Abstract

Ferroptosis, characterized by lipid peroxidation and iron-dependent oxidative damage, is a crucial factor in various diseases. Although researchers have extensively characterized ferroptosis in cancer and neurodegenerative disorders, its interaction with pathogenic infections remains underexplored. Recent research indicates that ferroptosis contributes to host cell damage during pathogen invasions, impacting disease outcomes. This review summarizes the characteristics, mechanisms, and regulatory networks of ferroptosis. It delineates the key regulatory steps of ferroptosis during infections caused by various pathogens, including viruses, bacteria, fungi, and parasites. Additionally, it examines changes in host markers and related signaling pathways. Furthermore, this review explores the potential similarities and differences among these pathogens and discusses therapeutic strategies for addressing pathogen-related diseases through ferroptosis-dependent mechanisms.

1 Introduction

Ferroptosis, an identified form of regulated cell death, has garnered significant attention due to its distinctive molecular mechanisms and implications in various diseases. Unlike conventional cell death pathways such as necrosis and apoptosis, ferroptosis has distinctive features. It is characterized by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS) (Dixon et al., 2012; Zheng and Conrad, 2025). While its molecular mechanisms remain incompletely understood, ferroptosis plays a critical role in disease pathogenesis, including cancer, neurodegenerative disorders, and ischemia-reperfusion injury (Dixon et al., 2012).

Despite substantial progress in elucidating the role of ferroptosis in disease, its interplay with pathogen infections has been relatively understudied. However, emerging evidence indicates a critical relationship between ferroptosis and host cell damage during pathogen invasions. Pathogens and the host immune response collectively dysregulate intracellular iron metabolism and ROS levels, ultimately leading to membrane damage via lipid peroxidation (Amaral and Namasivayam, 2021). This intricate relationship highlights ferroptosis as a key mechanism in infection-related pathogenesis.

In this review, we present a comprehensive overview of ferroptosis in pathogen-related infections, discussing its implications for disease progression and treatment. Specifically, we examine the similarities and differences in ferroptosis mechanisms across various pathogens, highlighting how these distinctions can inform future therapeutic strategies and related clinical challenges. Ultimately, we aim to provide insights into the therapeutic potential of ferroptosis-targeted strategies in infectious disease management.

2 Overview of ferroptosis

Ferroptosis, first identified in 2003 and formally named in 2012, is a distinct form of regulated cell death characterized by unique morphological, biochemical, and genetic features (Dixon et al., 2012; Dolma et al., 2003). Morphologically, ferroptosis presents with mitochondrial abnormalities, including shrinkage, increased membrane density, cristae loss, and plasma membrane rupture. Biochemically, ferroptosis depends on two key processes. ROS accumulation occurs primarily through ferrous iron (Fe2+)-mediated Fenton reactions. Additionally, enzymatic peroxidation of membrane polyunsaturated fatty acids (PUFAs) produces cytotoxic lipid peroxides. Together, these processes cause progressive membrane damage. Genetically, ferroptosis is associated with altered expression of key genes, such as glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and prostaglandin-endoperoxide synthase 2 (PTGS2). However, definitive molecular markers for ferroptosis remain elusive (Shen et al., 2025; Stockwell, 2022; Tang et al., 2021; Xiao et al., 2025a; Xiao et al., 2025a; Xiao et al., 2025b).

Cells employ various mechanisms to counter excessive lipid peroxides and prevent ferroptosis. Four main pathways have been identified:

The SLC7A11-GPX4 pathway: Active in both cytoplasm and mitochondria, this pathway relies on GPX4 to maintain cellular redox balance (Huang et al., 2025). Inhibition of GPX4 reduces intracellular glutathione (GSH) levels, disrupting redox balance and inducing lipid peroxide accumulation, thus triggering ferroptosis. Classic ferroptosis inducers like Erastin inhibit the amino acid transporter solute carrier family 7 member 11 (SLC7A11), thereby suppressing GPX4 levels. In addition, (1S,3R)-RSL3 (RSL3) directly inhibits GPX4, leading to decreased GSH levels. Recent studies indicate that peroxiredoxin 3 (PRDX3), a mitochondrial peroxidase, translocates to the cell membrane after peroxidation modification, potentially inducing ferroptosis by inhibiting cystine uptake (Cui et al., 2023; Yang et al., 2014). Furthermore, various pathogens have been shown to regulate ferroptosis through this pathway, including viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Liu et al., 2023b; Sun et al., 2025), hepatitis B virus (HBV) (Wang et al., 2023c), Epstein-Barr virus (EBV) (Yuan et al., 2022), rotavirus (RV), and highly pathogenic avian influenza A virus subtype H5N1 (H5N1) and pandemic influenza A virus subtype H1N1(H1N1) (Wei et al., 2024; Zhou et al., 2024a), and Japanese encephalitis virus (JEV) (Zhu et al., 2024). Additionally, bacteria including Pseudomonas aeruginosa (P. aeruginosa) (Dar et al., 2021), Staphylococcus aureus (S. aureus) (Hu et al., 2023a), and Mycobacterium tuberculosis (M. tuberculosis) (Ma et al., 2022a) modulate ferroptosis via this pathway.

