Targeting Ferroptosis and Cuproptosis for Antimicrobial Control in Postharvest Preservation

ABSTRACT

Spoilage and pathogenic microorganisms cause significant economic losses and food safety issues globally, driving the need for novel antimicrobial strategies beyond conventional methods. This review explores the potential of targeting two metal‐dependent regulated cell death pathways, ferroptosis and cuproptosis, for precision antimicrobial intervention in postharvest preservation. Ferroptosis is driven by iron‐dependent lipid peroxidation, while cuproptosis is characterized by copper‐induced aggregation of metabolic proteins and subsequent proteotoxic stress. We delineate their molecular mechanisms and highlight their operational presence in key bacterial and fungal pathogens. The review critically examines pioneering applications, such as iron‐loaded biodegradable films and copper‐based nanocomposites, which exploit these pathways to control spoilage microorganisms on various produce, thereby maintaining sensory quality and extending shelf life. We also propose that the co‐induction of ferroptosis and cuproptosis overwhelms microbial defenses by disrupting interconnected iron and copper homeostasis, amplifying oxidative stress, and impeding resistance development. Despite the promise, translating this paradigm into practical applications requires overcoming challenges related to targeted delivery, biosafety, and phytotoxicity. We conclude that leveraging these mechanistically distinct pathways, particularly through synergistic strategies, represents a transformative frontier for sustainable, efficient, and resistance‐resilient solutions to reduce postharvest losses and enhance food security.

1. Introduction

Fungi and bacteria are the primary causes of postharvest spoilage in fruits and vegetables (FV), leading to significant quality loss and food waste. Globally, postharvest losses of FV account for 20%–40% of total production (Ullah et al. 2025; Ashraf et al. 2025), largely driven by spoilage fungi such as Botrytis cinerea (B. cinerea) and soft‐rot bacteria such as Pseudomonas aeruginosa (P. aeruginosa) and Pectobacterium carotovorum (P. carotovorum) (Ezzouggari et al. 2024; Zhang et al. 2021; Mostafidi et al. 2020; Lawal et al. 2026). In addition, foodborne pathogens like Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), along with mycotoxin‐producing fungi, can compromise food safety without causing visible spoilage (Mostafidi et al. 2020). Therefore, effective antimicrobial strategies are essential for both preserving FV quality and ensuring food safety.

To address these challenges, various physical, chemical, and biological strategies have been developed, but each of these conventional approaches exhibits drawbacks (Figure 1). Physical approaches (e.g., refrigeration, modified atmosphere packaging, UV irradiation) mainly suppress rather than eradicate pathogens, often requiring high energy input and showing limited efficacy against resilient strains (Mostafidi et al. 2020; Ngolong Ngea et al. 2024). Chemical fungicides and bactericides face growing resistance issues and concerns over toxic residues (Liu et al. 2026). Biological control employs antagonistic microorganisms to offer more sustainable alternatives but suffers greatly from environmental instability (Ngolong Ngea et al. 2024; Mostafidi et al. 2020). Critically, these methods often achieve only transient growth suppression rather than durable eradication, which can allow pathogen persistence and disease recurrence. Therefore, new strategies capable of more thorough and long‐lasting pathogen control are urgently needed.

FIGURE 1.

Overview of postharvest losses in FV caused by spoilage and pathogenic microorganisms, and current preservation strategies. Postharvest losses cause severe global food waste and economic losses. Spoilage bacteria (e.g., Pseudomonas, Pectobacterium) and fungi (e.g., Botrytis, Penicillium) cause visible decay, off‐odors, and textural breakdown, resulting in product rejection. Toxigenic pathogens such as Escherichia, Staphylococcus, and Aspergillus contaminate produce without visible signs, posing health risks and triggering recalls. Conventional preservation includes physical methods (refrigeration, MAP, UV irradiation), chemical methods (synthetic fungicides and bactericides), and biological methods (antagonistic microorganisms, natural antimicrobials, plant defense elicitors). Physical methods are energy‐intensive and may have limited efficacy. Chemical methods face resistance, residue concerns, and consumer rejection. Biological methods offer sustainability but encounter variability, spectrum limitations, regulatory hurdles, and cost issues. Novel antimicrobial mechanisms with distinct modes of action and lower resistance risk are urgently needed.

In contrast to conventional strategies that primarily manipulate the external environment, targeting the internal metabolic homeostasis of microorganisms represents an emerging perspective. Iron and copper are essential micronutrients for microbial survival, playing indispensable roles in enzymatic catalysis, respiration, and antioxidant defense (Murdoch and Skaar 2022; Helmann 2025). However, recent studies demonstrate that excess intracellular iron or copper can trigger lethal cell death different from apoptosis and pyroptosis (Table 1). Ferroptosis is an iron‐dependent form of regulated cell death triggered by excessive lipid peroxidation. Excess intracellular Fe²⁺ fuels the Fenton reaction, generating reactive oxygen species (ROS) that oxidize membrane phospholipids (Dixon et al. 2012; Yang and Stockwell 2016). When the glutathione (GSH)‐glutathione peroxidase 4 (GPX4) antioxidant axis is overwhelmed, lipid peroxidation propagates, irreversibly disrupting membrane integrity and causing cell rupture. Cuproptosis, a recently identified copper‐dependent pathway, operates through a distinct mechanism. Excess copper directly binds to lipoylated proteins of the tricarboxylic acid (TCA) cycle, inducing protein aggregation that triggers iron–sulfur (Fe‐S) cluster protein loss and proteotoxic stress, ultimately leading to cell death (Tsvetkov et al. 2022). Unlike conventional strategies that target external cellular structures, both ferroptosis and cuproptosis exploit metal‐dependent metabolic vulnerabilities intrinsic to microbial cells. Food‐grade inducers based on iron or copper can harness these pathways to irreversibly kill both spoilage and pathogenic microorganisms, offering a novel preservation strategy that acts from within to complement existing approaches.

TABLE 1.

Morphological and biochemical features of programmed cell death pathways.

Types	Morphological features	Biochemical features	References
Apoptosis	Cell shrinkage, nuclear fragmentation and chromatin condensation, plasma membrane blebbing, formation of apoptotic bodies phagocytosed without inflammation	Caspase‐3/8/9 activation, DNA fragmentation, phosphatidylserine externalization, mitochondrial cytochrome c release	Feng et al. (2023)
Pyroptosis	Cell swelling and osmotic lysis, plasma membrane pore formation, bubble‐like protrusions, nuclear condensation without fragmentation	Caspase‐1/4/5/11 activation, gasdermin D cleavage, pore formation, IL‐1β/IL‐18 maturation and release, inflammasome assembly	Broz (2025)
Necroptosis	Organelle and cellular swelling, plasma membrane rupture, moderate chromatin condensation, release of cytoplasmic contents	RIPK1‐RIPK3‐MLKL complex activation, MLKL oligomerization, membrane disruption, ATP depletion, independent of caspases	Muszka et al. (2025)
Autophagy	Formation of double‐membrane autophagosomes, cytoplasmic vacuolization, degradation of organelles/proteins via lysosomal fusion	Enhanced lysosomal activity, LC3‐I to LC3‐II conversion, ATG5/ATG7/Beclin‐1 dependence	Feng et al. (2023)
Ferroptosis	Mitochondrial shrinkage and cristae loss, increased mitochondrial membrane density, no chromatin condensation	Iron overload, Fe2+‐dependent Fenton reactions, lipid peroxidation accumulation, GSH depletion and GPX4 inactivation, system Xc‐ inhibition	Liu et al. (2023); Feng et al. (2023)
Cuproptosis	Mitochondrial swelling and cristae reduction, rupture of mitochondrial outer membrane, protein aggregates in mitochondria	Cu2+ binding to lipoylated TCA cycle proteins, FDX1‐mediated copper toxicity, loss of Fe‐S cluster proteins, HSP70 upregulation	Liu et al. (2023); Feng et al. (2023)

2. Mechanisms of Mammalian Ferroptosis and Cuproptosis

Ferroptosis and cuproptosis were first discovered and are best characterized in mammalian cells (Dixon et al. 2012; Tsvetkov et al. 2022). We briefly outline these canonical mechanisms, which provide a mechanistic template for identifying functionally conserved targets in spoilage fungi and foodborne bacteria.

2.1. Classical Ferroptosis Pathways in Mammalian Cells

Ferroptosis is an iron‑dependent nonapoptotic cell death driven by the accumulation of lipid peroxides to lethal levels, culminating in membrane rupture (Newton et al. 2024; Dixon et al. 2012). It is governed by the balance between pro‑ferroptotic drivers and antioxidant defenses (Figure 2A). A labile Fe²⁺ pool generates lipid radicals via the Fenton reaction, while ferritinophagy‑mediated iron release further sensitizes cells to ferroptosis (Gao et al. 2022; Gao et al. 2016). The central defense is the GSH‐GPX4 axis. Cystine imported via system Xc⁻ is reduced to cysteine for GSH synthesis, and GPX4 utilizes GSH to reduce toxic lipid hydroperoxides (LOOHs), thereby halting the lipid peroxidation chain (Newton et al. 2024; Stockwell 2022). Recently, multiple GPX4‐independent systems have also been identified that suppress ferroptosis, such as suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10) (Newton et al. 2024; Stockwell 2022; Doll et al. 2019). When oxidative stress overwhelms these protective systems, lipid peroxidation propagates uncontrollably, resulting in irreversible membrane damage and cell death.

FIGURE 2.

