Recent progress in understanding ferroptosis mechanisms in infectious diseases.

Viral infections remain a major challenge to global health and economic stability. While antibody therapies and vaccines are central to current antiviral approaches, their effectiveness can be compromised by factors such as limited coverage, waning efficacy, and the potential for antibody-dependent enhancement, particularly amid ongoing viral mutations ( Merad and Martin, 2020 ; Xu et al., 2024 ). Consequently, the search for new therapeutic targets has become increasingly urgent. Burton et al. revealed that EBV-infected Burkitt-like cells generate significantly more lipid ROS than lymphoblastoid cell lines (LCL) when exposed to the ferroptosis inducer buthionine sulfoximine, highlighting their increased vulnerability to ferroptosis ( Burton et al., 2022 ). These results indicate that promoting ferroptosis could be a viable therapeutic approach for certain EBV-related tumors. Additionally, ferroptosis inducers such as RSL3, BQR, and Erastin have been shown to activate ferroptosis and inhibit the in vitro replication of PEDV and ASFV ( Chen et al., 2023b ; Li et al., 2023c ; Zhang et al., 2023a ). Modulating iron metabolism is another promising antiviral strategy. Many viral infections elevate intracellular iron levels, which support viral replication and contribute to disease severity. Iron chelators, including ICL670, 311, and DFO, have demonstrated the ability to suppress HIV-1 replication by inhibiting viral transcription and activation ( Debebe et al., 2007 ; Salhi et al., 1998 ; Tabor et al., 1991 ). Comparable methods are also effective against large DNA viruses-such as cowpox and HSV-1-that rely on iron-dependent enzymes ( Khadivjam et al., 2017 ; Romeo et al., 2001 ). By reducing cellular iron availability, chelation therapy can restrict viral proliferation and help protect cells from infection-induced damage. In addition to iron chelation, certain ferroptosis-modulating compounds, such as antioxidants like vitamin E and butylated hydroxytoluene, have shown effectiveness against viruses including SARS-CoV-2, HSV, HIV, et al ( Richards et al., 1985 ; Spada et al., 2002 ; Wang et al., 2020 ). Furthermore, ferrous-reactive endoperoxides, such as artemisinin and its derivatives, also display antiviral activity, likely by influencing iron metabolism and oxidative stress ( Creek et al., 2007 ; Efferth et al., 2008 ; Zhou et al., 2021 ). Despite these advances, the exact antiviral mechanisms of many ferroptosis regulators remain inadequately understood and require further study. Indeed, research exploring the relationship between ferroptosis and various viruses, including hepatitis viruses, HIV, JEV, and SARS-CoV-2, is evolving rapidly ( Carr et al., 2019 ; Kuo et al., 2020 ; Xiao et al., 2022 ; Yamane et al., 2022 ). Nonetheless, the precise pathophysiological links between ferroptosis and specific viral infections remain incompletely defined. A deeper mechanistic understanding of these interactions will be essential for the rational design of ferroptosis-targeted antiviral therapies and the advancement of novel treatment paradigms. However, the treatment process may encounter several challenges. First, ferroptosis-related compounds, such as Erastin, RSL3 and ML162, can lead to significant off-target effects and additional tissue damage, similar in viral infections. This lack of specificity poses a major obstacle to clinical translation, as s widespread distribution can damage healthy tissues dependent on normal iron metabolism and redox homeostasis. Therefore, targeted delivery strategies could be developed specifically for virus-infected cells. For example, virus-targeting antibodies or ligands that bind viral receptors can concentrate drugs in infected cells. An example of a targeted antiviral therapy is Lamivudine, which selectively targets viral polymerase to inhibit viral DNA synthesis by competing with deoxycytidine triphosphate (dCTP) in the treatment of HIV and HBV ( De Clercq and Li, 2016 ). Insights gained from the development of lamivudine may inform the creation of targeted therapies that exploit ferroptosis. Furthermore, the ferroptosis inducer PF-670462 selectively targets tumor cells and reduces their resistance to ferroptosis, thereby enhancing the immune system’s ability to eliminate these tumors ( Zhou et al., 2025 ). Drawing from these collective insights, developing ferroptosis inducers with viral selectivity remains a critical priority for clinical translation. Second, drug safety represents another major concern that requires thorough evaluation. Several compounds that can modulate ferroptosis pathways have been approved by the US Food and Drug Administration (FDA) for other indications, including DFO, deferasirox (DFX), sulfasalazine (SAS), and altretamine, for treating cancers and autoimmune diseases. However, their antiviral applications remain unexplored ( Hassannia et al., 2019 ; Jin et al., 2020 ). While these agents have demonstrated acceptable safety