The FSP1-CoQH2 antioxidant pathway: Located on the cell membrane, this pathway involves ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria-associated 2 (AIFM2). FSP1 employs nicotinamide adenine dinucleotide phosphate (NADPH) to produce reduced coenzyme Q10 (CoQ10), which degrades lipid peroxides on the cell membrane and prevents ferroptosis (Doll et al., 2019). Under certain conditions, FSP1 can also inhibit ferroptosis by activating membrane repair mediated by the endosomal sorting complex required for transport III (ESCRT-III).

The DHODH-CoQH2 pathway: Located within the inner mitochondrial membrane, this pathway involves dihydroorotate dehydrogenase (DHODH), which reduces coenzyme Q (CoQ) to coenzyme QH2 (CoQH2) when intracellular GPX4 levels decrease. CoQH2, an antioxidant, captures ROS and thus inhibits ferroptosis (Mao et al., 2021).

The GCH1-BH4 pathway: This pathway involves tetrahydrobiopterin (BH4) biosynthesized by guanosine triphosphate (GTP) cyclohydrolase-1 (GCH1). BH4 induces lipid remodeling and selectively inhibits phospholipid consumption at the tail ends of polyunsaturated fatty acids to suppress ferroptosis.

The FSP1-CoQH2, DHODH-CoQH2, and GCH1-BH4 pathways all converge on suppressing lipid peroxidation through the production of antioxidant metabolites. Currently, no pathogen-related associations have been reported for these three pathways. Recent studies have identified membrane-bound O-acyltransferase domain-containing 1/2 (MBOAT1/2) as novel ferroptosis suppressors. Regulated by the estrogen receptor and androgen receptor, respectively, MBOAT1/2 suppress ferroptosis by modifying phospholipids, presenting a distinct regulatory mechanism independent of GPX4 or FSP1 (Liang et al., 2023).

3 The role of ferroptosis in diseases

Ferroptosis plays a significant role in various diseases, particularly cancer, influencing both its occurrence and progression (Figure 1). Its involvement in tumor development and treatment is complex, influenced by oncogenes, tumor suppressors, and the tumor microenvironment (Xia et al., 2025; Xu et al., 2025). For example, in a K-ras-induced mouse model of lung cancer, knockout of RNA binding motif single-stranded interacting protein 1 (RBMS1) substantially suppresses lung cancer progression by inducing ferroptosis (Zhang et al., 2021). Additionally, under hypoxic conditions, hypoxia inducible factor 1 subunit alpha (HIF-1α) upregulates solute carrier family 1 member 1 (SLC1A1) to drive solid tumor resistance to ferroptosis. Concurrently, HIF-1α-driven lactate accumulation via lactate dehydrogenase A (LDHA) further enhances this resistance (Yang et al., 2023). Exploiting the high metabolic capacity of tumor cells, certain chemotherapeutic drugs like sorafenib and sulfasalazine induce ferroptosis in various cancer types. For example, melanoma cells resistant to targeted kinase inhibitors and immunotherapy become sensitive to ferroptosis, thereby enhancing the efficacy of targeted and immune therapies (Tsoi et al., 2018). In a pancreatic cancer mouse model, the small molecule N6-furfuryl adenine 11 (N6F11) selectively triggers GPX4 degradation in tumor cells, inducing ferroptosis. This process subsequently initiates high mobility group box 1 (HMGB1)-dependent anti-tumor immunity mediated by CD8+ T cells (Li et al., 2023a).