The mechanisms of canonical ferroptosis and cuproptosis. (A) The ferroptosis pathway in mammalian cells. Ferroptosis is an iron‐dependent form of regulated cell death driven by the lethal accumulation of lipid peroxides. The process is governed by a balance between pro‐ferroptotic drivers and antioxidant defense systems. The primary defense axis relies on the cystine/glutamate antiporter system Xc⁻, which imports cystine for the synthesis of the antioxidant tripeptide GSH. GPX4 subsequently uses GSH to reduce toxic LOOHs to non‐toxic lipid alcohols, thereby blocking lipid peroxidation. A parallel, GSH‐independent protective mechanism involves FSP1, which reduces CoQ10 to trap lipid radicals. Execution of ferroptosis requires a labile Fe²⁺ pool that generates ROS through the Fenton reaction to initiate lipid peroxidation, along with membrane phospholipids containing PUFAs, whose incorporation is mediated by key enzymes such as ACSL4 and LPCAT3. Ferritinophagy, the autophagic degradation of ferritin mediated by NCOA4, releases stored iron and sensitizes cells to death. Consequently, pharmacological blockade of system Xc⁻ (e.g., by erastin) or direct inhibition of GPX4 (e.g., by RSL3) acts as a potent trigger for ferroptosis. (B) The cuproptosis pathway in mammalian cells. Cuproptosis is a copper‐dependent form of regulated cell death initiated by excess intracellular copper that overwhelms homeostatic controls. The mitochondrial FDX1 plays a central role by reducing Cu²⁺ to the more toxic Cu⁺. Cu⁺ directly binds to the lipoyl moieties of lipoylated TCA cycle proteins, such as DLAT in the pyruvate dehydrogenase complex, triggering their aberrant oligomerization and aggregation. This aggregation results in the loss of function of these enzyme complexes, destabilization and loss of Fe‐S cluster‐containing proteins, and the induction of lethal proteotoxic stress that ultimately drives cell death. Abbreviations: γ‐GC, γ‐glutamylcysteine; ACSL4, acyl‐coA synthetase long‐chain family member 4; ALOX15, arachidonate 15‐lipoxygenase; ATP7A/B, ATPase copper transporting alpha/beta; CoQ, coenzyme Q; DLAT, dihydrolipoamide s‐acetyltransferase; FDX1, ferredoxin 1; GCL, γ‐glutamylcysteine synthase; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; GSSG, glutathione disulfid; LIAS, lipoic acid synthetase; LPCAT3, lysophosphatidylcholine acyltransferase 3; NCOA4, nuclear receptor coactivator 4; PLOHs, phospholipid alcohols; PLOOHs, phospholipid hydroperoxides; PUFA‐PL, polyunsaturated fatty acid containing phospholipids; PUFAs, polyunsaturated fatty acids; SLC31A1, solute carrier family 31 member 1; STEAP, six‐transmembrane epithelial antigen of prostate; TFR1, transferrin receptor 1; Xc‐, cystine/glutamate antiporter.

Ferroptosis can be induced by four main strategies (Stockwell 2022). Erastin blocks Xc⁻, RAS‐selective lethal 3 (RSL3) inactivates GPX4, ferroptosis inducer 56 (FIN56) depletes reduced CoQ10 and degrades GPX4, and ferroptosis inducer endoperoxide 2 (FINO2) supplies a peroxide oxidant (Stockwell 2022; Bersuker et al. 2019). Iron or polyunsaturated fatty acids (PUFAs) overload can also trigger ferroptosis (Stockwell 2022).

2.2. Classical Cuproptosis Pathways in Mammalian Cells

Cuproptosis is a copper‑dependent regulated cell death executed by the aggregation of lipoylated proteins, leading to proteotoxic stress and collapse of Fe‑S cluster protein networks, ultimately causing cell death (Xie et al. 2023; Tsvetkov et al. 2022). The pathway is triggered when excess intracellular copper overwhelms homeostatic controls (Figure 2B). A key step is the reduction of Cu²⁺ to the more reactive Cu⁺ by mitochondrial ferredoxin 1 (FDX1) (Tsvetkov et al. 2022). Cu⁺ then binds with high affinity to the thiol groups of lipoyl moieties on TCA cycle enzymes, notably the E2 subunit of pyruvate dehydrogenase (DLAT) (Tsvetkov et al. 2022; Xie et al. 2023). This binding induces aberrant oligomerization and aggregation of these lipoylated proteins, resulting in loss of their enzymatic function (Xie et al. 2023). The aggregation cascade further destabilizes Fe‑S cluster‑containing proteins, which are essential for electron transport and other vital processes (Tang et al. 2022; Wang et al. 2022). The combined effect is catastrophic proteotoxic stress and irreversible cellular collapse.

Pharmacological induction of cuproptosis is classically achieved by copper ionophores such as elesclomol, which shuttle copper directly into mitochondria, or by exposure to excess bioavailable copper (Tsvetkov et al. 2022; Yu et al. 2025). Both strategies converge on the same downstream events, demonstrating that forced copper overload is sufficient to trigger this lethal pathway.

3. Mechanisms of Microbial Ferroptosis and Cuproptosis

The mechanisms of ferroptosis and cuproptosis have been extensively characterized in mammalian systems, but whether and how these pathways translate to microorganisms remains an emerging field of inquiry.

Different from classical ferroptosis and cuproptosis characterized in mammalian systems, microbial counterparts are uniquely shaped by the evolutionary arms race with plants, driving the development of specialized metal acquisition and detoxification systems that reflect distinct metabolic architectures (Bachman and Weiser 2015). Plants deploy nutritional immunity strategies, sequestering metals to limit pathogen access while simultaneously utilizing copper and iron as toxic weapons to induce microbial death (Rodríguez‐Ramos et al. 2023; Bachman and Weiser 2015). In response, microorganisms have evolved sophisticated metal acquisition systems, including siderophore‐mediated iron uptake and high‐affinity copper transporters, to scavenge these scarce nutrients from host tissues (Wang et al. 2025). This evolutionary arms race has also rendered microbes vulnerable to metal overload, a vulnerability that plants exploit through iron‐ and copper‐induced ferroptosis and cuproptosis during infection (Vasquez‐Montaño et al. 2020).

The following parts will examine the evidence for iron‐ and copper‐induced cell death in bacteria and fungi, where distinct cellular architectures necessitate re‐examination of established paradigms.

3.1. Ferroptosis Pathways in Microbes

While ferroptosis is well‐established in mammalian systems as an iron‐dependent form of cell death driven by lipid peroxidation, its relevance in microorganisms is increasingly recognized. This section examines the emerging evidence for ferroptosis‐like pathways in bacteria and fungi, highlighting both conserved mechanisms and organism‐specific adaptations in iron metabolism and oxidative stress responses.

3.1.1. Ferroptosis‐Like Death in Fungi

As eukaryotic organisms, fungi and mammals share conserved cellular machinery that governs iron metabolism and oxidative stress responses, forming the basis for a common ferroptotic pathway (Figure 3A).

FIGURE 3.

The mechanisms of ferroptosis‐like death in microorganisms. Created with BioGDP.com (Jiang et al. 2025b). (A) Ferroptosis‐like death in fungi. Fungi and mammals share a core ferroptotic machinery characterized by iron dependency, Fenton‐chemistry‐driven generation of lipid peroxides, and incorporation of PUFAs into membrane phospholipids via ACSL4, with the GSH‐GPX4 axis serving as a central antioxidant defense. However, fungal iron acquisition relies on reductive iron assimilation (e.g., the Ftr1/Fet34 complex) and siderophore‐mediated uptake (e.g., Arn1p/Sit1p). Ferric reduction employs redundant FRE family reductases, and the ferroportin homolog MoFpn1 in M. oryzae undergoes autophagic degradation to drive iron accumulation and ferroptotic death. Fungal membranes contain ergosterol, whose conjugated double bonds provide intrinsic antioxidant protection and can be compromised by azole antifungals that inhibit ergosterol synthesis. Additional fungal‐specific modulators include manganese lipoxygenase and the PPZ1‐TORC1 signaling axis linking nutrient sensing to ferroptosis sensitivity. (B) Ferroptosis‐like death in bacteria. Bacterial ferroptosis‐like death is driven by iron‐catalyzed Fenton chemistry and subsequent lipid peroxidation, sharing a core execution mechanism with mammalian ferroptosis. Bacteria acquire iron through secreted siderophores that chelate Fe³⁺. The ferric siderophore complexes are imported via TBDTs and ABC transporters. Inside the cell, Fe³⁺ is reduced to Fe²⁺ by diverse ferric reductases (e.g., flavin reductases, siderophore‐interacting proteins) or directly taken up as Fe²⁺ by the Feo system. The labile Fe²⁺ pool reacts with H₂O₂ to generate hydroxyl radicals, which attack membrane PUFAs, triggering lipid peroxidation and lethal oxidative damage. Unlike mammalian cells, which rely on the GPX4 antioxidant axis, bacteria prevent iron toxicity through multilayered transcriptional control centered on Fur. Upon binding a [2Fe‐2S] cluster, Fur represses siderophore synthesis and iron transport genes, restricting labile iron accumulation. Ferroptosis‐like death thus occurs only when this homeostatic network is overwhelmed, representing a failure of active iron management that can be exploited by iron‐based antimicrobial strategies. Abbreviations: ABC transporter, ATP‐binding cassette transporter; ACSL4, acyl‐coA synthetase long‐chain family member 4; Arn1p/Sit1p, siderophore iron transporter; CM, cell membrane; CoQ, coenzyme Q; Cys, cysteine; Cys2, cystine; Fe‐S, iron‐sulfur cluster; FeoB, ferrous iron transporter B; Fet34, multicopper ferroxidase; Ftr1, high‐affinity iron permease FTR1; Fur, ferric uptake regulator; GCL, γ‐glutamylcysteine synthase; Glu, glutamate; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; GSSG, glutathione disulfid; IM, inner membrane; LPCAT3, lysophosphatidylcholine acyltransferase 3; MoFpn1, ferroportin 1; NCOA4, nuclear receptor coactivator 4; PBP, periplasmic binding protein; PLOHs, phospholipid alcohols; PLOOHs, phospholipid hydroperoxides; PUFA‐PL, polyunsaturated fatty acid containing phospholipids; PUFAs, polyunsaturated fatty acids; sid, siderophore; SLC39A14, solute carrier family 39 member 14; SLC7A11/SLC3A2, solute carrier family 7 member 11/solute carrier family 3 member 2; STEAP3, six‐transmembrane epithelial antigen of prostate 3; TBDT, TonB‐dependent transporter; TFR1, transferrin receptor 1.

