Background: Fe 3 O 4 nanoparticles (NPs, also known as iron oxide NPs; IONPs) have high biocompatibility and low biotoxicity. They are widely used in the eld of biotechnology for targeted delivery, image formation, and photothermal therapy. NP biodistribution is determined by macrophage capture in vivo, and recently, the induction of macrophage polarization into the M1 phenotype by IONPs has become a hot topic in research. Previous research has shown that IONPs can induce ferroptosis of ovarian cancer cells and ischemic cardiomyocytes. In this study, we exposed macrophages to synthesized Fe 3 O 4 NPs (100 nm in diameter) and determined the effects of NPs in inducing cell death by RNA sequencing.Results: We observed that after 48 h exposure to NPs, there was a change in the macrophage phenotype and a reduction in cell viability. Then, we demonstrated that NPs could induce macrophage cell damage by increasing intracellular reactive oxygen species and by repressing the mitochondrial membrane potential. Furthermore, we investigated the underlying mechanisms of ferroptosis of macrophages using RNA sequencing and change in ultrastructural morphology, and found that ferroptosis was caused by the upregulation of p53 expression and inhibition of SLC7A11 expression, as their protein levels after 48 h exposure to Fe 3 O 4 NPs were consistent with erastin-induced ferroptosis.Conclusions: These results provide an insight into the molecular mechanisms underlying ferroptosis induced by Fe 3 O 4 NPs in macrophages and provide a basis for the biotoxicity study of Fe 3 O 4 NPs in vivo.

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