Introduction

Iron is an essential micronutrient for humans with multiple physiological functions, mainly including oxygen transport, energy production, maintaining healthy immune systems and improving cognitive function [1]. Despite being an essential metal for maintaining healthy condition, iron is a very toxic metal due to its redox-active nature. Therefore, the cellular and systemic level of iron is tightly regulated to maintain iron homeostasis. Dysregulation of iron metabolisms results in a number of pathological conditions [2], such as iron overload-related hemochromatosis and injury of multiple organs, and iron deficiency-related anemia. Ferroptosis is an iron-dependent and lipid-mediated form of programmed or regulated cell death (RCD), which was first described by Dixon et al. in 2012 [3]. The discovery of ferroptosis marks a new milestone for understanding the pathogenesis of iron dysregulation-related diseases. This new form of RCD is morphologically and biochemically distinct from other forms of RCD, such as apoptosis, necroptosis and unregulated necrosis. Morphologically, it is characterized by the abnormalities of mitochondria, such as shrunken mitochondria with decreased or disappeared cristae, increased mitochondrial membrane density, and the ruptured mitochondrial outer membrane, and usually along with normal nuclear size [3]. Three key biochemical events have been identified to be involved in induction of ferroptosis; they are dysregulated iron metabolism-mediated accumulation of labile iron, iron-dependent lipid peroxidation of plasma membrane and collapse of redox homeostasis [4] (Fig. 1).

Fig. 1
figure 1

Mechanisms of Ferroptosis induction. Three key biochemical events have been identified to be involved in induction of ferroptosis: dysregulated iron metabolism-mediated accumulation of labile iron, iron-dependent lipid peroxidation of plasma membrane and collapse of redox homeostasis. AA arachidonic acid, ACSL4 acyl-CoA synthetase long-chain family member 4, AdA adrenic acid, ALOXs lipoxygenases, CoA coenzyme A, CoQ10 coenzyme Q10, FSP ferroptosis suppressor protein, FPN ferroportin, GPX4 glutathione peroxidase 4, GSR glutathione-disulfide reductase, GSH glutathione, GSS GSH synthetase, GSSG oxidized glutathione, LPCAT3 lysophosphatidylcholine acyltransferase 3, NADPH reduced nicotinamide adenine dinucleotide phosphate, PE phosphatidylethanolamine, PUFA polyunsaturated fatty acid, System xc.− sodium-independent, anionic amino acid transport system, TF transferrin, TFR1 transferrin receptor protein 1

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Iron metabolism is strictly controlled at both the cellular and systematic level to ensure iron supplies are nutritionally sufficient, but not toxic to the body [5]. For cellular iron metabolisms, multiple approaches are involved in regulating intracellular level of iron, including uptake, utilization, storage, export and turnover of iron storage or iron-containing proteins. Briefly, cells acquire iron from transferrin via endocytosis which is mediated by transferrin receptor 1 (TFR1). Following uptake, intracellular iron is transferred to organelles mainly mitochondria where it is utilized for heme and Fe–S cluster biosynthesis. When iron is overloaded, excessive iron is stored in ferritin or exported via ferroportin (FPN). Under the condition of iron deficiency, TFR1-mediated iron uptake, ferritinophagy-mediated ferritin degradation, and Nrf2-mediated heme degradation [6] are induced, while FPN-mediated iron export is inhibited, leading to an increase in iron availability within the cell. For systemic iron regulation, iron efflux from cells to the bloodstream is a critical mechanism for maintaining systemic iron balance, which is negatively regulated by hepcidin, a peptide hormone, and positively regulated by FPN, the sole iron exporter. These regulatory mechanisms coordinate to maintain iron homeostasis. The accumulation of redox-active iron (free Fe2+) due to dysregulated iron metabolisms plays an indispensable role in triggering lipid peroxidation and ferroptosis. Understanding of the iron homeostatic pathways is critical for effectively managing ferroptosis-related diseases.

Lipid peroxidation is not only a hallmark of ferroptosis, but also the executioner of ferroptosis [4]. Arachidonic acid (AA, C20:4) and adrenic acid (AdA, C22:4) have been identified to be the major substrates of lipid peroxidation involved in ferroptosis induction. In the process of lipid synthesis, AA and AdA are converted to their respective acyl-coenzyme A (acyl-CoA) forms, which are catalyzed by acyl-coenzyme A synthetase long-chain family member 4 (ACSL4). AA-CoA and AdA-CoA are further transformed by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to form AA/AdA–phosphatidylethanolamine (PE), which are oxidized by specialized enzymes lipoxygenase (ALOX) and cytochrome P450 oxidoreductase (POR) to generate AA/AdA-PE-OOHs, leading to ferroptosis.