Ferroptosis in various human diseases. Ferroptosis has played important roles in multiple system diseases, such as lung diseases, nervous system diseases, breast -related diseases, liver diseases, pancreatic diseases, intestinal diseases, reproductive diseases, musculoskeletal system diseases. Created by Figdraw.

Beyond cancer, mounting evidence suggests that iron dysregulation, oxidative stress, and GPX4 suppression are key features of ferroptosis in neurodegenerative diseases and cognitive impairments. Ferroptosis plays a crucial role in the occurrence and progression of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and stroke (Dang et al., 2022). For instance, iron overload can trigger ferroptosis in microglia via the vesicle transport gene SEC24 homolog B (SEC24B), leading to neurodegenerative changes (Ryan et al., 2023).

Infectious pathogens often trigger oxidative stress responses in host cells, which can either facilitate pathogen infection or counteract it by promoting host cell death to halt infection progression. Iron ions are vital for cellular physiology and are particularly important during pathogen infections, placing iron at a critical nexus of host-pathogen interactions, where it serves as a key determinant of micronutrient competition between pathogens and hosts. To date, at least 50 pathogen-associated infections have been linked to ferroptosis.

In 2002, Barluzzi et al. reported that iron overload worsens Cryptococcus neoformans (C. neoformans)-induced meningoencephalitis. However, as the concept of ferroptosis had yet to be established, a definitive connection could not be drawn (Barluzzi et al., 2002). In July 2018, Bogacz et al. suggested that deficiency in Trypanosoma cruzi tryparedoxin peroxidase results in lethal iron-dependent lipid peroxidation, leading to ferroptosis, with mitochondrial iron playing a pivotal role. Later that year, in November, Dar et al. found that Pseudomonas aeruginosa induces bronchial epithelial cell ferroptosis by exploiting host polyunsaturated phospholipids (Bogacz and Krauth-Siegel, 2018; Dar et al., 2018). These studies marked the beginning of research into the relationship between ferroptosis and pathogen infection. In 2020, Kuo et al. demonstrated that emodin inhibits hepatic stellate cell activation by hepatitis B virus X protein (HBx) through endoplasmic reticulum stress and ferroptosis pathways, thereby suppressing liver fibrosis and introducing ferroptosis into virus research (Kuo et al., 2020).

4 The role of ferroptosis in infection4.1 Ferroptosis in viral infections

The interaction between viral infection and ferroptosis is complex and multifaceted. Iron, crucial for cellular enzymes, maintains cell function and supports viral replication. Viruses can alter cellular iron metabolism by disrupting iron uptake mechanisms or by exploiting iron transport proteins as viral receptors. While virus-induced ferroptosis can limit the spread of infection within the host, some viruses have evolved to exploit this pathway to facilitate their own proliferation and evade immune surveillance. As previously described, ferroptosis hinges on elevated iron levels and lipid peroxide accumulation, countered by antioxidants like GPX4 and GSH. Investigating iron metabolism during viral infection, alongside ferroptosis regulatory mechanisms, can deepen our understanding of viral pathophysiology and provide new therapeutic insights.

4.1.1 Hepatitis viruses

Hepatitis viruses, including hepatitis A virus (HAV), HBV, and hepatitis C virus (HCV), cause liver inflammation and damage, leading to acute or chronic hepatitis. Severe cases can result in liver cirrhosis, cancer, or death. These viruses influence ferroptosis in complex ways, impacting cellular and organ function (Figure 2). For instance, the HBx protein, a key regulator of viral infection and replication, is also linked to hepatocellular carcinoma (HCC). Deng et al. revealed that HBx induces protein arginine methyltransferase 9 (PRMT9) expression in HCC cells. PRMT9 then targets heat shock protein family A member 8 (HSPA8) and enhances arginine methylation at residues R76 and R100. The resulting elevation in HSPA8 upregulates CD44 expression, collectively suppressing ferroptosis in HBV-associated hepatic cancer cells and thereby promoting tumor progression (Deng et al., 2023). Moreover, hepatic stellate cells (HSCs) are pivotal in the development of liver fibrosis. Upon liver damage or inflammation, activated HSCs transform into myofibroblasts, promoting collagen fiber production and liver connective tissue proliferation. Recent findings indicate that HBV-infected hepatocytes (LO2 cells) secrete extracellular vesicles containing miR-222, which suppresses transferrin receptor (TFRC) expression in HSCs (LX2 cells). This suppression inhibits ferroptosis and promotes stellate cell activation, ultimately leading to liver fibrosis (LF) (Zhang et al., 2023b).

