Ferroptosis is involved in the benzene-induced hematotoxicity via mitochondrial ROS-ferritinophagy pathway.

Benzene, a common environmental contaminant that significantly impacts the hematopoietic system. Although benzene toxicity has been well documented, the exact molecular mechanisms involved remain unclear. This study aimed to explore the role of ferroptosis in benzene-induced hematotoxicity and uncover the underlying mechanisms. Rats exposed to benzene exhibited reduced peripheral blood cell counts, elevated serum iron concentrations, and increased expression of proteins associated with autophagy and ferroptosis within their bone marrow (BM) cells. In addition, inhibition of autophagy in benzene-exposed rats alleviated weight loss, peripheral blood cell abnormalities, iron dysregulation, and ferroptosis signaling activation. To further investigate the cellular mechanisms, we conducted in vitro experiments in which the benzene metabolite hydroquinone (HQ) was found to elicit ferroptosis and disrupt autophagy functionality in JHP cells. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) alleviated these adverse effects. Additionally, HQ induced damage to mitochondria in JHP cells, as evidenced by a decline in mitochondrial membrane potential (MMP) and an increase in mitochondrial reactive oxygen species (mtROS). Collectively, our results demonstrate that mtROS-dependent autophagy participates in ferroptosis induced by benzene, providing a significant theoretical foundation for the pathogenesis and potential interventions underlying benzene-induced hematotoxicity.