Gold nanoparticles (AuNPs) have been widely used in biomedical field due to their unique physical and chemical properties, and thus caused increased potential human health risks. However, at present, the toxic effect and related mechanisms of AuNPs are still largely unknown, especially their neurotoxicity risk were long-term underestimated. In this work, we found that AuNPs treatment induced the quiescence of neural stem cells (NSCs) by upregulating the expression of inhibitors of DNA binding/differentiation proteins 4 (ID4) in a size-effect dependent manner. Further mechanism analysis showed that AuNPs treatment enhanced the N6-methyladenosine (m6A) modification and thereafter mRNA stability of ID4 via downregulating the expression of demethylase ALKBH5, leading to increased ID4 expression in an m6A reader IGF2BP3 dependent manner and subsequent NSCs quiescence. In summary, our findings demonstrated that m6A modification-dependent ID4 upregulation was indispensable for NSCs quiescence and neurotoxicity induced by low-dose AuNPs, which provide a novel insight for recognizing the health risk of AuNPs and a new strategy for preventing AuNPs-induced disorder of stem cell development.

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