Ferroptosis and hepatitis viruses. Hepatitis B virus (HBV) modulates ferroptosis through multiple mechanisms: HBV can upregulate miR-222, affecting reactive oxygen species (ROS) levels; enhance active iron pool via serine/arginine-rich splicing factor 2 (SRSF2)/proliferating cell nuclear antigen clamp-associated factor (PCLAF); and, via its proteins HBV X protein (HBx) and HBV surface protein (HBs), regulate expression of key mediators such as fatty acid desaturase 2 (FADS2), acyl-CoA synthetase long-chain family member 4 (ACSL4), tripartite motif containing 37 (TRIM37), and factors involved in endoplasmic reticulum (ER) stress. Hepatitis A virus (HAV) 3C protease (3Cpro) promotes ferroptosis by influencing lipid ROS accumulation, while Hepatitis C virus (HCV) disrupts lipid metabolism by targeting enzymes including FADS2. Created by Figdraw. Arrows indicate activation (→) and inhibition (⊣).

Several studies have affirmed the reciprocal relationship between viral hepatitis infection and ferroptosis. Komissarov et al. (2021) observed that the 3C protein of HAV induces ferroptosis when expressed in isolation in human cells (HEK293, HeLa, and A549) (Komissarov et al., 2021). This form of cell death triggered by the 3C protein can be effectively inhibited by ferroptosis inhibitors, marking the initial evidence that viral proteases can trigger ferroptosis (Komissarov et al., 2021). Pan et al. investigated the connection between HBV and stellate cell ferroptosis. Their findings revealed that hepatitis B surface antigen (HBsAg) promotes N6-methyladenosine modification of tripartite motif containing 37 (TRIM37) mRNA stability, which stabilizes TRIM37 expression. TRIM37 then induces ferroptosis in stellate cells through ubiquitination-dependent mechanisms, reducing cell viability and impairing male fertility (Pan et al., 2023). Additionally, Shi et al. observed that HBV-positive HCC patients with higher serum selenium levels exhibit better prognoses. Through in vitro experiments, they determined that low-dose selenium suppresses ferroptosis by upregulating GPX4 expression, thereby attenuating HBV-induced hepatotoxicity (Shi et al., 2023a).

Significant differences exist in the ferroptosis mechanisms of HAV, HBV, and HCV. HBV typically causes chronic infections, suppressing ferroptosis sensitivity in tumor cells, thereby promoting tumor proliferation and liver fibrosis. This capacity for persistence and adaptation is characteristic of HBV-associated cancer cells. In contrast, HAV and HCV primarily induce acute infections and tend to promote viral dissemination by inducing ferroptosis (Komissarov et al., 2021; Yamane et al., 2022). These findings underscore that hepatitis viruses can either hinder or facilitate ferroptosis through diverse mechanisms, offering crucial insights into liver disease progression. Further exploration of this interplay can establish a theoretical foundation for developing novel therapeutic strategies.

4.1.2 Human immunodeficiency virus

Human immunodeficiency virus (HIV) infects the human immune system, resulting in the depletion of crucial immune cells, particularly CD4+ T lymphocytes. This gradual immune deterioration increases susceptibility to opportunistic infections, leading to severe complications. The HIV-1 Tat protein, a transcriptional activation protein of HIV, promotes viral gene transcription and replication, while also regulating host cell gene expression, thus impacting host cell biological functions. Kannan et al. discovered that HIV-1 Tat protein upregulates ACSL4 expression via miR-204 (Kannan et al., 2023). This upregulation leads to increased levels of oxidized phosphatidylethanolamine, lipid peroxidation, upregulation of lipase (LIP) and ferritin heavy chain (FTH1), downregulation of GPX4, and mitochondrial outer membrane rupture. Consequently, this process induces ferroptosis in mouse primary microglia (mPMs), a phenomenon also observed in HIV-1 transgenic rats and HIV-positive human brain samples (Kannan et al., 2023). (Figure 3).

