Implications of ferroptosis in silver nanoparticle-induced cytotoxicity of macrophages

Metal nanoparticles (NPs) are widely used in daily life and commercial activities owing to their unique physicochemical properties. Consequently, there is an increasing risk of daily and occupational exposure to metal NPs, which raises concerns regarding their health hazards. Programmed cell deaths (PCDs) have been clarified to be involved in metal NP-induced cytotoxicity, including apoptosis, autophagy, and pyroptosis. However, whether and how ferroptosis, a newly recognized PCD, contributes to metal NP-induced cell death remain unclear. In this study, we investigated the ferroptotic effects of two representative metal NPs, silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs), on macrophages in vitro. Our results revealed that AgNPs, rather than AuNPs, induced non-apoptotic PCD, accompanied by lipid peroxidation and iron homeostasis disorders, which are two hallmarks of ferroptosis, in macrophages. Treatment with a ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine) reversed AgNP-induced PCD, corroborating the induction of ferroptosis upon exposure to AgNPs. Moreover, our results revealed that smaller AgNPs elicited greater ferroptotic effects on macrophages than larger ones. Importantly, ferroptosis in AgNP-treated macrophages was mainly triggered by AgNPs per se rather than by Ag ions. Overall, our study highlights the ferroptotic effects elicited by AgNPs in macrophages, which will promote the understanding of their cytotoxic effects and facilitate the safer design of metal nanoproducts.