Oxidative stress acts as a double-edged sword by being both a physiological messenger in signal transduction pathways and a detrimental factor in various pathological conditions [7]. Under physiological conditions, redox balance is maintained due to equivalent cellular prooxidant and antioxidant capacity. Under such conditions, redox-dependent signaling is involved in many physiological processes, including cell growth, metabolism, hormone signaling, and immune regulation. In pathological situations, excessive oxidative stress is induced due to collapse of redox homeostasis triggered by damaged mitochondrial respiration chain or imbalanced redox-related enzymes, which in turn leads to various toxic effects including cell death induction. As discussed above, iron is a redox-active element, and the accumulation of cellular iron, particular labile iron, results in oxidative stress via Fenton reaction, and tissue injury associated with ferroptosis induction. A number of antioxidants have been identified to block lipid peroxidation via scavenging free radicals, mainly including solute carrier family 7 member 11 (SLC7A11)- glutathione (GSH), glutathione peroxidase 4 (GPX4), Nuclear factor erythroid 2-related factor 2 (Nrf2), nicotinamide adenine dinucleotide phosphate (NADPH) and Coenzyme Q10 (CoQ10) [8]. Accordingly, suppression of these antioxidant systems promotes oxidative stress and lipid peroxidation, which in turn contributes to ferroptosis.

Accumulated evidence suggests that ferroptosis is implicated in various pathological conditions including chemical-induced toxicities [9,10,11,12,13]. These biochemical events involved in ferroptosis induction provide reasonable targets for effectively manipulating ferroptosis, and targeting these events represents a practical approach to fight against a variety of toxicities and diseases associated with ferroptosis.

Ferroptosis induction by food-borne mycotoxins

Food contamination has been recognized as a global public health challenge, posing a serious threat to human and animal health. The common food contaminants include mycotoxins, heavy metals, residues of pesticides and veterinary drugs, as well as process contaminants. Understanding of the mechanisms involved in the harmful effects induced by the food contaminants is necessary for developing mechanism-based approach to manage this health issue. Numerous studies have demonstrated that ferroptosis is involved in the injuries of multiple organs in response to certain types of mycotoxins [14,15,16,17,18,19,20,21,22,23,24,25], providing novel insight into the mechanisms underlying mycotoxin-induced toxicities. The key findings (summarized in Table 1) are described in details below.

Table 1 Induction of ferroptosis by food-borne mycotoxins
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Deoxynivalenol

Deoxynivalenol (DON) is one of the most common forms of trichothecene and primarily occurs in wheat, corn, barley, and oats. The major DON-producing fungal species include Fusarium culmorum and Fusarium graminearum. Besides its acute toxicity, DON may produce other toxic effects, such as gastrointestinal toxicity, hepatotoxicity, immunotoxicity, developmental toxicity, and reproductive toxicity [26]. To investigate the involvement of ferroptosis in DON-induced gastrointestinal toxicity, using a piglet model of DON-induced intestinal injury, Liu et al. unraveled that dietary supplementation with DON at doses of 1.0 and 3.0 mg/kg increased oxidative stress markers malondialdehyde (MDA) and protein carbonyl in the duodenum, jejunum and ileum, accompanied by changes in expression of a number of ferroptosis-related genes, such as upregulation of ferroptotic gene (DMT1) and downregulation of anti-ferroptotic genes (FPN, FSP1 and CISD1) [15]. To critically confirm ferroptosis induction in DON-induced intestinal injury, the authors assessed effect of deferiprone (DFP), a ferroptotic inhibitor, on DON-induced cytotoxicity in porcine small intestinal IPEC-J2 cells, and results showed that DON-induced cytotoxicity was significantly inhibited in the presence of DFP, further supporting an important contribution of ferroptosis to DON-induced gastrointestinal toxicity.