Ferroptosis and human immunodeficiency virus (HIV). The HIV Tat protein inhibits nuclear factor erythroid 2-related factor 2 (NRF2), reducing cysteine availability and glutathione (GSH) synthesis, thereby weakening antioxidant capacity. HIV-1 infection causes ferritin accumulation and lysosomal damage, which releases ferrous iron (Fe2+) that promotes lipid peroxidation. miR-29, via bromodomain-containing protein 4 (Brd4) inhibition, further enhances iron-mediated oxidative stress. The Tat protein also upregulates acyl-CoA synthetase long-chain family member 4 (ACSL4) via miR-204, increasing polyunsaturated fatty acid (PUFA) peroxidation, leading to the accumulation of lipid hydroperoxides (PLOOH) and iron overload, and ultimately triggering ferroptosis and cell death. Created by Figdraw. Arrows indicate activation (→) and inhibition (⊣).

HIV-associated neurocognitive disorders (HAND) encompass memory and behavioral impairments commonly observed in HIV patients, even during combination antiretroviral therapy. Studies indicate that HIV infection can trigger ferroptosis in neurons and glial cells, contributing to white and gray matter damage and the onset of neurodegenerative pathology (Sfera et al., 2022). Methamphetamine (METH), a potent central nervous system (CNS) stimulant, exacerbates neurotoxicity in HIV patients. Sfera et al. discovered that the combined effect of METH and HIV-1 Tat induces oxidative stress, increasing ferroptosis in BV2 microglial cells, thereby elevating HAND risk. Notably, NFE2 like bZIP transcription factor 2 (NRF2) counters this ferroptosis damage by regulating SLC7A11, offering a potential therapeutic avenue (Sfera et al., 2022). These studies underscore the significance of the HIV-ferroptosis link in understanding the pathophysiological mechanisms underlying HIV-related neurological damage, offering new insights into neurodegeneration mechanisms. Further research in this area may yield novel neuroprotective therapeutic strategies for HIV-related neurological disorders.

4.1.3 Coronaviruses

Coronaviruses are single-stranded positive-sense RNA viruses within the family Coronaviridae, infecting both humans and animals. They primarily induce respiratory tract infections, varying from mild symptoms to severe complications like pneumonia. Among the various subtypes, some, such as SARS-CoV, middle east respiratory syndrome coronavirus (MERS-CoV), and the recent SARS-CoV-2, have caused global health crises.

Numerous studies have shown that SARS-CoV-2 infection leads to alterations in lipid metabolism and multi-organ damage (Figure 4). Specifically, the spike protein and ORF3a protein of SARS-CoV-2 compromise cellular antioxidant capacity by downregulating NRF2, thereby promoting ferroptosis (Liu et al., 2023b; Nguyen et al., 2022). A study in 2022 pinpointed ACSL4 as a pivotal regulator of ferroptosis, playing a critical role in the formation of replication organelles during SARS-CoV-2 replication. Targeting ACSL4 with drugs like raloxifene and pioglitazone reduces viral load, presenting a novel strategy to inhibit ferroptosis and decrease viral production (Kung et al., 2022). Moreover, Han et al. discovered that SARS-CoV-2 infection induces ferroptosis in human sinoatrial node (SAN)-like pacemaker cells, characterized by ROS accumulation and altered expression of ferroptosis-related genes including SLC7A11, ACSL4, CP, TF, and GPX4. This implicates ferroptosis as a potential mechanism underlying post-SARS-CoV-2 arrhythmias. Additionally, the study identified two candidate drugs, deferoxamine and imatinib, capable of blocking SARS-CoV-2-associated ferroptosis (Nguyen et al., 2022). Recent studies have also shown that SARS-CoV-2 induces ferroptosis through distinct viral proteins: the membrane protein promotes membrane associated RING-CH-Type Finger 1(MARCHF1)/GPX4-mediated ferroptosis by enhancing lipid accumulation, while the accessory protein Orf7b triggers both apoptosis and ferroptosis (Deshpande et al., 2024; Sun et al., 2025). Beyond direct viral protein-mediated ferroptosis, iron overload in SARS-CoV-2 patients directly contributes to hyperferritinemia and systemic inflammation. Consequently, increased ferritin levels might trigger nuclear receptor coactivator 4(NCOA4)-mediated ferritinophagy (Jia et al., 2021; Li et al., 2024a). Furthermore, SARS-CoV-2-induced acute respiratory distress syndrome during pregnancy may result in fetal hypoxia, subsequently triggering tissue acidosis and excessive release of iron from hemoglobin and transferrin, thereby exacerbating lipid peroxidation and ultimately predisposing neonatal neural cells to ferroptosis (Jovandaric et al., 2022). Collectively, these findings highlight the role of the spike protein, ORF3a protein, membrane protein, and accessory ORF7b protein in promoting ferroptosis through multiple pathways, thereby facilitating viral infectivity and replication. Ultimately, the significance of lipid metabolism in regulating ferroptosis during coronavirus infection underscores the need for investigating novel therapeutic interventions.