profiles in their approved indications, their safety in the context of acute or chronic viral infections remains unclear. Potential concerns include the narrow therapeutic window, individual patient variability in iron metabolism, and possible adverse effects on host immune function and normal cellular processes dependent on iron-containing enzymes. Therefore, systematic evaluation in viral infection models is essential. In parallel, screening FDA-approved drug libraries for compounds capable of modulating ferroptosis pathways could facilitate the identification of safe and effective antiviral treatments while leveraging existing safety data to potentially reduce development timelines. Third, the generalizability of ferroptosis-related agents is constrained by the diverse clinical manifestations and progression of various viral infections. Different viruses exhibit distinct replication strategies, tissue tropisms, and interactions with host iron metabolism pathways, which may result in varying susceptibility to ferroptosis induction. This pathogen diversity necessitates the development of virus-specific or at least viral-family-specific therapeutic strategies. Given their extensive use in tumor therapy, it is crucial to prioritize research on diseases associated with EBV and HBV. The insights gained from this research could then facilitate the gradual expansion of these agents’ applications to other viral infections. However, preclinical studies must assess ferroptosis-based therapies across different viral pathogens, accounting for variations in viral load, infection stage, and host immune status. Pharmacological modulation of ferroptosis has shown considerable promise in the management of bacterial infections, particularly in M. tuberculosis infection and sepsis. Several clinical studies have demonstrated that patients receiving vitamin E, selenium, and/or N-acetylcysteine (NAC, a glutathione precursor) as adjunctive treatments alongside standard M. tuberculosis antibiotic therapy exhibit an enhanced host response to treatment compared to those administered a placebo ( Amaral et al., 2014 ; Campa et al., 2017 ; Ingold et al., 2018 ; Mahakalkar et al., 2017 ). Building on these clinical observations, modulating macrophage inflammatory responses and ferroptosis with various drugs has been shown to decrease the bacterial load of M. tuberculosis laying the groundwork for new antimicrobial agents ( Amaral et al., 2019 ; Geng et al., 2023 ). The therapeutic relevance of ferroptosis modulation extends beyond M. tuberculosis to sepsis, a life-threatening systemic response that commonly arises from bacterial infection. Kang et al. demonstrated that GPX4 negatively regulates macrophage pyroptosis and septic lethality in mice by attenuating lipid peroxidation ( Kang et al., 2018 ). Consistently, administration of vitamin E conferred protection to the mice from lethal sepsis ( Kang et al., 2018 ). Of note, animals treated with NAC and deferoxamine exhibited enhanced resistance to lethal sepsis ( Ritter et al., 2004 ; Vlahakos et al., 2012 ). This protective effect was attributed to increased glutathione levels and decreased availability of free iron. Taken together, these findings substantiate the therapeutic relevance of ferroptosis regulation in bacterial pathogenesis. The convergence of antioxidant supplementation, glutathione restoration, and iron chelation strategies highlights ferroptosis as a viable and multifaceted therapeutic target, warranting further clinical investigation in the treatment of bacterial infectious diseases. Emerging evidence suggests that ferroptosis represents a therapeutically exploitable pathway in both fungal and parasitic infections, with distinct intervention strategies demonstrating efficacy across different pathogen models. In fungal infections, exogenous Fe 2+ has been shown to trigger ferroptosis in Aspergillus flavus ( A. flavus ) spores by activating NADPH oxidases (NOXs), hindering A. flavus infection ( Yao et al., 2021 ). Similarly, deferoxamine and Fer-1 successfully prevented iron-dependent ROS accumulation and lipid peroxidation, preventing cell death in rice sheaths during avirulent M. oryzae infection ( Dangol et al., 2019 ). In the context of parasitic infections, treatment combined with dihydroartemisinin (DHA) and RSL3 significantly enhances resistance to Toxoplasma infection ( Huang et al., 2022 ; Wang et al., 2023a ). Additionally, Fer-1 treatment in an in vitro infection model resulted in a decrease in malaria parasite-associated lipid peroxides; in vivo , mice given Erastin before exposure to the malaria parasite had a delay of up to 2 days in the start of blood infection ( Kain et al., 2020 ). These observations substantiate ferroptosis as a mechanistically pertinent and pharmacologically tractable target in fungal and parasitic infectious diseases.

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.

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 (Fe 2+ )-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 ).