In both kingdoms, ferroptosis is characterized by iron dependency, accumulation of lipid peroxidation products, and distinct morphological changes such as mitochondrial shrinkage and increased membrane density (Shang et al. 2025). The Fenton reaction, in which Fe²⁺ reacts with H₂O₂ to generate hydroxyl radicals, is functionally conserved as well. Both systems rely on PUFAs as substrates for lipid peroxidation, with enzymes such as ACSL4 facilitating their incorporation into membrane phospholipids (Shang et al. 2025; Lee and Roh 2025). Furthermore, the GSH‐GPX4 axis serves as a critical antioxidant defense, where its disruption leads to unchecked lipid peroxide accumulation and cell death (Samalova et al. 2014; Fernandez and Wilson 2014).

Despite these mechanistic parallels, ferroptosis regulation in fungi exhibits distinct features across each step of the ferroptotic cascade. Regarding iron uptake, mammals primarily acquire iron through receptor‐mediated endocytosis of transferrin‐bound iron, whereas fungi employ specialized strategies, including reductive iron assimilation (RIA) and siderophore‐mediated iron uptake (Shang et al. 2025; Nevitt and Thiele 2011). For example, in Candida albicans (C. albicans), RIA relies on a high‐affinity iron permease (Ftr1) and a multicopper ferroxidase (Fet34), which oxidizes Fe²⁺ to Fe³⁺ and channels it directly to Ftr1 for transport into the cytoplasm (Ziegler et al. 2011). C. albicans also expresses transporters such as Arn1p/Sit1p, which specifically mediate the uptake of ferrichrome‐type siderophores (Heymann et al. 2002). For iron valence state conversion, both kingdoms utilize STEAP family proteins to reduce Fe³⁺ to Fe²⁺ (Shang et al. 2025). However, fungal systems exhibit greater redundancy in these reductases, with multiple FRE homologs responding to environmental iron availability (Bairwa et al. 2017; Chhabra et al. 2020). Regarding iron efflux, the membrane protein MoFpn1 in Magnaporthe oryzae (M. oryzae) functions as a ferroportin homolog that exports both Fe²⁺ and Fe³⁺, and its selective degradation via autophagy represents a critical fungal‐specific trigger for ferroptosis by promoting intracellular iron accumulation (Long et al. 2025). In lipid peroxidation, both kingdoms utilize lipoxygenases (LOXs) to catalyze PUFA oxidation, but fungi possess unique isoforms such as manganese LOX identified in M. oryzae (Oliw 2022). Moreover, fungal membranes incorporate ergosterol, whose conjugated double bonds confer intrinsic antioxidant capacity (Qian et al. 2024; Li et al. 2024a; Dupont et al. 2021). This feature renders fungi intrinsically less sensitive to ROS‐induced peroxidation than animal cells under ferroptotic stress. However, treatment with azole antifungals, which inhibit ergosterol synthesis, induces significant membrane stress that may counteract this inherent protection (Revie et al. 2018; Luna‐Tapia et al. 2021). Beyond these differences, fungi also exhibit completely distinct regulatory mechanisms absent in mammals. The PPZ1‐TORC1 signaling axis in C. albicans represents a fungal‐specific pathway that links nutrient sensing to ferroptosis sensitivity through autophagy modulation (Miao et al. 2025).

Although sharing core ferroptotic machinery with mammals, fungi exhibit distinct iron uptake systems, unique LOXs, and ergosterol‐mediated membrane protection. Additionally, in some fungal pathogens, ferroptosis is required for infection‐related development, so blocking this process through iron chelation or LOX inhibition may directly disrupt the infection cycle, offering a strategy conceptually distinct from host‐protective chelation (Helmann 2025; Murdoch and Skaar 2022). These features not only expand our understanding of eukaryotic cell death but also provide promising targets for developing antifungal therapies that circumvent resistance mechanisms prevalent in clinical settings.

3.1.2. Ferroptosis‐Like Death in Bacteria

Given the fundamental nature of iron and lipid metabolism in eukaryotes, researchers have begun to investigate whether a similar process of regulated and iron‐dependent death occurs in prokaryotes. While direct evidence for a conserved and endogenous pathway mirroring the mammalian system is still ambiguous, there is compelling evidence for an FLD in bacteria (Figure 3B).

The pathway of bacterial iron toxicity begins with the acquisition of iron from the environment. To survive in iron‐limited conditions, bacteria synthesize and secrete high‐affinity chelators called siderophores (Schalk 2025; Calvanese et al. 2024). These low‐molecular‐weight molecules, which utilize catecholate, hydroxamate, or α‐hydroxycarboxylate functional groups to chelate Fe³⁺, are exported extracellularly, where they scavenge iron from the surrounding environment or from host proteins such as transferrin and lactoferrin (Schalk 2025; Vijay et al. 2023). The resulting siderophore‐Fe³⁺ complexes are then recognized by specific outer membrane TonB‐dependent transporters (TBDTs), which exhibit remarkable specificity for particular siderophores or closely related families (Celia et al. 2016; Schalk 2025; Schalk et al. 2012). Energy for transport across the outer membrane is transduced by the inner membrane TonB‐ExbB‐ExbD complex, which harnesses the proton motive force to drive conformational changes in the TBDT (Celia et al. 2016). Following translocation into the periplasm, the siderophore‐Fe³⁺ complex is bound by periplasmic binding proteins and delivered to ATP‐binding cassette (ABC) transporters for inner membrane passage into the cytoplasm (Schalk 2025). Notably, pathogens such as P. aeruginosa may express over a dozen distinct TBDTs, enabling utilization of both endogenously produced siderophores and xenosiderophores from competing microorganisms, reflecting the intense evolutionary pressure to acquire this essential nutrient (Chan and Burrows 2023; Schalk 2025).

Once internalized, the critical step of iron release from the siderophore complex occurs. This process invariably involves the reduction of Fe³⁺ to Fe²⁺. Bacteria employ diverse ferric reductases for this purpose, which can be broadly categorized as soluble or membrane‐bound enzymes (Cain and Smith 2021). Soluble ferric reductases include nonspecific flavin reductases, such as Fre in E. coli, which use reduced flavins (e.g., FMNH₂) generated from NAD(P)H to reduce various Fe³⁺ complexes (Cain and Smith 2021; Trindade et al. 2019). More specialized are the siderophore‐interacting proteins (SIPs) like YqjH in E. coli, which binds specifically to catecholate siderophores, and the [2Fe‐2S] cluster‐containing FhuF that targets hydroxamate‐type siderophores (Matzanke et al. 2004; Miethke and Marahiel 2007). Membrane‐bound ferric reductases, such as the di‐heme cytochrome b₅₆₁ family protein FrcB in Bradyrhizobium japonicum or the FpvG protein involved in pyoverdine utilization in P. aeruginosa, transfer electrons across the cytoplasmic membrane to reduce Fe³⁺‐siderophores in the periplasm or extracellular space (Ganne et al. 2017; Cain and Smith 2021). Additionally, some systems like the mycobacterial transporter IrtAB feature a membrane‐tethered siderophore‐interacting domain that couples ferric siderophore import directly with reduction (Arnold et al. 2020; Cain and Smith 2021). This conversion is essential because Fe²⁺ has a much lower affinity for the siderophore, facilitating its dissociation. An alternative route involves the Feo system, where the FeoB protein directly transports ferrous iron Fe²⁺ across the membrane using energy from nucleotide hydrolysis (Shin et al. 2021; Calvanese et al. 2024). This GTPase/ATPase‐driven permease is particularly critical in low‐oxygen environments where ferrous iron predominates and plays an essential role in the virulence of pathogens such as S. aureus (Shin et al. 2021).

The liberated ferrous iron can then participate in the Fenton reaction, a harmful process within the cell where Fe²⁺ reacts with hydrogen peroxide (H₂O₂), a byproduct of aerobic respiration. This reaction generates highly reactive hydroxyl radicals and regenerates Fe³⁺ (Abeydeera 2025). The hydroxyl radical is one of the most potent ROS known. Due to its extreme reactivity, it indiscriminately attacks nearby cellular components, with a primary target being the PUFAs within the bacterial cell membrane. This attack initiates a process of lipid peroxidation and damages proteins, DNA, and other essential cellular components, ultimately causing cell death (Ye et al. 2020; Hrioua et al. 2021). Therefore, it underpins the activity of iron‐based antimicrobials such as Fe(hinokitiol)₃ and Fe(8‐hydroxyquinoline)₃, which have demonstrated potent bactericidal effects against MRSA by leveraging Fenton chemistry to induce oxidative damage (Abeydeera 2025).

