Iron-dependent ferroptosis participated in benzene-induced anemia of inflammation through IRP1-DHODH-ALOX12 axis

Benzene, a widely existing environmental pollutant, gives huge harm to the hematopoietic system. Iron is one of the raw materials for the creation of blood cells, but the role of iron in the blood toxicity of benzene is still unknown. Here, we examined the role of iron homeostasis in benzene-induced toxicity both in vivo and in vitro. In this study, mice exposed to benzene at 50 ppm for 8 weeks demonstrated the anemia of inflammation, mainly manifested as the decreased serum Fe²⁺, increased serum ferritin and inflammation factors (TNF-α, IL6, IL1β) in the plasma of mice. Furthermore, we found that iron maldistribution in the spleen and bone marrow is accompanied by inflammation reaction and ferroptosis. In the vitro study, benzene metabolite 1,4-BQ stimulated the obvious ROS production and ferroptosis activation in the normal B lymphocytes cells. Meanwhile, from the molecular perspective, the combined proteomics and transcriptome enriched the ferroptosis pathway, and we further confirmed the increased expression of iron regulator IRP1, ferroptosis-regulator DHODH, and fatty acids metabolism enzyme ALOX12 were the crucial participators in regulating benzene-mediated iron metabolism imbalance and ferroptosis. Particularly, the targeted and un-targeted metabolomics in the vivo and vitro study further emphasized the importance of DHODH in benzene-induced ferroptosis. In conclusion, this study revealed that iron-dependent ferroptosis participated in benzene-induced anemia of inflammation and provided a constructive perspective on targeting ferroptosis for the prevention and control of benzene toxicity.