While diverse pathogens employ distinct strategies to disrupt host cell metabolism, they remarkably converge on ferroptosis as a common cell death mechanism. Specifically, these evolutionarily distant pathogens target distinct nodes within the same ferroptosis signaling cascade, ultimately driving ferroptosis in host cells. As illustrated in Figure 8 , all examined pathogens converge on three core molecular nodes despite their heterogeneous initial intervention strategies. Convergent mechanisms of pathogen-induced ferroptosis. Diverse pathogens employ distinct mechanisms to drive ferroptosis by systematically targeting three critical nodes of iron homeostasis, lipid peroxidation, and antioxidant defense. (A) Iron homeostasis disruption:Hepatitis B virus (HBV) upregulates transferrin receptor (TFRC)-mediated Fe 2+ influx, while Human adenovirus 7 (HAdV-7), Mycobacterium tuberculosis ( M. tuberculosis ), Pseudomonas aeruginosa (P. aeruginosa ), and other bacteria promote iron accumulation through alternative pathways. (B) Lipid peroxidation amplification: Trypanosomes , Schizosaccharomyces pombe ( S. pombe ), and Human herpesvirus 7 (HHV-7) promote lipid peroxidation within mitochondrial membranes ; human immunodeficiency virus (HIV), Coxsackievirus A6 (CVA6), Japanese encephalitis virus (JEV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), murine coronavirus (M-CoV) and P. aeruginosa accelerate cytoplasmic lipid peroxidation. (C) Antioxidant defense failure: Rhinovirus (RV) and Malaria inhibit solute carrier family 7 member 11 (SLC7A11)-mediated cystine uptake; whereas hepatitis A virus (HAV), SARS-CoV-2, M. tuberculosis , and P. aeruginosa inhibit GPX4; HIV, pandemic influenza A virus subtype H1N1 (H1N1), and Herpes simplex virus 1 (HSV-1) further attenuate antioxidant capacity by downregulating nuclear factor erythroid 2-related factor 2 (NRF2) or hypoxia-inducible factor 1-alpha (HIF-1α)-mediated transcription. Small molecule modulators including Erastin, RSL3, and BQR are shown as chemical modulators. Created by Figdraw. Arrows indicate activation (→) and inhibition (⊣). First, iron homeostasis disruption. HBV upregulates TFRC expression to promote Fe 2+ influx, while HAdV-7, M. tuberculosis , and P. aeruginosa employ distinct mechanisms to perturb Fe 2+ homeostasis and promote intracellular iron accumulation. The accumulated Fe 2+ generates substantial ROS through Fenton chemistry, thereby triggering the ferroptosis cascade. Second, lipid peroxidation amplification. Trypanosomes, S. pombe , and HHV-7 promote mitochondrial lipid peroxidation, whereas M-CoV and P. aeruginosa accelerate cytoplasmic lipid peroxidation. Together, these pathogens exacerbate lipid ROS accumulation. Third, antioxidant defense failure. RV and malaria parasites inhibit SLC7A11 expression, disrupting cystine uptake and depleting GSH precursors, thereby compromising cellular antioxidant capacity. Consequently, GPX4 (both mitochondrial and cytoplasmic isoforms) loses its capacity to reduce lipid hydroperoxides. Additionally, HIV, H1N1, HSV-1, and SARS-CoV-2 further attenuate this defense pathway by downregulating NRF2 or HIF-1α expression. The synergistic action of these three mechanisms culminates in overwhelming accumulation of lipid ROS, driving lipid peroxidation in mitochondria and cytoplasm and thus triggering ferroptosis execution. This integrative analysis reveals a conserved biological principle: despite vast evolutionary distances and heterogeneity in their infection strategies, phylogenetically diverse pathogens demonstrate remarkable convergence in their ferroptosis induction mechanisms. They systematically target three critical nodes: iron homeostasis, lipid peroxidation, and the SLC7A11-GPX4 antioxidant axis. By attacking these nodes, pathogens drive cells toward an irreversible death pathway. Consequently, modulation of these shared nodes (whether through iron chelation, GSH restoration, GPX4 stabilization, or lipid peroxidation inhibition) may offer broad-spectrum therapeutic strategies, providing a theoretical foundation for developing pan-pathogenic antimicrobial agents.