However, a significant challenge in inducing FLD in bacteria is the sophisticated regulatory control exerted by the Ferric Uptake Regulator (Fur). In response to elevated intracellular iron, Fur binds a [2Fe‐2S] cluster via cysteine residues at a specific site, which drives its dimerization and enables sequence‐specific DNA binding (Ding 2025). This [2Fe‐2S] cluster assembly is enzymatically catalyzed by the Fe‐S cluster scaffold protein IscU (Ding 2025; Bennett et al. 2022; Sato et al. 2021). When intracellular iron is abundant, this [2Fe‐2S] cluster‐bound Fur represses genes involved in siderophore synthesis and iron transport, effectively shutting down further iron acquisition (Ding 2025; Calvanese et al. 2024). This negative feedback loop prevents the cytosolic accumulation of labile iron that would otherwise drive Fenton chemistry. Beyond Fur, other regulatory factors, such as small non‐coding RNA RyhB, sRNA VaRyhB, and atypical orphan response regulator SsoR, also fine‐tune iron homeostasis (Jie et al. 2025; Li et al. 2024b; Massé et al. 2005; Massé and Gottesman 2002). Therefore, for iron toxicity to occur, these multilayered homeostatic mechanisms must be overwhelmed, either by a sudden massive iron influx that exceeds regulatory capacity or by conditions that impair these regulatory systems. This regulatory barrier explains why iron‐induced death is not merely a function of environmental iron concentration but rather a consequence of failing homeostatic control.

In essence, bacterial FLD parallels mammalian ferroptosis in its core execution phase: iron‐catalyzed Fenton chemistry and subsequent lipid peroxidation. The critical distinction lies in the regulatory systems whose failure permits this process. Mammalian ferroptosis is primarily suppressed by the dedicated antioxidant enzyme GPX4, whereas bacteria rely on multilayered transcriptional networks centered on Fur to maintain iron homeostasis. Bacterial iron toxicity thus represents a failure of active homeostatic management rather than mere iron overload, which is a notable vulnerability that can be strategically exploited in antimicrobial development.

3.2. Cuproptosis Pathways in Microbes

Parallel to the emerging understanding of ferroptosis in microorganisms, the investigation of cuproptosis has similarly extended into the microbial world, where distinct cellular architectures and metal homeostasis networks shape its specific manifestations. This section examines cuproptosis‐like mechanisms in microbes, highlighting both evolutionary conservation and kingdom‐specific adaptations.

3.2.1. Cuproptosis‐Like Death in Fungi

As eukaryotes, fungi are more likely to possess a conserved cuproptosis pathway (Figure 4A). Indeed, copper‐based compounds are potent antifungal agents, and the principles of copper toxicity are broadly similar to those in mammals, involving copper accumulation and protein aggregation (Fatima et al. 2024). The disruption of Fe‐S cluster proteins is also a recognized mechanism of copper toxicity in fungi (Garcia‐Santamarina et al. 2017).

FIGURE 4.

The mechanisms of cuproptosis‐like death in microorganisms. Created with BioGDP.com (Jiang et al. 2025b). (A) Cuproptosis‐like death in fungi. Fungi and mammals share a core cuproptotic mechanism in which excess copper targets mitochondrial lipoylated TCA cycle proteins such as DLAT, inducing their aggregation, Fe‐S cluster protein dysfunction, and lethal proteotoxic stress. However, fungi acquire copper primarily through high‐affinity Ctr family transporters. Because fungi lack the mitochondrial reductase FDX1, Cu²⁺ must first be reduced to Cu⁺ at the plasma membrane by FRE family metalloreductases prior to import. Host nutritional immunity exploits this vulnerability by concentrating copper within phagosomes. In response, fungi activate multilayered defenses regulated by transcription factors including Mac1 and AceA, such as synthesis of metallothioneins (e.g., CUP1, Cmt1/Cmt2, Crd2), copper efflux via the P‐type ATPase CrpA, chaperone‐mediated distribution, and vacuolar sequestration through the ESCRT pathway. When these protective systems are overwhelmed, copper accumulates in mitochondria and triggers the conserved aggregation cascade accompanied by upregulation of stress chaperones such as HSP70, ultimately leading to mitochondrial collapse. (B) Cuproptosis‐like death in bacteria. Copper‐induced cell death in bacteria mirrors key features of eukaryotic cuproptosis, including copper‐driven aggregation of lipoylated proteins, disruption of Fe‐S clusters, and lethal proteotoxic stress, despite the absence of mitochondria. Excess copper enters the cytoplasm through nonspecific porins and TBDTs (e.g., OprC) in Gram‐negative bacteria or via importers such as YcnJ in Gram‐positive species, where the reducing intracellular environment generates reactive Cu⁺. Homeostasis is actively maintained by efflux systems, notably the Cue system (CopA ATPase and CueO oxidase) and the CusCFBA tripartite complex, along with copper chaperones and glutathione buffering. When these defenses are overwhelmed, Cu⁺ binds to lipoylated TCA cycle proteins (e.g., DLAT), triggering their aggregation, and dismantles [4Fe‐4S] clusters, which inactivates key dehydratases and releases iron that fuels Fenton chemistry and oxidative damage. A bacterium‐specific vulnerability involves direct Cu⁺ binding to GAPDH, which inhibits glycolysis and, together with TCA cycle disruption, produces a combinatorial metabolic collapse. Abbreviations: AceA, isocitrate lyase; cha, chalkophores; CM, cell membrane; CopA, copper‐exporting P‐type ATPase; CopC, copper resistance protein C; CopD, copper resistance protein D; CopZ, copper chaperone; CrpA, Cu ATPase transporter; Ctr, copper transporter; CueO, multicopper oxidase; CueR, copper efflux regulator; Cus, copper efflux system protein; DLAT, dihydrolipoamide S‐acetyltransferase; ESCRT, endosomal sorting complexes required for transport; EV, extracellular vesicle; Fe‐S, iron‐sulfur cluster; FRE, ferric reductase; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; IM, inner membrane; IscA, iron‐sulfur cluster assembly protein; Pco, plasmid‐encoded copper resistance system; TBDT, TonB‐dependent transporter.

Fungi actively acquire copper through dedicated uptake systems to meet essential physiological demands, as this metal serves as a critical cofactor for enzymes involved in respiration, antioxidant defense, iron acquisition, and pathogenesis (Festa and Thiele 2011). The high‐affinity copper transporters of the Ctr family are conserved across fungal species and mediate the copper uptake process (Jia et al. 2025; Moraes et al. 2023). Fungi possess both plasma membrane Ctr proteins for high‐affinity copper uptake from the environment and vacuolar membrane Ctrs such as Ctr2 that mobilize stored copper from the vacuole lumen into the cytosol during deficiency (Gómez‐Gallego et al. 2019). The number of these transporters varies across species, ranging from two in Saccharomyces cerevisiae to four in Aspergillus fumigatus (A. fumigatus), with some fungi like Schizosaccharomyces pombe requiring heteromeric assembly of Ctr4 and Ctr5 to form a functional complex (Beaudoin et al. 2006; Park et al. 2014; Shi et al. 2021). Notably, this uptake is restricted to Cu⁺. Mammalian cells can internalize Cu²⁺ as the mitochondrial reductase FDX1 can reduce Cu²⁺ to Cu⁺ within the organelle (Zulkifli et al. 2023). But fungi lack FDX1 homologs, so they must finish the reduction exclusively at the cell surface via plasma membrane metalloreductases like the FRE family prior to Ctr‐mediated import (Shi et al. 2003).

The essential requirement of copper, however, is exploited by the mammalian host as an antimicrobial strategy through nutritional immunity, wherein immune cells actively concentrate copper within phagosomes to kill engulfed fungi (Garg et al. 2024; Moraes et al. 2023). In response to such host‐imposed copper stress, fungi have evolved sophisticated multilayered defense systems. Upon sensing copper excess via transcription factors such as Mac1 and AceA, fungi activate multilayered detoxification mechanisms, which include synthesis of metallothioneins, copper storage into vesicles, copper efflux, and inhibition of copper absorption (Moraes et al. 2023). Metallothioneins are cysteine‐rich proteins that chelate excess copper. For example, S. cerevisiae employs CUP1, C. neoformans encodes Cmt1 and Cmt2 with clustered Cys‐X‐Cys motifs, and Candida albicans utilizes Crd2. A. fumigatus additionally relies on the copper‐exporting P‐type ATPase CrpA to efflux copper, and its transcription factor AceA coordinates both copper and zinc detoxification by regulating CrpA and ZrcA. Notably, Paracoccidioides species lack conventional metallothioneins but may compensate through an extended C‐terminal domain in their copper chaperone for superoxide dismutase (CCS), which features negatively charged and hydrophilic residues capable of metal binding, suggesting an alternative copper buffering strategy. Intracellular copper distribution is also mediated by other chaperones such as Atx1, Cox17, and Ccs1. Recent evidence also reveals that the ESCRT pathway provides an additional layer of defense by mediating the vacuolar sequestration of excess copper via the Ctr3 transporter (Jia et al. 2025). Through these coordinated mechanisms, fungi prevent cytoplasmic copper overload and the induction of cuproptosis. Understanding this evolutionary competition informs the design of copper‐based antifungal strategies that could overwhelm these fungal defense mechanisms.

When this protective barrier is overwhelmed, copper ions accumulate in the cytosol and specifically target mitochondria, where they bind directly to lipoylated TCA cycle proteins, particularly DLAT, inducing their aggregation. Concurrently, copper toxicity compromises Fe‐S cluster protein function. This dual attack triggers severe proteotoxic stress, accompanied by the upregulation of cytoprotective chaperones such as HSP70 as a hallmark of the cellular stress response, ultimately culminating in mitochondrial collapse and cell death (Wang, Gui, et al. 2025; Tsvetkov et al. 2022).

