁶A levels were inhibited by 3-deazidyladenosine (DAA). Further prediction result revealed that multiple m⁶A-modified sites occur on NRF2 mRNA with high confidence level, implicating that m⁶A modification on NRF2 mRNA may affect the protein expression of NRF2. In conclusion, our data together suggest that m⁶A modification play critical roles in cadmium-induced bronchial epithelial cell damage, during which NRF2 signaling pathway may act as an important bridge for m⁶A modification to regulate cellular damage. This study offer a promising avenue for further investigation into the mechanisms underlying cadmium-induced bronchial epithelial cell damage from the perspective of RNA epigenetics.