Male reproductive dysfunction, mainly testicular damage, is a key toxic effect induced by DON. It has been reported that testicular iron homeostasis plays an important role in spermatogenesis as well as testosterone synthesis [27]. Iron overload and ferroptosis induction are expected to cause damage to the testicular structure and impairment of its functions. To determine the contribution of ferroptosis to DON-induced reproductive toxicity, using a mouse model of DON-induced testicular injury, Yang et al. demonstrated that oral administration of DON at doses of 1.0 and 2.0 mg/kg BW for 4 weeks caused elevated generation of ROS and MDA in testicular tissues, suggesting oxidative stress was induced by DON exposure [16]. Furthermore, they found that treatment with DON resulted in iron accumulation in testis. Accordingly, lipid peroxidation was induced in response to DON exposure in testicular tissues. Taken together, the authors conclude that the induction of ferroptosis may contribute to DON-induced male reproductive toxicity. The findings implicate that targeting ferroptosis may be an effective approach to prevent DON-induced gastrointestinal and reproductive toxicity.

Patulin

Patulin (PAT) is a food-borne mycotoxin commonly found in moldy fruits and fruit-based products. Toxicities induced by PAT mainly include immunotoxicity, neurotoxicity, hepatotoxicity and nephrotoxicity [28]. Kidney is a key toxic target of PAT, while ferroptosis is implicated in certain types of kidney injuries, which lead the scientists to investigate the role of ferroptosis in PAT-induced renal toxicity. Hou et al. reported that treatment with PAT at doses of 2.5, 5, and 10 mg/kg via intraperitoneal injection triggered acute kidney injury (AKI) evidenced by changes in the levels of biochemical markers, such as increased levels of CRE, urea, kidney injury molecule-1 (KIM-1), cystatin-C (Cys-C) and LCN2, along with pathological changes, such as edema, shallow staining of cytoplasm, narrowed renal tubular lumen and dilated glomerular capillaries [17]. They further demonstrated that autophagy-mediated ferroptosis was involved in PAT-induced AKI illustrated by indicators of autophagy and ferroptosis, including elevated iron content in kidney, increased autophagosome formation, and specific morphological changes in mitochondria, such as decreased volume of the mitochondrial crape and the number of mitochondrial cristae, and accompanied by induction of oxidative stress. In addition, HKC cells were used to validate the contribution of ferroptosis to PAT-induced nephrocyte toxicity and results showed that pretreatment with Fer-1, a well-known inhibitor of ferroptosis, or deferoxamine (DFO), a specific iron chelator, restored expression levels of NCOA4 and FTH1, and inhibited iron accumulation and membrane lipid peroxidation, which were consistent with that found in the mouse model. Using HK2 and 293 T cells, we found that PAT alone was not able to trigger ferroptosis in these cells supported by the data that ferroptosis inhibitors (Fer-1, Lip-1, DFO) failed to protect these cells from PAT-induced cell death. However, PAT was capable of potentiating these renal cells to a well-known ferroptosis inducer RSL3-mediated ferroptosis. Moreover, PAT aggravated folic acid-induced ferroptosis-associated acute kidney injury in a mouse model, evidenced by further increased levels of iron accumulation and lipid peroxides, and decreased GPXs activity and GSH levels in response to combination of PAT and folic acid compared with folic acid alone exposure [18]. In addition to the involvement of ferroptosis in PAT-induced nephrotoxicity, a recent study by Sun et al. reported that ferroptosis also contributed to PAT-induced cardiotoxicity [19]. These data provide a clear link between ferroptosis and PAT-related nephrotoxicity and cardiotoxicity.

T-2 toxin

T-2 toxin is another representative of trichothecene, produced mainly by Fusarium sporotrichioides. Toxic targets for T-2 include intestines, spleen, and lymph nodes, bone marrow, spleen, testis, ovary, and heart [29]. Mechanistically, the toxic effects of T-2 toxin are associated with induction of oxidative stress and cytotoxicity. To examine the implication of ferroptosis in T-2 toxin-induced toxicities, using cell culture models, Wang et al. showed that subtoxic concentrations of T-2 toxin (2.5–10 nM) significantly enhanced ferroptosis inducer RSL3 or Erastin-induced ferroptosis in HEK293T and H1299 cells [20]. Later, a study by Ma et al. reported that high concentration of HT-2 toxin (200 nM) triggered ferroptosis in sheep leydig cells, which was evidenced by elevated iron accumulation, lipid peroxides, along with decreased expression of GPX4 and SLC7A11, and up-regulated expression of acyl-CoA synthetase long chain family member 4 (ACSL4) [21]. Moreover, the key findings have been also validated in a mouse model, including reduction of GPX4/GSH and increase of ACSL4 in testicular tissues. The data implicate that subtoxic level of T-2 toxin is capable of increasing sensitivity of cells to ferroptosis induction, whereas toxic level of HT-2 toxin alone is able to induce ferroptosis.