Thus, while fungi share the core lipoylated protein targeting mechanism with animals, they possess additional multilayered defense systems that operate upstream to prevent cuproptosis induction. Elucidating these fungal‐specific protective layers reveals exploitable vulnerabilities, suggesting that combining copper‐based compounds with inhibitors of these defense mechanisms could potentiate cuproptosis and enhance antifungal efficacy.

3.2.2. Cuproptosis‐Like Death in Bacteria

Copper‐induced cell death in bacteria, termed cuproptosis‐like death (CLD), shares fundamental mechanistic features with eukaryotic cuproptosis despite the absence of mitochondria in prokaryotic cells (Figure 4B).

The process initiates when excess copper accumulates within the bacterial cytoplasm, where the reducing environment rapidly converts the less toxic Cu²⁺ to the highly reactive Cu⁺ form. In Gram‐positive Bacillus subtilis, the membrane protein YcnJ functions as a copper importer, whose extracellular CopC domain specifically acquires Cu²⁺ from the membrane‐associated protein YcnI, although whether YcnJ transports Cu²⁺ or reduces it to Cu⁺ during translocation remains unresolved (de Oliveira Silva et al. 2025). Once internalized, the reducing cytoplasmic environment ensures that copper ultimately exists as Cu⁺, which is then bound by the copper chaperone CopZ and safely delivered to P₁B‐type ATPase efflux pumps like CopA for export to prevent cytosolic damage (Pellosi et al. 2025; Samanovic et al. 2012). In Gram‐negative bacteria, copper uptake involves a multi‐step relay across the double membrane. Copper crosses the outer membrane via porin‐mediated passive diffusion or through TBDTs like P. aeruginosa OprC, which binds both Cu⁺ and Cu²⁺ (Bhamidimarri et al. 2021; Andrei et al. 2020; Balasubramanian et al. 2011; Speer et al. 2013). But these porins or transporters are considerably less selective and are often evolved for other cations (Rensing and McDevitt 2013). This nonspecific uptake renders bacteria particularly vulnerable to copper overload when environmental concentrations rise. In the periplasm, copper is captured by chaperones such as CopC and delivered to inner membrane transporters. These include P₁B‐type ATPases, MFS transporters, and CopD family proteins, though their import mechanisms remain poorly understood (Palmer and Rosenzweig 2026; Andrei et al. 2020; Wijekoon et al. 2015). To cope with copper toxicity, Gram‐negative bacteria employ two major efflux systems. The Cue system serves as the primary aerobic defense by exporting cytoplasmic Cu⁺ via the P₁B‐type ATPase CopA and oxidizing it to less toxic Cu²⁺ in the periplasm via the multicopper oxidase CueO (Ishihara et al. 2023; Becam et al. 2025; Chen et al. 2025). While in emergency, the Cus system responds under anaerobic conditions or high copper stress by directly extruding periplasmic Cu⁺ to the extracellular space through the tripartite CusCFBA complex (Fung et al. 2013; Andrei et al. 2020; Chen et al. 2025). Organisms lacking the Cus system, such as Salmonella, may employ alternative proteins like CueP to manage periplasmic copper (Méndez et al. 2022). Together, these diverse mechanisms form a coordinated network that maintains copper homeostasis across different cellular compartments.

When homeostatic mechanisms are overwhelmed, accumulated Cu⁺ directly induces widespread protein aggregation, mirroring the hallmark feature of eukaryotic cuproptosis (Wang, Gui, et al. 2025). Although bacteria lack the FDX1 reductase that in mammals mediates copper reduction within mitochondria, the core phenomenon of abnormal protein aggregation, particularly affecting conserved TCA cycle proteins such as those with lipoic acid modifications, represents a convergent mechanism of proteotoxic stress across kingdoms (Wang, Gui, et al. 2025). Studies in E. coli demonstrate that Cu⁺ triggers aggregation of proteins enriched in cysteine and histidine residues (Zuily et al. 2022). This mechanism is conserved in pathogens such as S. aureus, where copper induces specific aggregation of lipoylated proteins, including DLAT (Xue et al. 2024).

The molecular targets of copper toxicity in bacteria also include Fe‐S clusters, which serve as essential cofactors for dehydratases involved in branched‐chain amino acid biosynthesis and TCA cycle enzymes. Copper ions preferentially dismantle [4Fe–4S] clusters, displacing iron and causing enzyme inactivation (Tan et al. 2014; Chaturvedi and Henderson 2014). This disruption creates conditional auxotrophy for branched‐chain amino acids, fundamentally compromising bacterial metabolism (Macomber and Imlay 2009). The released iron from degraded Fe‐S clusters further fuels Fenton chemistry, amplifying oxidative stress and creating a lethal positive feedback loop (Macomber and Imlay 2009). Beyond attacking existing clusters, copper also competes with iron for the metal‐binding site in IscA, a key scaffold protein for Fe‐S cluster biogenesis, thereby inhibiting the assembly of new [4Fe‐4S] clusters in E. coli (Tan et al. 2014).

Copper toxicity in bacteria is amplified through Fenton‐like reactions generating ROS. Copper interacts with H₂O₂ to produce hydroxyl radicals, damaging lipids, proteins, and nucleic acids. Released iron from degraded Fe‐S clusters further fuels this oxidative stress, creating a lethal feedback loop. To counter this, GSH serves as an intracellular buffer, temporarily binding excess copper (Stewart et al. 2020). For survival under high copper stress, some bacteria harbor plasmid‐based systems such as Pco, which provide enhanced resistance (Fang et al. 2016). These layered defenses collectively enable bacteria to withstand copper‐induced oxidative assault. Bacteria also employ chaperones like DnaK to counter this proteotoxicity, indicating that protein aggregation represents a central and direct pathway of copper toxicity alongside oxidative stress (Zuily et al. 2022).

Beyond these shared oxidative mechanisms, bacteria exhibit unique vulnerabilities that distinguish their copper‐induced death from eukaryotic cuproptosis. Most distinctively, a bacterial‐specific pathway identified in S. aureus involves direct Cu⁺ binding to glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), inhibiting this central glycolytic enzyme and inducing a metabolic starvation state (Riboldi et al. 2026). This mechanism bypasses TCA‐cycle‐specific targeting, creating a parallel route to energy failure that has not been described in eukaryotic cuproptosis. The simultaneous disruption of both principal energy‐generating pathways, the TCA cycle through lipoylated protein aggregation and glycolysis through GAPDH inhibition, creates a combinatorial metabolic collapse that rapidly overwhelms bacterial defenses.

Understanding these multifaceted mechanisms offers promising therapeutic strategies for combating antibiotic‐resistant infections by exploiting this ancient toxicity pathway.

3.3. Reciprocal Facilitation of Ferroptosis and Cuproptosis

While ferroptosis is classically defined by iron‐dependent lipid peroxide accumulation, and cuproptosis by copper‐induced aggregation of lipoylated proteins, their combination offers remarkable synergistic potential against bacterial pathogens (Figure 5).

FIGURE 5.

The interplay of ferroptosis and cuproptosis in microbes. Created with BioGDP.com (Jiang et al. 2025b). Ferroptosis and cuproptosis synergistically kill bacteria by converging on multiple shared targets. Both metals drive Fenton/Haber‐Weiss chemistry with H₂O₂ to generate hydroxyl radicals that initiate lipid peroxidation and membrane damage. In eukaryotes, mitochondria integrate the two pathways, but in bacteria, this role is taken by the respiratory chain and cytosolic TCA cycle enzymes. Fe‐S clusters are a key convergent node, as copper dismantles clusters and impairs their biogenesis, releasing iron that further fuels Fenton reactions, while iron‐driven lipid peroxidation disrupts membrane integrity. Both metals deplete GSH, crippling peroxidase defenses and exacerbating lipid peroxidation. Copper stress triggers adaptive upregulation of iron uptake. Consequently, restricting iron while supplying copper creates a synthetic lethal condition that mimics host nutritional immunity. Abbreviations: CM, cell membrane; CopA, copper‐exporting ATPase; CueO, multicopper oxidase; CueR, copper efflux regulator; Fe‐S, iron‐sulfur cluster; Fet3, multicopper ferroxidase; Ftr1, high‐affinity iron permease; GSH, glutathione; IscA, iron‐sulfur cluster assembly protein.

Both metals exploit Fenton/Haber‐Weiss chemistry, reacting with H₂O₂ to generate highly destructive hydroxyl radicals. H₂O₂ serves as both a common substrate and a critical regulatory hub. It is endogenously produced during bacterial respiration and exogenously deployed by host phagocytes for antimicrobial defense. The presence of iron and copper converts this moderately toxic molecule into overwhelming oxidative stress. However, this bidirectional relationship demands careful consideration, as excessive hydroxyl radical generation may activate bacterial antioxidant defenses including catalase and superoxide dismutase, potentially attenuating combination efficacy. Thus, precise modulation of local H₂O₂ concentrations emerges as a key determinant of successful iron‐copper combination therapy. The generated hydroxyl radicals initiate lipid peroxidation, abstracting hydrogen atoms from PUFAs in membrane phospholipids. Iron and copper together amplify this membrane damage, accelerating loss of integrity beyond that achieved by either metal alone. This combinatorial membrane attack represents a critical point of synergistic vulnerability.

