Ferroptosis in viral infection: the unexplored possibility

Virus-induced cell death has long been thought of as a double-edged sword in the inhibition or exacerbation of viral infections. The vital role of iron, an essential element for various enzymes in the maintenance of cellular physiology and efficient viral replication, places it at the crossroads and makes it a micronutrient of competition between the viruses and the host. Viruses can interrupt iron uptake and the antioxidant response system, while others can utilize iron transporter proteins as receptors. Interestingly, the unavailability of iron facilitates certain viral infections and causes cell death characterized by lipid peroxide accumulation and malfunction of the antioxidant system. In this review, we discuss how iron uptake, regulation and metabolism, including the redistribution of iron in the host defense system during viral infection, can induce ferroptosis. Fenton reactions, a central characteristic of ferroptosis, are caused by the increased iron content in the cell. Therefore, viral infections that increase cellular iron content or intestinal iron absorption are likely to cause ferroptosis. In addition, we discuss the hijacking of the iron regulatoy pathway and the antioxidant response, both of which are typical in viral infections. Understanding the potential signaling mechanisms of ferroptosis in viral infections will aid in the development of new therapeutic agents.