Ferroptosis in viral infection: the unexplored possibility

Abstract

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.

Mitochondria-mediated oxidative stress during viral infection

“…involving mitochondria and lipid peroxidation. Whether and how viruses interfere with, and manipulate, this pathway remains to be investigated [98].…”

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

“…These agents are potential COVID-19 treatments, while their inhibitors have been studied as ferroptosis inducers in cancer cells ( Subburayan et al, 2020 ; Yang and Lai, 2020 ). Moreover, Fer-1 and Lip-1 have been evaluated for efficacy against viral infections and neurodegeneration ( Chen K. et al, 2021 ; Wang et al, 2021 ).…”

Revisiting Regulated Cell Death Responses in Viral Infections

“…However, the inhibition of this antioxidant activity results in loss of control over lipid peroxidation which in turn facilitates ferroptosis. Apart from this, the increased Fe uptake or/and inhibition of Fe export promotes ferroptosis by increasing the free Fe content in the cell [12].…”

“…In this view, viruses have evolved strategies to interfere with the host cell ferroptosis for their own benefits, such as an interruption of host cell Fe uptake and the suppression of the host antioxidant response system. Apart from this, some viruses can also utilize host Fe transporters as viral receptors to enter the host cell thus promoting viral infections by promoting ferroptosis [12].…”

“…There are many types of RCD reported so far, and they can be either non-inflammatory or pro-inflammatory [10,11]. Lesser-known non-apoptotic RCD associated with viral infection are ferroptosis, parthanatos [12,13], entosis [14], mitochondrial permeability transition (MPT)-dependent necrosis, pyroptosis, pyronecrosis [15,16] and anoikis [17]. NETosis or Etosis (neutrophil extracellular traps formation) plays a crucial role in host immune responses, where neutrophil granulocytes are activated through immune regulatory functions such as (i) phagocytosis, (ii) formation of reactive oxygen species (ROS), (iii) degranulation, and (iv) generation of neutrophil extracellular traps (NETs) [18][19][20], alkaliptosis (a pH-dependent form of regulated non-apoptotic cell death) [21], and oxeiptosis (ROS-induced caspase-independent apoptosis) [22,23].…”