ZnO Nanoparticle Exposure Disrupted Iron–Sulfur Protein Functions to Increase Macrophage Erythrophagocytosis and Disturb Systemic Iron Recycling

Although anemia is a common systemic toxicological manifestation of zinc product overload, the underlying mechanisms remain elusive. Therefore, we explored the mechanisms underlying the anemia caused by exposure to zinc oxide nanoparticles (ZnO NPs), which are a widely utilized Zn product. We observed that ZnO NP-exposed mice developed evident anemia due to disrupted spleen iron metabolism. Since spleen iron metabolism relies on macrophages, we further investigated how ZnO NP exposure affected macrophage function. Results indicated that ZnO NP exposure triggered macrophage metabolic reprogramming to facilitate erythrophagocytosis and blunted the response of iron exporter ferroportin to enhanced erythrophagocytosis, thereby causing iron retention and ultimately impeding macrophage iron recycling. Mechanistically, Zn 2+ released from ZnO NPs occupied the cluster-binding cysteines of iron–sulfur proteins, regulating glucose metabolism and ferroportin expression to suppress their activity, thereby inducing metabolic reprogramming and suppressing iron export. Our research unveils a category of nanobio interactions underlying ZnO NPs biotoxicity.