In eukaryotic cells, mitochondria serve as the central hub integrating ferroptosis and cuproptosis by orchestrating Fe‐S cluster biogenesis, buffering redox status, and serving as the primary site for copper‐induced aggregation of lipoylated TCA cycle enzymes such as DLAT (Liu and Chen 2024). Mitochondrial dysfunction simultaneously amplifies lipid peroxidation through enhanced ROS production and triggers proteotoxic stress via copper accumulation, thereby synergizing both death pathways within a single organelle. Iron and copper homeostasis are further intertwined through shared biosynthetic pathways that converge on the Golgi apparatus. Copper serves as an essential cofactor for the multicopper ferroxidase Fet3, which acquires copper in the Golgi lumen via the P‐type ATPase Ccc2 and the chloride channel Gef1 before trafficking to the plasma membrane for high‐affinity iron uptake, while iron availability reciprocally influences the expression of copper detoxification genes such as the CrpA efflux pump (Moraes et al. 2023).

In bacteria, which lack mitochondria and Golgi apparatus, this integrative role is assumed by the cytoplasmic membrane‐embedded respiratory chain and the cytosolic TCA cycle enzymes (Denic et al. 2023; Fung et al. 2013). Together, they form a coupled energy production network wherein iron‐driven lipid peroxidation compromises membrane integrity while copper‐induced protein aggregation disrupts core metabolism, creating a convergent metabolic collapse that mirrors the mitochondrial synergy observed in eukaryotes. A pivotal shared target is Fe‐S clusters, essential cofactors for respiratory enzymes and TCA cycle dehydratases. Copper toxicity not only directly damages existing Fe‐S cluster enzymes, releasing free iron that further fuels Fenton chemistry and amplifies oxidative stress, but also impairs the Fe‐S cluster biogenesis machinery itself, as demonstrated by the induction of the alternative Suf system under copper stress conditions (Fung et al. 2013). This positive feedback loop simultaneously disrupts both the TCA cycle and respiratory chain, inducing metabolic collapse characterized by ATP depletion and NADH/NAD⁺ imbalance. The resultant energy failure compounds direct oxidative injury, rapidly overwhelming bacterial homeostasis. Beyond Fe‐S cluster targeting, bacterial iron‐copper crosstalk is highly specific. In Caulobacter crescentus, the TonB‐dependent iron transporter CciT is required for copper resistance, as enhanced iron uptake reduces copper accumulation (Cherry et al. 2025). Disrupted iron homeostasis conversely sensitizes bacteria to copper. In E. coli, zinc excess upregulates iron uptake, causing iron accumulation that poisons the copper‐responsive transcription factor CueR (Xu et al. 2019). This dysregulates copA and cueO while activating the secondary Cus system, thereby decreasing copper tolerance (Xu et al. 2019).

Both metals also converge on GSH, the primary intracellular redox buffer. Copper directly binds GSH thiol groups, while overwhelming oxidative stress consumes it. This depletion synergistically cripples bacterial defenses by compromising GSH‐dependent peroxidases that normally reduce lipid peroxides, thereby exacerbating iron‐driven membrane damage. Autophagy serves as another shared regulatory mechanism influencing both ferroptosis and cuproptosis. Autophagic processes can modulate iron availability through ferritinophagy (degradation of iron‐storage ferritin) and may similarly influence copper homeostasis, thereby setting the activation threshold for both metal‐induced death programs (Liu and Chen 2024).

But actually, the combination of iron restriction and copper supplementation is more effective at inducing microbial death than simply increasing both metals. This is because copper toxicity triggers an adaptive response in bacteria. Upon copper stress, cells actively upregulate iron uptake systems, such as the FbpABC and Ftr transporters, to support the synthesis of [4Fe‐4S] clusters and maintain ROS detoxification (Steunou et al. 2020). When iron is readily available, this adaptive repair mechanism allows bacteria to partially counteract copper‐induced damage, thereby surviving the assault. Conversely, limiting iron availability while simultaneously exposing cells to copper creates a synthetic lethal condition. The bacteria are unable to repair copper‐damaged Fe‐S clusters or fuel antioxidant defenses, leading to metabolic collapse and heightened sensitivity even at low copper concentrations (Steunou et al. 2020). This iron restriction strategy, which mirrors host nutritional immunity, offers a powerful approach to enhance copper‐based antimicrobial efficacy while minimizing metal pollution.

Ultimately, the distinct death pathways complement one another. Iron potentiates lipid peroxidation as its primary executing mechanism, while copper simultaneously induces proteotoxic stress through lipoylated protein aggregation. This multi‐target assault on membranes, metabolism, and proteins presents a formidable challenge to bacterial resistance mechanisms, as pathogens must simultaneously overcome multiple independent lethal pathways.

4. Targeting Ferroptosis and Cuproptosis for Postharvest Protection

Although initially developed for oncology (Luo et al. 2022; Xie et al. 2023), ferroptosis and cuproptosis inducers have been extended to medical antimicrobial uses as cancer cells and pathogenic microbes share similar vulnerability to metal‐induced toxicity (Wang et al. 2025). For wound infections, copper‐based nanozymes have demonstrated antibacterial activity against E. coli and methicillin‐resistant S. aureus (MRSA) by amplifying cuproptosis under near‐infrared irradiation, while iron starvation strategies have been validated in MRSA‐infected diabetic wound models to enhance cuproptosis‐like bacterial death (Gao et al. 2025; Fang et al. 2025). In systemic bacterial infections, such as tuberculosis, copper ionophores like disulfiram and elesclomol are being investigated for their ability to exploit Mycobacterium tuberculosis (M. tuberculosis) vulnerability to copper toxicity (Dawi et al. 2025). In acute pneumonia, Cu₂O‐BSO nanoparticles trigger CLD in MRSA and P. aeruginosa for nebulized treatment (Hu et al. 2025), while Fe/TNT@NM nanozymes induce ferroptosis to eradicate P. aeruginosa biofilms and alleviate lung injury (Du et al. 2025).

The success of these metal‐based antimicrobial strategies in medicine paves the way for their translation to postharvest FV preservation, because medical pathogens like S. aureus and E. coli also cause foodborne illness, and postharvest spoilage involves fungi such as Penicillium and Botrytis sensitive to metal ions as well. Several pioneering studies have used metal homeostasis disruption as an antimicrobial principle (Table 2), delivering iron or copper ions by different methods to induce FLD and CLD for postharvest preservation.

TABLE 2.

The application of ferroptosis and cuproptosis in fruit and vegetable preservation.

Mechanism	Delivery methods	FV types	Target microbes	Forms of iron/copper	References
Ferroptosis	Free iron‐based synergies	Hami melon, cherry tomato	E. coli O157:H7	FeSO4 combined with ultrasound‐emulsified cinnamaldehyde nanoemulsion (CALNO)	Sun et al. (2024)
		—	L. monocytogenes	Blue light‐assisted FeSO4 treatment	Zhu et al. (2025)
	Ion‐loaded biopolymer films and coatings	Grape, purple kale, cherry tomato	P. aeruginosa	FeSO4@carboxymethyl chitosan (CMCS) agar‐based film	Sun et al. (2025b)
		Tangerine, cherry tomato, grape	Penicillium expansum	FeSO4@Fe2(SO4)3@GEL@agar composite film	Sun et al. (2025a)
		Wax apple	Fusarium sp.	Chitosan composite coating containing tannic acid (TA)‐Fe	Guo et al. (2025)
	Iron‐based nanomaterials	Peach	A. flavus	Myco‐synthesized iron oxide nanoparticles (Fe2O3 NPs)	Akbar et al. (2024)
		Blueberry	S. aureus, L. monocytogenes, S. enterica, E. coli	Silver‑iron nitroprusside nanoparticles (Ag‐FeNNPs) incorporated starch‐xanthan gum (ST‐XG) films	Zhang et al. (2025)
		Strawberry	Broad‐spectrum	Fe‐DNA‐curcumin nanocomposite @ chitosan coating	Li et al. (2025b)
		Pepper	Enterobacter, Chryseobacterium	Fe‐P nanomaterials (Fe‐P NMs)	Cheng et al. (2025)
		Apple	S. aureus, E. coli, MARS, A. niger	Urushiol (U1) and its antiseptics (U2, U3)‐functionalized silver‐coated nanoscale zero‐valent iron composites (Ag@ZVI NPs1‐3)	Li et al. (2025a)
		Strawberry	—	Chitosan and iron oxide nanoparticles (NPs) supplemented with ginger and garlic extracts and combined with Fe3O4 NPs	Sani et al. (2024)
		Apple	E. coli, S. aureus	Methylcellulose/chitosan nanofiber‐based composites doped with lactoferrin‐loaded Ag‐MOF nanoparticles	Tavassoli et al. (2024)
		Cherry tomato	L. monocytogenes, S. aureus, E. coli, S. enterica, A. flavus, and Penicillium chrysogenum	Iron‐based metal‐organic framework (MOF) with carbon quantum dots (CD@MOF) particles incorporated into agar/gelatin (Agar/Gel) blend polymers	Riahi et al. (2024)
		Apple	E. coli	Ni1Co1Fe1‐MOFs and Ni6Co3Fe1‐MOFs	Pu et al. (2024)
	Iron chelation	Blueberry	A. alternata, F. fujikuroi	Deferoxamine mesylate acted as an iron chelator	Gu et al. (2025)
Cuproptosis	Copper‐loaded composite films	Cherry tomato, purple kale	E. coli O157:H7	CuSO4@natamycin(Nata) @Carboxymethylcellulose@ Agar film	Sun et al. (2025c)
	Copper‐based nanoparticles	Tomato	B. cinerea	Chitosan‐decorated copper oxide nanocomposite (CH@CuO NPs)	Ismail et al. (2023)
		Watermelon	A. citrulli	Biosynthesized copper nanoparticles (Bio‐CuNPs)	Noman et al. (2023)
		Mango	Colletotrichum gloeosporioides	Copper oxide nanoparticles (CuO NPs) synthesized by Azadirachta indica	Joshi et al. (2025)
		Potato	Pectobacterium carotovorum	Synthetic copper nanoparticles (Cu‐NPs) from citrus peels	Usman et al. (2024)
	Copper‐based nanozymes	Banana, apple	E. coli, S. aureus	Copper‐taxfolin (CuTax) nanozyme/chitosan edible coating	Luo et al. (2025)
		Cherry tomato	E. coli, S. aureus	Chitosan/ZIF‐67‐Cu MOF nanozyme/carboxymethyl cellulose film	Xu et al. (2025)
		Strawberry	E. coli, S. aureus	Copper ion‐lysozyme (CuLyz) nanozyme/PVA/tannic acid hydrogel film	Li et al. (2025c)
	Copper‐based MOFs and stimuli‐responsive systems	Peach, grapes, blueberry	S. aureus, E. coli, B. cinerea	α‐Lipoic acid (LA) @Cu‐MOF film (pH/humidity dual‐responsive)	Men et al. (2025)
		Blueberry	Postharvest pathogenic fungi	Copper‐based metal‐organic frameworks (F‐HKUST)/ethyl cellulose/gelatin electrospun Fiber loading carvacrol (humidity‐triggered)	Xie et al. (2025)
		Cherry tomato	E. coli, S. aureus	Cu‐chlorogenic acid nanoparticles (Cu‐CGA NPs) /karaya gum/gelatin film (NIR‐responsive)	Jiang et al. (2025a)
Interplay of ferroptosis and cuproptosis		Banana	E. coli, S. aureus	Fe/Cu‐metal organic framework (MOF)‐tartaric acid (TA) complexes	Yu et al. (2026)
		Strawberry	B. cinerea	CuFe twinned nanocrystals (CuFe NCs) composite film	Liu et al. (2025)
		Strawberry	B. cinerea	Cu‐Fe/sodium alginate (SA) /gelatin (GL) film	Lu (2024)

