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