Zearalenone

Zearalenone (ZON or ZEA/ZEN) is a nonsteroidal estrogenic mycotoxin produced mainly by Fusarium graminearum, and is commonly found in corn, wheat, oats, rice and soybean. Reproductive system (testis and ovary) is a major toxic target of ZON [30]. To determine if ferroptosis induction contributed to ZON-induced reproductive toxicity, using a mouse model of ZON-induced testicular toxicity, Li et al. analyzed a number of ferroptosis-related makers and results showed that iron accumulation, lipid peroxidation and impaired antioxidant system were observed in ZON-treated mice (30 μg/kg of ZON for 5 weeks) [22]. Moreover, inhibition of ferroptosis by its inhibitor Fer-1 partially protected testis from ZON-induced testicular injury, accompanied by reduction of iron accumulation, lipid peroxidation and restoration of antioxidant capacity. Collectively, the data suggest that the induction of ferroptosis is partially responsible for ZON-induced reproductive toxicity, denoting the likely potential for targeting ferroptosis in the prevention or treatment of ZON-mediated toxicity.

Aflatoxins

Aflatoxins (AFs) are a group of mycotoxins commonly found in maize, peanuts and cereals, and are synthesized primarily by Aspergillus flavus and Aspergillus parasiticus. Aflatoxin B1 (AFB1) is a key member of aflatoxins with numerous toxic effects, including immunotoxicity, hepatotoxicity, cardiotoxicity, reproductive toxicity, inflammation and carcinogenicity [31]. Using a chick model of AFB1-induced heart injury, Zhao et al. demonstrated that dietary consumption of 1.0 mg AFB1/kg for 3 weeks caused an apparent cardiotoxicity, evidenced by elevated activity of creatine kinase (CK), along with pathological changes, such as cardiomyocyte necrosis and hemorrhage with perivascular cell infiltrations [23]. Furthermore, AFB1 supplementation up-regulated mRNA levels of transferrin receptor 1 (TFR1), heat shock protein beta-1 (HSPB1) and solute carrier family 11 member 2 (SLC11A2), and down-regulated mRNA levels of transferrin (TF), and antioxidant enzyme GPX1 and iodothyronine deiodinase 2 (DIO2) in heart tissues, suggesting possible involvement of iron-dysregulation-mediated ferroptosis in AFB1-induced heart damage. H9c2 cardiomyocytes were used to further confirm the contribution of ferroptosis, and results showed that treatment with AFB1 induced a reduced cell viability and an increased ROS production. More importantly, morphologically observation by transmission electron microscopy unraveled that smaller mitochondria with damaged cristae and ruptured membrane were observed in AFB1-treated cells, which are the typical morphologies of ferroptosis, further supporting ferroptosis is induced in response to AFB1 exposure.

Given a possibility of simultaneous exposure to two or more food-borne mycotoxins for humans, combined toxicities of multiple mycotoxins have been evaluated. Some of studies demonstrated that ferroptosis was induced in response to combined mycotoxins. For example, Lin et al. reported that triple combination of ZEN, DON, and AFB1 induced jejunal injury in a mouse model [24]. Mechanistically, they found that this triple combination exposure resulted in increased oxidative stress and decreased antioxidant capacity, leading to mitochondrial damage. Furthermore, the triple combination disrupted iron metabolisms, leading to elevated Fe [2]+ concentration, which was well correlated with changes in expression of ferroptosis-related genes, such as up-regulation of transferrin receptor 1 (TFR1), ferritin heavy chain 1 (FTH1), and solute carrier family 3 member 2 (Slc3a2). The data indicate that the induction of ferroptosis is implicated in co-exposure of ZEN, DON, and AFB1-induced intestinal toxicity. A transcriptomic study by Frangiamone et al. revealed that co-exposure to AFB1 and OTA led to a significant change of ferroptosis signaling pathway in human lymphoblastic T cells, which may contribute to the combination-induced immune toxicity [32].

