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Deoxynivalenol (DON) is the most common mycotoxin contaminant in food and feed. DON accumulation in food chain severely threatens human and animal health due to the toxic effects on the reproduction system. However, the underlying mechanism of DON on male reproductive dysfunction is still in debate and there is little information about whether DON triggers testicular ferroptosis. In this study, male C57BL/6 mice were divided into 4 groups and treated by oral gavage with 0, 0.5, 1.0, 2.0 mg/kg BW DON for 28 days. Firstly, we proved that male reproduction dysfunction was induced by DON through assessing testicular histopathology, serum testosterone level as well as blood-testis barrier integrity. Then, we verified ferroptosis occurred in DON-induced testicular dysfunction model through disrupting iron homeostasis, increasing lipid peroxidation and inhibiting system Xc - /Gpx4 axis. Notably, the present data showed DON reduced antioxidant capacity via blocking Nrf2 pathway to lead to the further weakness of ferroptosis resistance. Altogether, these results indicated that DON caused mice testicular ferroptosis associated with inhibiting Nrf2/System Xc-/GPx4 axis, which provided that maintaining testicular iron homeostasis and activating Nrf2 pathway may be a potential target for alleviating testicular toxicity of DON in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Iron is an important metal element involved in the regulation of male reproductive functions and has dual effects on testicular tissue. A moderate iron content is necessary to maintain testosterone synthesis and spermatogenesis. Iron overload can lead to male reproductive dysfunction by triggering testicular oxidative stress, lipid peroxidation, and even testicular ferroptosis. Ferroptosis is an iron-dependent form of cell death that is characterized by iron overload, lipid peroxidation, mitochondrial damage, and glutathione peroxidase depletion. This review summarizes the regulatory mechanism of ferroptosis and the research progress on testicular ferroptosis caused by endogenous and exogenous toxicants. The purpose of the present review is to provide a theoretical basis for the relationship between ferroptosis and male reproductive function. Some toxic substances or danger signals can cause male reproductive dysfunction by inducing testicular ferroptosis. It is crucial to deeply explore the testicular ferroptosis mechanism, which will help further elucidate the molecular mechanism of male reproductive dysfunction. It is worth noting that ferroptosis does not exist alone but rather coexists with other forms of cell death (such as apoptosis, necrosis, and autophagic death). Alleviating ferroptosis alone may not completely reverse male reproductive dysfunction caused by various risk factors.