Ferroptosis and coronaviruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells via angiotensin-converting enzyme 2 (ACE2) receptors, with involvement of heparan sulfate proteoglycans (HSPG) and is modulated by extracellular lactoferrin. Viral proteins, including Spike, open reading frame 3a (ORF3a), open reading frame 7b (ORF7b), and M protein, impact cellular redox balance and ferroptosis-related pathways. The Spike protein and ORF3a inhibit nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant responses, reducing glutathione (GSH) synthesis and weakening glutathione peroxidase 4 (GPX4) activity, while ORF7b activates cellular myelocytomatosis oncogene (cMyc) to disrupt redox homeostasis. M protein promotes GPX4 ubiquitination via membrane associated ring-CH-type finger 1 (MARCHF1), further impairing antioxidant defense. Reduced cysteine and GSH levels enhance lipid peroxidation, with acyl-CoA synthetase long-chain family member 4 (ACSL4) and acyl-CoA synthetase long-chain family member 1 (ACSL1) driving the biosynthesis of peroxidation-prone fatty acids (arachidonic acid/adrenic acid, AA/AdA). Accumulation of lipid hydroperoxides (LOOH) and ferrous iron (Fe2+) promotes reactive oxygen species (ROS) generation, ultimately leading to ferroptosis. Created by Figdraw. Arrows indicate activation (→) and inhibition (⊣).

4.1.4 Influenza viruses

Influenza viruses, including influenza A virus (FLU A) and influenza B virus (FLU B), are single-stranded negative-sense RNA viruses classified under the Orthomyxoviridae family. These viruses predominantly spread via respiratory droplets, affecting the upper respiratory tract and potentially leading to severe complications like pneumonia and mortality. FLU A notably activates HIF-1, influencing ferroptosis-related metabolism and the expression of key proteins like ACSL4 and GPX4. This activation induces ferroptosis in mouse lung epithelial (MLE-12) cells, contributing to lung congestion, edema, and inflammation (Huang et al., 2023). (Figure 5) Moreover, H1N1 infection triggers differential expression of ferroptosis-related genes and metabolites in human nasal epithelial progenitor cells (hNEPCs). Through upregulation of NRF2/Kelch-like ECH-associated protein 1 (KEAP1) expression, H1N1 modulates glutamine metabolism in hNEPCs, inducing ferroptosis and nasal mucosal epithelial inflammation (Liu et al., 2023a). Beyond its effects on nasal epithelial cells, H1N1 infection also accelerates ferroptosis and lung injury via tripartite motif containing 46 (TRIM46)-mediated ubiquitination of SLC7A11 (Zhou et al., 2024a). In mouse models, the glutamine inhibitor JHU-083 effectively mitigates H1N1-induced immune system damage, presenting a promising therapeutic strategy for virus-induced nasal inflammation (Liu et al., 2023a). Ouyang et al. demonstrated that FLU A hemagglutinin interacts with NCOA4 and Tax1 binding protein 1 (TAX1BP1) to promote ferritinophagy and the formation of ferritin-NCOA4 condensates, thereby facilitating viral replication (Ouyang et al., 2024). Additionally, another study from Wei et al. showed that H5N1 triggers oxidative stress and ferroptosis through TRIM21-mediated regulation of the sequestosome 1 (SQSTM1/p62)-NRF2-KEAP1 axis, further facilitating viral replication (Wei et al., 2024). Notably, ferroptosis-related disruptions are not confined to human-infecting strains alone. Swine influenza virus (SIV), an influenza A virus prevalent in swine populations, can also infect humans under certain conditions, causing zoonotic infections. Research indicates that SIV infection disrupts intracellular iron metabolism and suppresses SLC7A11/GPX4 axis activation in A549 cells. Consequently, this disruption promotes cellular lipid peroxidation and iron-dependent cell death, facilitating viral replication (Cheng et al., 2022). Collectively, these findings underscore the intricate relationship between influenza virus infection and ferroptosis mechanisms, particularly in disrupting epithelial cells of the upper respiratory tract and lungs, thereby enhancing viral replication. Understanding this interaction is crucial for unraveling the pathophysiology of viral infections and may reveal novel therapeutic strategies for influenza.