4.1. Ferroptosis‐Based Strategies in Postharvest Protection

The historical use of iron in food preservation dates back to 1810, when Peter Durand patented tin‐coated iron cans. This innovation prevented direct food contact with iron while enabling long‐term storage through heat sterilization. In the 20th century, iron‐based oxygen absorbers were developed, utilizing iron powder to remove headspace oxygen and inhibit aerobic spoilage. These historical applications serve as practical precursors to contemporary mechanistic exploitation of ferroptosis in food preservation.

Current ferroptosis‐based interventions can be categorized by the delivery and formulation strategy employed, each designed to overcome the inherent challenges of applying iron in complex postharvest environments.

4.1.1. Free Iron‐Based Synergies

Direct supplementation of excess Fe²⁺ is the most intuitive ferroptosis induction strategy, but its independent efficacy is limited. A recent study demonstrated that FeSO₄ exposure drove Listeria monocytogenes into a viable but non‐culturable (VBNC) state rather than ferroptosis, representing a latent safety risk (Liu et al. 2023). Sun et al. (2024) overcame such limitations by combining FeSO₄ with ultrasound‐emulsified cinnamaldehyde nanoemulsion, thus amplifying membrane damage, intracellular leakage, and biofilm suppression against E. coli O157:H7. Addressing the VBNC problem directly, Zhu et al. (2025) applied blue light to FeSO₄‑treated L. monocytogenes, achieving a 94.73% viability reduction within 4 h, accompanied by iron accumulation, ROS burst, and lipid peroxidation. Proteomics revealed downregulation of iron homeostasis and oxidative stress defense genes (Zhu et al. 2025).

These findings establish that free Fe²⁺ requires synergistic partners to enforce ferroptotic death and counteract microbial evasion. A likely reason is that microbial cell walls and membranes act as permeability barriers that restrict passive Fe²⁺ influx, while the co‐applied agents or physical fields increase membrane permeability or directly disrupt its integrity, thereby permitting lethal intracellular iron accumulation.

4.1.2. Ion‐Loaded Biopolymer Films and Coatings

The other prevalent approach is incorporating Fe²⁺ or Fe³⁺ into edible polysaccharide matrices such as carboxymethyl chitosan, agar, or gelatin. These films create a surface‐confined iron pool that resists scavenging by fruit phenolics and pectins while establishing a favorable microenvironment for ferroptosis at the pathogen interface. For instance, FeSO₄–cinnamaldehyde nanoemulsion–carboxymethyl chitosan films effectively triggered ferroptotic hallmarks against E. coli O157:H7 and P. aeruginosa, while simultaneously suppressing biofilm genes (Sun et al. 2025a, 2025b). Similarly, chitosan coatings double‐crosslinked by tannic acid and Fe³⁺ limit gas exchange and reduce oxidative damage, thereby extending wax apple shelf life (Guo et al. 2025).

These films illustrate iron's dual role as ferroptosis inducer and matrix crosslinker, enabling effective postharvest antimicrobial control.

4.1.3. Iron‐Based Nanomaterials

Iron‐based nanomaterials encapsulate iron to realize controlled release and synergistic oxidative damage. Nanoparticles (NPs) and metal‐organic frameworks (MOFs) are two common forms used in postharvest applications.

NPs are amorphous or semi‐crystalline structures formed through coordination, electrostatic, or hydrogen‐bonding interactions. Iron is entrapped within these particles via coordination‐driven self‐assembly, metal‐phenolic complexation, or co‐precipitation during green synthesis, converting soluble ions into stable and dispersible nanoscale delivery units. Direct‐contact killing relies on nanoparticle adhesion to microbial surfaces followed by membrane disruption or localized ROS generation. Green‐synthesized Fe₃O₄‐chitosan coatings exemplify this approach, reducing strawberry weight loss and suppressing fungal infection through sustained contact‐mediated activity (Sani et al. 2024). Smart stimuli‐responsive delivery exploits environmental cues for targeted release. Fe‐DNA‐curcumin NPs release iron and curcumin specifically in bacterial acidic microenvironments, achieving pH‐responsive precision that maximizes ferroptotic damage at infection sites (Li et al. 2025b). Catalytic oxidative amplification leverages the Fenton or Fenton‐like activity of iron‐based NPs to continuously generate hydroxyl radicals from endogenous or exogenous H₂O₂. Ag‐decorated zero‐valent iron NPs inactivate 99% of bacteria within 60 min through sustained hydroxyl radicals’ production (Li et al. 2025a), while silver‐iron nitroprusside NPs embedded in starch‐xanthan gum films extend blueberry shelf life through combined catalysis and sustained ion release (Zhang et al. 2025).

MOFs are highly ordered crystalline frameworks in which iron nodes are periodically linked by organic ligands through coordination bonds, possessing precisely controllable pore architectures. Iron‐based MOF‐carbon dot hybrids in agar‐gelatin films blocked UV and preserved cherry tomatoes for 24 days (Riahi et al. 2024), and trimetallic Ni–Co–Fe MOFs with alginate coatings inhibited E. coli on apple via Fenton‑like catalysis (Pu et al. 2024). Their ordered porosity sustains antimicrobial release, while iron nodes continuously catalyze ROS generation, combining passive delivery with active oxidative killing.

Collectively, these nanomaterial strategies transform iron into sustainable ferroptosis inducers by providing spatiotemporal control over ion release and enabling synergistic oxidative damage at the microbial interface.

4.1.4. Iron Chelation as a Blockade Strategy

Rather than overloading, deferoxamine mesylate chelates Fe²⁺ to suppress ferroptosis in host tissues. In blueberries infected by Alternaria alternata and Fusarium fujikuroi, fungal invasion triggers host lipid peroxidation and membrane damage characteristic of ferroptosis (Gu et al. 2025). By chelating iron, deferoxamine mesylate interrupts the Fenton reaction, reduces H₂O₂ and malondialdehyde, preserves GSH and membrane lipid unsaturation, and decreases lesion area, thereby protecting fruit from infection‐associated ferroptotic injury (Gu et al. 2025). This demonstrates that ferroptosis manipulation in postharvest contexts can target both pathogen and host, depending on the therapeutic goal.

4.2. Cuproptosis‐Based Strategies in Postharvest Protection

The application of copper for antimicrobial purposes in food also has deep historical roots. Ancient practices include the use of copper vessels for water purification in Egypt and the utilization of bronze tableware, valued for its natural ability to preserve food freshness and inhibit pathogens (Wang et al. 2025). The modern era of copper‐based antimicrobials began in 1882 with the discovery of Bordeaux mixture by Millardet in France, who found that a blend of copper sulfate and lime effectively controlled grape and peach downy mildew (Lamichhane et al. 2018; Ashraf et al. 2025). Commercialized by 1885, this fungicide became a cornerstone of agricultural crop protection and remains in use today (Garinie et al. 2024). In the 20th century, copper pots were commonly employed for cooking and sterilizing FV preserves.

The ancient antimicrobial use of copper has now been reconceptualized through the lens of cuproptosis. However, compared to ferroptosis, cuproptosis‐based postharvest applications are still at an early stage, and current studies can similarly be classified by delivery format.

4.2.1. Copper‐Loaded Composite Films

The simplest strategy incorporates copper salts directly into biopolymer matrices, where Cu²⁺ ions serve as the primary antimicrobial agent. A CuSO₄@natamycin@carboxymethylcellulose@agar composite film leveraged Cu²⁺ to induce cuproptosis in E. coli O157:H7, downregulating Fe‐S cluster protein genes while synergistically reducing bacterial counts in planktonic and biofilm states (Sun et al. 2025c). Copper ions simultaneously acted as crosslinkers, improving film barrier properties, and effectively lowered E. coli O157:H7 counts on cherry tomatoes and purple kale.