Ferroptosis, a regulated form of cell death, plays a significant role in the infection processes of various pathogens. It induces inflammation by accumulating lipid peroxides and iron ions, leading to the generation of reactive oxygen species. Although certain ferroptosis inhibitors can mitigate these inflammatory cascades, their therapeutic potential for pathogen infections requires further investigation. Nonetheless, studying the connection between ferroptosis and pathogen infections continues to enhance our understanding of infection processes and their underlying mechanisms. Comparative analysis of diverse pathogens has uncovered several unifying themes in ferroptosis regulation. First, manipulation of host iron metabolism represents a common strategy employed by pathogens, achieved either through inducing iron overload or through suppressing iron-dependent ferroptosis. Second, lipid peroxidation control serves as a critical regulatory node, with pathogens modulating GPX4, GSH, and antioxidant pathways to either promote or prevent ferroptosis depending on their replication strategies. Third, the context-dependent duality of ferroptosis is evident: it can facilitate pathogen spread by eliminating immune surveillance cells or conversely restrict infection by clearing infected cells. Together, these shared mechanistic patterns suggest that ferroptosis represents a fundamental regulatory node in host-pathogen interactions, which may be commonly exploited by diverse pathogens to modulate infection outcomes. Despite the progress made in understanding the mechanisms of ferroptosis, several significant issues remain regarding its translation into clinical therapy. First, it is essential to clarify the role of ferroptosis in infections caused by different pathogens. Such clarity will aid in comprehending its specific mechanisms across various infections and help identify new therapeutic targets. In parallel, further research on the potential role of ferroptosis in chronic infections may provide new insights for developing effective treatment strategies. Beyond mechanistic understanding, the safety and efficacy of ferroptosis-related drugs must be validated through rigorous clinical trials. Collectively, by addressing these challenges and pursuing these research directions, we can establish a solid foundation for the clinical application of ferroptosis, ultimately advancing the treatment of infectious diseases and broadening our approach to managing both acute and chronic infections.

The heightened vulnerability of children to pathogen-induced ferroptosis stems from their unique developmental physiology. Children demonstrate enhanced intestinal iron absorption due to developmental upregulation of intestinal divalent metal transporter 1 (DMT1) expression during rapid growth and enhanced hepcidin sensitivity ( Yanatori and Kishi, 2019 ). However, iron storage capacity in developing organs, particularly the liver and spleen, increases progressively with age ( Lynch et al., 2018 ). This mismatch between iron intake and storage capacity creates a physiological vulnerability: while robust iron uptake supports accelerated hematopoiesis and tissue expansion necessary for normal growth, it simultaneously increases children’s vulnerability to pathogen-driven iron dysregulation and the subsequent activation of ferroptosis pathways. Childhood infectious diseases exemplify this vulnerability. M. tuberculosis induces ferroptosis by manipulating iron homeostasis and lipid peroxidation pathways, with progressive primary pulmonary tuberculosis and tuberculous meningitis as particularly severe manifestations ( Amaral et al., 2024 ; Amaral et al., 2014 ). Similarly, childhood viral infections, including EBV, SARS-CoV-2, H1N1, JEV, HAdV-7, and EV-A71, induce ferroptosis through disruption of iron homeostasis, lipid metabolism, and antioxidant defense systems ( Liu et al., 2023a ; Liu et al., 2025 ; Nguyen et al., 2022 ; Yang et al., 2022 ; Yuan et al., 2022 ; Zhao et al., 2024b ). Among these, EBV primarily causes infectious mononucleosis in children and adolescents upon primary infection and is closely associated with pediatric malignancies such as Burkitt lymphoma ( Liu et al., 2025 ). Notably, JEV and HAdV-7 cause severe disease in children, with JEV being a leading cause of viral encephalitis and HAdV-7 associated with severe pneumonia ( Li et al., 2025 ; Tandale et al., 2023 ). Moreover, EV-A71 is the primary causative agent of hand, foot, and mouth disease (HFMD) in children ( Lian et al., 2023 ). Beyond its role in HFMD, EV-A71 preferentially targets and replicates in human motor neurons, where it triggers neurodegeneration by inducing ferroptosis ( Chooi et al., 2024 ). Importantly, these pathogenic stressors may produce prolonged ferroptosis effects in children because pediatric immune responses differ fundamentally from adult responses, thereby prolonging the window of pathogenic susceptibility. Ferroptosis-targeted therapeutic strategies in children present distinctive challenges that demand careful consideration. Ferroptosis modulators must operate within an exceptionally narrow therapeutic window. Excessive iron limitation may impair normal hematopoiesis and neurological development, while inadequate dosing fails to prevent pathogen-induced ferroptosis. These constraints are further complicated by hepatorenal immaturity in children, which alters drug metabolism and clearance kinetics. Consequently, rigorous pharmacokinetic characterization and age-stratified dosing optimization are essential. Systematic research addressing these gaps will enable development of truly age-adapted therapeutic strategies that balance pathogen-specific ferroptosis susceptibility exploitation against the developmental requirements of pediatric hosts.