Ferroptosis and influenza viruses. Influenza A virus (FLU A), highly pathogenic avian influenza A virus subtype H5N1(H5N1), pandemic influenza A virus subtype H1N1(H1N1), and swine influenza virus (SIV) can modulate ferroptosis pathways by targeting key molecules. H5N1 and H1N1 promote degradation of nuclear factor erythroid 2-related factor 2 (NRF2), impairing cellular redox defense. FLU A activate hypoxia-inducible factor 1-alpha (HIF-1α), resulting in increased inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) expression, further contributing to oxidative and nitrosative stress. Viral such as SIV and H1N1 can inhibit cystine import through system xc⁻, limiting cysteine and glutathione (GSH) synthesis and weakening glutathione peroxidase 4 (GPX4)-mediated antioxidant protection. Tax1 binding protein 1 (TAX1BP1)/nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy increases free Fe⁺, fueling the Fenton reaction and generating lipid reactive oxygen species (ROS). These processes culminate in lipid peroxidation, ROS accumulation, and ferroptosis during influenza virus infection. Created by Figdraw. Arrows indicate activation (→) and inhibition (⊣).

4.1.5 Herpesviruses

Herpesviruses, including herpes simplex virus types 1 and 2 (HSV-1/2), varicella zoster virus (VZV), EBV, and human herpesviruses 6, 7, and 8 (HHV-6/7/8), are DNA viruses within the Herpesviridae family. These viruses are responsible for a range of human diseases, and recent studies suggest that ferroptosis may play a crucial role in their pathogenesis (Figure 6). Yuan et al. discovered that EBV activates the p62/KEAP1/NRF2 signaling pathway, which in turn increases the expression of SLC7A11 and GPX4. This upregulation reduces the sensitivity of nasopharyngeal carcinoma (NPC) cells to ferroptosis, thereby fostering chemoresistance and tumor progression (Yuan et al., 2022). Building on this, Zhang et al. found that TNF-α can inhibit EBV reactivation by acting on tumor necrosis factor receptor 1 (TNFR1) and modulating the GPX4-mediated ferroptosis pathway (Zhang et al., 2025). In contrast to EBV’s tumor-associated mechanisms, HSV-1 can cause encephalitis, leading to brain inflammation and neurological dysfunction. Typically, this occurs when the virus reactivates during oral herpes recurrences and enters the central nervous system. A 2023 study revealed that HSV-1 infection enhances the ubiquitination and degradation of NRF2 by the E3 ubiquitin ligase Keap1, disrupting cellular redox homeostasis and promoting ferroptosis in the mouse central nervous system. This ferroptosis leads to CNS inflammation. Notably, ferroptosis inhibitors or proteasome inhibitors can effectively alleviate HSV-1-associated encephalitis by inhibiting NRF2 degradation (Xu et al., 2023). Extending the neurological implications of herpesvirus-induced ferroptosis, HHV-7 infections are mild and asymptomatic. However, Chang et al. highlighted that HHV-7 infection of Schwann cells in the peripheral nervous system induces oxidative stress through cytochrome c oxidase subunit 4I2 (Cox4i2) and regulates ferroptosis-related gene expression via the extracellular regulated mitogen-activated protein kinase (MAPK) signaling pathway. This induction of ferroptosis in Schwann cells promotes neuroinflammation, leading to facial nerve damage (Chang et al., 2021). Taken together, further exploration of the herpesvirus-ferroptosis relationship may elucidate cellular biological processes underlying disease development, offering insights for more effective treatment strategies.

Ferroptosis and herpesviruses. Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV1) interfere with glutathione peroxidase 4 (GPX4) activity directly or through modulation of sequestosome 1 (SQSTM1/p62) - Kelch-like ECH-associated protein 1 (Keap1)- nuclear factor erythroid 2-related factor 2 (NRF2), decreasing the cellular capacity to clear lipid peroxides, subsequently triggering pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase(MAPK)/c-Jun N-terminal kinase (JNK) through transforming growth factor-β-activated kinase 1 (TAK1). Human herpesvirus 7 (HHV-7) enhances oxidative stress via cytochrome c oxidase subunit 4 isoform 2 (Cox4i2), promoting ROS accumulation. Excess iron (Fe2+) and the resulting lipid ROS drive lipid peroxidation, ultimately leading to ferroptosis during herpesvirus infection. tumor necrosis factor-alpha (TNF-α) recognizes tumor necrosis factor receptor 1 (TNFR1) and inhibits EBV infection by upregulating the expression of GPX4. Created by Figdraw. Arrows indicate activation (→) and inhibition (⊣).

