p53 Promotes Ferroptosis in Macrophages Treated with Fe₃O₄ Nanoparticles

Abstract

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.

Surface-Charge-Driven Ferroptosis and Mitochondrial Dysfunction Is Involved in Toxicity Diversity in the Marine Bivalve Exposed to Nanoplastics

“…27,36 While ferroptosis and mitochondrial dysfunction are not directly correlated, mitochondrial dysfunction can lead to cellular conditions that favor ferroptosis. 25,27 The proteomics-based protein−protein interaction (PPI) network highlighted glycogen phosphorylase protein as critical in the metabolic processes induced by p-NPs (Figure 3f). In the n-NP group, proteins with the highest centrality were the upstream in-frame stop codon and glyceraldehyde-3-phosphate dehydrogenase, indicating their pivotal role in maintaining system balance in n-NP- treated bivalves (Figure 3g and Figure S6c, and Data Set S6).…”

“…Generally, a decrease in the GSH/GSSG ratio and an increase in Fe 2+ indicate ferroptosis. 25,27,56 Lipid peroxidation (LPO), known to harm cell membranes, lipoproteins, and other lipid-containing structures, is a direct consequence of the overaccumulation of ROS (Figure 5f and Figure S7d), and the core feature of ferroptosis. 57,58 In cells exposed to p-NPs (especially ≥5.4 × 10 10 particles/mL), there was a noticeable increase in the number of lipid droplets (Figure 5g and Figure S7e).…”

Nanoparticles‐induced potential toxicity on human health: Applications, toxicity mechanisms, and evaluation models

“…that PS microplastics trigger mitochondrial damage and apoptosis through ROS‐driven calcium overload. Wu et al 247 . showed that Fe 3 O 4 ‐NPs can cause mitochondrial damage and reduce macrophage viability after 48 h treatment, inducing a shift of macrophage polarization to the M1 phenotype.…”

“…This is consistent with the study by Li et al 246 that PS microplastics trigger mitochondrial damage and apoptosis through ROS-driven calcium overload. Wu et al 247 showed that Fe 3 O 4 -NPs can cause mitochondrial damage and reduce macrophage viability after 48 h treatment, inducing a shift of macrophage polarization to the M1 phenotype. It has been reported that SiO 2 -NPs can induce MMP depolarization in cardiomyocytes and reduce ATP production, resulting in Ca 2+ damage.…”

Versatile Switchable Targeted Polysiloxanes for High-Resolution Visualization of Mitochondrial and Lysosomal Interactions during Ferroptosis

“…However, there is a distinct lack of research on the full range of ONOO – fluctuations in mitochondria and lysosomes during ferroptosis. The impact of ONOO – fluctuations on mitochondrial and lysosomal interactions is also rare. ,, To fill this gap, high-precision fluorescent probes with flexible targeting capabilities should be developed to observe ONOO – and mitochondrial–lysosomal interactions during ferroptosis. − The study of these cellular physiological processes will contribute to understanding the pathogenesis of the disease, meanwhile optimizing the therapeutic and interventional measurements for the disease. − …”