Fumonisins

Fumonisins (FBs) are a main group of mycotoxins commonly found in maize and maize-based products, which are produced mainly by Fusarium verticillioides and Fusarium proliferatum. Fumonisin B1 (FB1) is a key member of fumonisins with multiple toxic effects. It has been well documented that oxidative stress is induced by FB1, which is supported by reactive oxygen species (ROS) generation, lipid peroxidation and impaired anti-oxidant capacity, such as decreased levels of anti-oxidant glutathione (GSH) content and reduced expression or activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) [33, 34]. As mentioned above, oxidative stress and lipid peroxidation are two key biochemical events of ferroptosis, it is therefore speculated that ferroptosis might be involved in FB1-induced cytotoxicity. This hypothesis needs to be tested in future studies.

Mechanisms involved in ferroptosis induction by mycotoxins

As mentioned above, ferroptosis involves various biochemical events, mainly including disrupted iron homeostasis, collapsed redox balance and lipid peroxidation, and which have been found to be targeted by mycotoxins to promote ferroptosis (Fig. 2). The mechanistic findings pave the way for developing ferroptosis-based approach to fight against toxic effects of these mycotoxins.

Fig. 2
figure 2

Ferroptosis induction by food-borne mycotoxins. Ferroptosis is involved in the toxicities induced by certain types of mycotoxins via targeting iron metabolism, antioxidant systems and lipid peroxidation. Abbreviations: DON deoxynivalenol, PAT patulin, ZON zearalenone, AFB1 aflatoxin B1

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Disrupting iron homeostasis and metabolism by mycotoxins

Iron metabolism is regulated by multiple approaches, including uptake, storage and exportation. Dysregulation of iron metabolism was induced by DON [15, 16], PAT [17] and ZON [22]. Specifically, exposure to DON led to up-regulation of iron uptake-related TFR1, whereas iron storage-related ferritin heavy/light chain (FTH/FTL) and iron export protein FPN were down-regulated in testicular tissues or intestinal tissues, indicating iron homeostasis was disrupted by DON, which might account for the accumulation of cellular iron and ferroptosis induction by DON [15, 16]. Regarding the role of dysregulated iron metabolism in PAT-induced toxicity, it has been shown that treatment with PAT reduced the expression of FTH1 and NCOA4, and increased the expression of SFXN1, a transmembrane protein responsible for mitochondrial iron transportation [19], which is supposed to be due to increased degradation of ferritin via NCOA4-mediated autophagy (ferritinophagy), leading to accumulation of cellular iron content.

Impairing antioxidant systems

Intact antioxidant defense systems protect against ferroptosis, whereas collapsed redox homeostasis promotes ferroptosis. SLC7A11 is a key component of the antioxidant systems responsible for the regulation of ferroptosis, which exerts antioxidant activity via mediating cellular uptake of extracellular cystine in exchange for intracellular glutamate, thereby promoting GSH synthesis [35]. A study by us demonstrated that treatment with PAT induced a concentration-dependent inhibition of cystine uptake in renal cells, indicating SLC7A11 activity was suppressed [18]. Accordingly, the intracellular levels of cysteine and GSH were concentration-dependently reduced in response to PAT exposure, accompanied by elevated ROS generation. Further mechanistic investigation unraveled that inhibition of SLC7A11 activity by PAT was attributed to its ability to promote beclin1-SLC7A11 complex formation via AMPK-mediated beclin 1 phosphorylation. These findings provide mechanistic interpretation for the sensitization effect of PAT on ferroptosis inducer RSL3-induced nephrocyte toxicity. In addition, decreased expression of SLC7A11 was observed in response to exposure of DON [16], HT-2 toxin [21] or ZON [22]. GPX4, a lipid hydroperoxidase, suppresses ferroptosis via converting lipid hydroperoxides to lipid alcohols, thereby preventing lipid peroxidation [36]. GPX4 inhibition leads to lipid peroxidation, which in turn mediates ferroptosis. Several studies reported that GPX4 was downregulated by PAT [17], DON [15, 16] or ZON [22] in either cell culture or animal models, supporting GPX4 as a target for these mycotoxins to trigger ferroptosis. Nrf2 is a key player in antioxidant defense systems through transcriptional regulation the expression of a battery of genes involved in controlling oxidative stress [37]. The protective role of Nrf2 against ferroptosis is established in certain conditions [38]. Inhibition of Nrf2 pathway was induced by exposure to DON [16] or ZON [22], evidenced by reduced its mRNA/protein levels and suppression of its transcriptional target genes HO-1, NQO-1, SOD and CAT. Taken together, the findings suggest that the impaired antioxidant defense system is involved in ferroptosis induction by these mycotoxins.