Overall, as a carcinogenic virus, EBV shares similar mechanisms with HBV, both of which facilitate tumor progression and induce chemotherapy resistance by suppressing ferroptosis sensitivity in tumor cells. In contrast, herpesviruses including HSV-1 and HHV-7 more closely resemble coronaviruses and influenza viruses in promoting viral infection through ferroptosis induction. This process is closely related to the inflammatory responses observed in both acute and chronic infections. In the acute phase, the inflammatory response can enhance iron metabolism, thereby facilitating ferroptosis. Conversely, in chronic infections, persistent inflammation may dysregulate ferroptosis as a consequence of viral immune evasion, thereby creating a favorable environment for the continuous proliferation and spread of the virus.

4.1.6 Other viruses

Ferroptosis is implicated in various viral infection processes, including tumor cell death triggered by Newcastle disease virus (NDV), encephalitis caused by JEV, and tissue damage induced by human adenovirus type 7 (HAdV-7), enterovirus A71(EV-A71) and et al (Chooi et al., 2024; Kan et al., 2021; Kung et al., 2022; Yang et al., 2022; Zhao et al., 2024b; Zhu et al., 2023, Zhu et al., 2024). Notably, NDV, classified as an oncolytic virus, exploits ferroptosis as an antitumor mechanism by promoting E3 ubiquitin ligase parkin (PRKN)-mediated ubiquitination and degradation of Yes-associated protein (YAP) at Lysine 90 (Lys90) while concurrently activating the p53/SLC7A11/GPX4 pathway, thereby intensifying ferroptosis in tumor cells (Kan et al., 2021; Sun et al., 2024). This highlights the critical role of oncolytic viruses in cancer therapy. Similarly, both JEV and HAdV-7 infection have been demonstrated to induce ferroptosis through upregulation of iron-dependent lipid peroxidation and suppression of antioxidant defenses, most notably GPX4 downregulation (Yang et al., 2022; Zhou et al., 2024b; Zhu et al., 2024). Collectively, both DNA and RNA viruses can promote viral replication and induce inflammatory responses by triggering ferroptosis. Together, these findings illustrate the central involvement of ferroptosis in diverse aspects of viral pathogenesis, highlighting its potential as a pivotal mechanism underlying virus-induced cellular damage.

The interplay between virus and ferroptosis is a burgeoning area of research that promises to unveil novel insights into the cellular processes underlying disease development. Understanding how these viruses manipulate ferroptosis can not only deepen our comprehension of their pathogenic mechanisms but also pave the way for innovative treatment strategies. As research progresses, these findings will provide a fresh perspective on viral pathogenesis and drug development, potentially leading to more effective therapeutic interventions for a range of viral infections (Chen et al., 2023b; Li et al., 2023c; Zhang et al., 2023a). Table 1 summarizes the diverse roles of ferroptosis in viral infections, revealing how different viruses either promote or suppress ferroptosis to facilitate infection or tumor progression.

PathogensMechanismsExperimental modelsOutcomesReferenceHAVInduce ferroptosis by 3Cpro293T, HelaEnhance virus replication(Komissarov et al., 2021)HBVRegulate GPX4HSCsAlleviate hepatic stellate cell fibrosis(Kuo et al., 2020)Mediate GPX4 ubiquitination by TRIM37Human Sertoli cellsReduce the viability of human support cells(Pan et al., 2023)Regulate the SRSF2/PCLAF tv1 axisHCCInduce sorafenib resistance(Liu et al., 2023c)Regulate the miR-222/TFRC axisLO2, LX-2Promote liver fibrosis(Zhang et al., 2023b)Regulate HBx/PRMT9/HSPA8/CD44 axisHCCPromote cancer progression(Deng et al., 2023)Upregulate SLC7A11/GPX4HCCPromote cancer progression(Wang et al., 2023c)HCVRegulate ferroptosis through FADS2Huh7.5, 293FT, PH5CH8, A549Inhibit virus replication(Yamane et al., 2022)HIVRegulate ferroptosis-driving molecules/Facilitate the occurrence of neurodegenerative diseases(Sfera et al., 2022)