4.2.2. Copper‐Based Nanoparticles

Copper nanoparticles enhance surface reactivity and ion release kinetics compared to copper salts, with copper oxide or zero‐valent copper serving as the active antimicrobial core. Azadirachta indica‐mediated CuO nanoparticles, where copper oxide directly contacts and damages fungal membranes, controlled Colletotrichum gloeosporioides on mango (Joshi et al. 2025). Citrus peel–derived Cu‐NPs inhibited Pectobacterium carotovorum on potatoes through sustained copper ion release (Usman et al. 2024). Chitosan‐decorated CuO nanocomposites against B. cinerea on tomatoes prolonged copper residence time on hydrophobic fruit surfaces, thus extending antifungal action (Ismail et al. 2023).

4.2.3. Copper‐Based Nanozymes

Copper‐based nanozymes exploit the catalytic activity of copper coordination centers to actively generate ROS and disrupt microbial antioxidant defenses. CuTax nanozymes, in which copper ions coordinate with taxifolin, exhibited peroxidase‐like activity and GSH depletion, with copper serving as the catalytic center that drove E. coli and S. aureus inactivation (Luo et al. 2025). CS/ZIF‐67‐Cu, where copper doping into the ZIF‐67 framework introduced dual oxidase‐ and peroxidase‐like activities, enabled continuous ROS generation from ambient air (Xu et al. 2025). Incorporated into carboxymethyl cellulose films, copper's catalytic function inhibited microbial proliferation on cherry tomatoes.

4.2.4. Copper‐Based MOFs and Stimuli‐Responsive Systems

The most advanced systems exploit copper nodes within MOF frameworks to achieve environmental responsiveness. LA@Cu‐MOF films, where copper ions form the structural nodes of the framework, exhibited dual pH/humidity responsiveness. α‐Lipoic acid release was enhanced in weakly acidic and high‐humidity microenvironments, while copper itself contributed antimicrobial activity against S. aureus, E. coli, and B. cinerea (Men et al. 2025). F‐HKUST loaded with carvacrol, where copper nodes provided anchoring sites for the antifungal compound, maintained blueberry quality for 12 days at 24°C (Xie et al. 2025). Cu‐chlorogenic acid nanoparticles, with copper‐polyphenol coordination enabling photothermal conversion, achieved 99% bacterial killing under near‐infrared irradiation and extended cherry tomato storage life threefold (Jiang et al. 2025a).

However, most of these studies attribute antimicrobial efficacy to general mechanisms such as copper ion release, membrane disruption, or ROS generation, without verifying cuproptosis‐specific hallmarks. The deliberate induction of cuproptosis with verification of lipoylated protein aggregation, Fe‐S cluster destabilization, or FDX1‐dependent copper reduction remains an underexploited opportunity. Bridging this gap would transform copper from a broad‐spectrum biocide into a mechanistically precise antimicrobial strategy.

4.3. Synergistic Strategies of Ferroptosis and Cuproptosis

Although ferroptosis and cuproptosis have individually shown promise, their synergistic function remains largely unexplored in postharvest applications. While no study has explicitly combined these two programmed death pathways, several Fe–Cu bimetallic systems have demonstrated their antimicrobial potential.

In CuFe twin crystal nanozymes, Cu²⁺ serves as an electron donor to sustain Fe²⁺ levels, enabling continuous Fenton‐driven hydroxyl radical generation and downregulation of ergosterol biosynthesis genes in B. cinerea (Liu et al. 2025). Similarly, a doctoral dissertation demonstrates that Cu₈Fe₂ NCs exhibited superior antifungal activity against B. cinerea and maintained long‐lasting efficacy for up to 210 days (Lu 2024). Meanwhile, Fe/Cu MOF‐tartaric acid complexes exhibited dual functionality, including antibacterial activity against S. aureus and E. coli (MIC = 0.0625 mg/mL) and anti‐browning effects via 76.03% polyphenol oxidase inhibition (Yu et al. 2026).

These studies collectively demonstrate that Fe–Cu bimetallic systems offer synergistic advantages over single‐metal counterparts, including enhanced stability, multifunctional bioactivities, and potential for commercial translation.

5. Current Challenges and Future Directions

Despite some attempts that have integrated ferroptosis and cuproptosis into postharvest preservation, significant knowledge gaps still exist. The most fundamental challenge lies in the limited molecular understanding of these death pathways within microbial systems. Current mechanistic frameworks are predominantly extrapolated from mammalian models, leaving microbe‐specific effector molecules and hallmarks poorly characterized. The majority of existing studies merely elevate metal ion concentrations and attribute antimicrobial effects to conventional metal toxicity, without establishing a verifiable mechanistic link to ferroptotic or cuproptotic features. Moreover, the dynamic defense strategies employed by microbes under ion stress are neglected. Many pathogens actively downregulate metal uptake transporters, upregulate efflux systems, and initiate chelation responses to evade toxicity, but few studies have attempted to subvert these adaptive mechanisms or to target alternative regulatory checkpoints beyond metal influx. Furthermore, the synergistic interplay between iron‐ and copper‐driven death pathways remains largely unexplored. Safety evaluations including migration assessments, long‐term stability, and sensory impacts are also critically lagging. Together, these challenges severely impede the translation of ferroptosis and cuproptosis concepts into practical and sustainable postharvest protection.

Future research should therefore advance in several interconnected directions (Figure 6). A central priority is the engineering of next‐generation delivery systems capable of actively overcoming microbial defenses. Stimuli‐responsive smart materials, such as nanocarriers or edible coatings that release Fe²⁺ and Cu²⁺ specifically in response to pathogen‐derived cues, are essential to maximize antimicrobial specificity while minimizing phytotoxicity. These systems can be further armed with ionophore‐like carriers to facilitate transporter‐independent metal entry, or loaded with small‐molecule inhibitors targeting metal efflux pumps and uptake repression circuits, thereby directly subverting the microbial adaptive response. Equally important is a deepened mechanistic investigation into iron‐copper synergy itself, which represents a promising avenue to simultaneously breach microbial defense and ensure dosage safety. Existing evidence demonstrates that iron restriction can markedly increase microbial susceptibility to copper, suggesting that precise manipulation of the ratio and temporal sequence of these two metals may achieve synergistic lethality at substantially reduced concentrations. Such an approach would circumvent the robust defense responses triggered by high levels of a single metal and inherently mitigate concerns over heavy metal residues. To unravel these dynamics, research must move beyond single‐species models and employ polymicrobial consortia and biofilm systems, integrating multi‐omics approaches with single‐cell imaging to map metabolic network disruptions and spatiotemporal death signatures under dual‐metal stress. Finally, rigorous toxicological and migration studies are imperative to ensure that metal ions from these advanced materials remain within strict regulatory limits and do not accumulate in the edible portions of the produce. The long‐term stability of these pro‐oxidant systems under variable storage conditions, such as temperature fluctuations and humidity, and their impact on the sensory and nutritional quality of a wide range of horticultural commodities must be systematically evaluated as well.

FIGURE 6.

Future directions of ferroptosis and cuproptosis in the food industry. Key challenges include developing stimuli‐responsive delivery systems that release Fe²⁺ and Cu²⁺ upon pathogen signals to ensure specificity, understanding metal synergy within polymicrobial communities to preempt resistance, and rigorously evaluating safety, migration, and long‐term stability to maintain produce quality. Overcoming these barriers requires interdisciplinary efforts across materials science, microbiology, food chemistry, and toxicology.

Achieving this critical balance will demand interdisciplinary collaboration at the intersection of materials science, food chemistry, microbiology, and toxicology, paving the way for a new paradigm of sustainable and precisely orchestrated postharvest protection.

6. Conclusion

In summary, this review has delineated the considerable potential of ferroptosis and cuproptosis, two distinct yet interconnected metal‐dependent cell death pathways, as novel and potent mechanisms for postharvest antimicrobial intervention. We have detailed the conserved molecular machinery underlying each pathway—iron‐driven lipid peroxidation for ferroptosis and copper‐induced aggregation of metabolic proteins for cuproptosis—and highlighted their independent applications through advanced material‐based strategies such as edible films and nanocomposites. Crucially, we have built a compelling case for the superior efficacy of a synergistic approach, arguing that the co‐induction of these pathways creates an unresolvable metabolic crisis in microbial pathogens by exploiting their intertwined metal homeostasis networks, thereby amplifying oxidative stress and presenting a significantly higher barrier to resistance. However, the translation of this promising paradigm from concept to commercial reality is still contingent upon overcoming significant challenges, particularly those pertaining to biocompatibility and biosafety, the precision of targeted delivery systems, long‐term stability under commercial storage conditions, and overall economic viability. Overcoming these challenges will be crucial to harnessing ferroptosis and cuproptosis as powerful tools for enhancing the sustainability and efficiency of global postharvest preservation, ultimately reducing food loss and waste.

Author Contributions

Yuan Feng: data curation, software, investigation, writing – original draft, visualization, conceptualization, methodology. Jinyue Sun: conceptualization, methodology, writing – review and editing, resources, validation, formal analysis. Rui‐Qi Qian: conceptualization, methodology, investigation, resources, data curation. Xiaodong Zheng: resources, validation, conceptualization, methodology. Wen‐Wen Zhou: conceptualization, funding acquisition, project administration, supervision, writing – review and editing, validation, resources.

Conflicts of Interest

The authors declare no conflicts of interest.