Promoting lipid peroxidation

Lipid peroxidation is an essential step for induction of ferroptosis and involves multiple enzyme-catalyzed processes, mainly including ACSL4-mediated formation of AA/AdA-CoA derivatives, LPCAT3-dependent production of AA/AdA–PE and ALOX-catalyzed generation of AA/AdA-PE-OOHs [39]. Especially, the promoting effect of ACSL4 on ferroptosis is well established in certain models [40,41,42]. It has been shown that up-regulation of ACSL4 was induced by PAT [17], T-2 toxin [20] or AFB1 [23], implicating the contribution of ACSL4-mediated lipid peroxidation to PAT/T-2/AFB1-induced ferroptosis.

Targeting ferroptosis for alleviating mycotoxin-induced toxicities

As discussed above, the induction of ferroptosis is involved in the toxic effects induced by certain types of mycotoxins. Targeting ferroptosis is therefore a reasonable approach to manage the toxicities of these mycotoxins. Selenium is an essential micronutrient for humans, and the biological functions of selenium is largely attributed to its incorporation as selenocysteine into selenoproteins, such as GPXs, a superfamily of enzymes functioning in the antioxidant defense systems [43]. A study by Zhao et al. showed that selenium supplementation ameliorated AFB1-induced cardiotoxicity via increasing antioxidant capacity and inhibiting ferroptosis signaling in either cell culture or animal model [23]. Lycopene is a carotenoid present in various fruits and vegetables, such as tomatoes, carrots, grapefruit, watermelons, and papaya. It has been shown that lycopene possesses many biological activities including antioxidant [44]. Lin et al. demonstrated that lycopene was able to suppress the triple combination (ZEN, DON, and AFB1)-induced intestinal epithelial cell ferroptosis in a mouse model, which is mechanistically associated inhibiting oxidative stress and preventing mitochondrial damage [24]. Melatonin is a pineal hormone with diverse physiological functions, which is synthesized and secreted principally by the pineal gland of the endocrine system [45]. In addition to its critical role in the regulation of sleep and circadian rhythms, numerous studies have demonstrated that melatonin could offer protection against chemical-induced injury of multiple organ systems including testis. Ma et al. found that melatonin attenuated T-2 toxin-induced testicular toxicity both in vitro and in vivo [21]. Mechanistically, the data uncovered that T-2 toxin exposure decreased expression of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme of PPP that is involved in GSH synthesis via production of NADPH, which in turn contributed to T-2 toxin-mediated oxidative stress, whereas treatment with melatonin up-regulated G6PD and suppressed oxidative stress, eventually protected testis from T-2 toxin-induced ferroptosis. Knockdown of G6PD abolished the protective effect of melatonin on T-2 toxin-induced cytotoxicity, supporting the pivotal role of G6PD induction in melatonin-mediated protection on T-2 toxin testicular toxicity. Together, these findings suggest that targeting ferroptosis is an effective approach to combat against toxicities induced by certain types of mycotoxins.

Conclusions and future perspectives

The induction of ferroptosis is involved in the toxicities induced by certain types of mycotoxins, such as PAT, DON, T-2 toxin, ZON, AFB1 or their combinations. The induction of ferroptosis by these mycotoxins is primarily mediated by disrupting iron homeostasis, collapsing redox balance and promoting lipid peroxidation. Targeting ferroptosis is a reasonable and practical approach to prevent the toxicities of these mycotoxins. There are a number of issues need to be addressed for a better utilization of ferroptosis-based approach in managing mycotoxin-induced toxicities associated with ferroptosis.

Validation of in vitro data in vivo models

Some studies discussed above have been performed in vitro models only, validations of these in vitro data are needed using appropriate in vivo models.

Cell /tissue type-specificity in ferroptosis induction by mycotoxins

Most existed studies show that the induction of ferroptosis by mycotoxins is detected in one or two types of cells or tissues. Given the multiple-organ toxicities of these mycotoxins, further studies are needed to determine whether the induction of ferroptosis by these mycotoxins is cell/tissue type-dependent or general mechanism underlying the toxicities induced by these mycotoxins.

Primary targets for mycotoxins to trigger ferroptosis

It has been suggested that multiple targets or mechanisms are involved in mycotoxin-induced ferroptosis. Further studies are needed to identify the primary target(s) by which these mycotoxins induce ferroptosis.