Skip to main content
Download PDF

The multifaceted role of ferroptosis in infection and injury and its nutritional regulation in pigs

Journal of Animal Science and Biotechnology volume 16, Article number: 29 (2025) Cite this article

Abstract

Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by iron overload and excessive lipid peroxidation. To date, numerous studies in human and mouse models have shown that ferroptosis is closely related to tissue damage and various diseases. In recent years, ferroptosis has also been found to play an indispensable and multifaceted role in infection and tissue injury in pigs, and nutritional regulation strategies targeting ferroptosis show great potential. In this review, we summarize the research progress of ferroptosis and its role in infection and tissue injury in pigs. Furthermore, we discuss the existing evidence on ferroptosis regulation by nutrients, aiming to provide valuable insights for future investigation into ferroptosis in pigs and offer a novel perspective for the treatment of infection and injury in pigs.

Introduction

Cell death can be classified into accidental cell death and regulated cell death (RCD) [1]. RCD is a mechanism by which the host maintains cell function and homeostasis. In addition to apoptosis and autophagy, which have been widely studied, some non-apoptotic RCDs, such as pyroptosis, ferroptosis and necroptosis, have been identified in recent years. Ferroptosis is an iron-dependent form of non-apoptotic cell death with unique metabolic and morphological characteristics and signaling pathways that differ from other cell deaths [2]. Briefly, ferroptosis is characterized by disorder of iron metabolism, overproduction of reactive oxygen species (ROS) and lipid peroxidation, as well as the failure of glutathione peroxidase 4 (GPX4) and System Xc− (a cysteine/glutamate antiporter system) [3, 4]. Morphologically, shrinking mitochondria, ruptured mitochondrial membranes, and decreased mitochondrial crest can be observed in cells undergoing ferroptosis under transmission electron microscopy [5].

In recent years, numerous evidence has demonstrated that ferroptosis plays a significant role in human diseases and organ injuries [6]. Molecular drugs and nutrients that target ferroptosis can effectively mitigate organ damage and prevent the development of diseases [7, 8]. Although ferroptosis in pigs has been poorly studied, current evidence has established a link between ferroptosis and infection and tissue damage of pigs [9, 10]. Here, we review current knowledge regarding the role of ferroptosis in various infection and tissue injury in pigs, and summarize some dietary nutrients that regulate ferroptosis. This review aims to deepen the understanding of the multifaceted role of ferroptosis in injury and disease of pigs, and targeting ferroptosis as a therapeutic strategy by nutritional regulation.

Characteristics and pathways of ferroptosis

Dysregulated iron metabolism

Ferroptosis is characterized by iron-dependent lipid peroxidation and accumulation of toxic ROS [11] (Fig. 1). Fe3+ binds to transferrin (TF) and forms a complex with TF receptor 1 (TFR1), thus entering the cells. The intracellular Fe3+ is converted to Fe2+ and stored in the labile iron pool (LIP) for later use. Ferritin, which is composed of ferritin heavy chain (FTH) and ferritin light chain (FTL), is the main protein that regulates the storage and utilization of intracellular iron [12]. The excess Fe2+ can be oxidized to Fe3+ and exported by ferroportin (FPN). Increased iron uptake, decreased iron storage, and inadequate iron efflux can lead to the increase of LIP. Excessive accumulation of Fe2+ triggers the Fenton reaction that causes ROS overproduction and lipid peroxidation, and subsequently initiates ferroptosis, which is confirmed by the use of iron chelators and iron supplements [13]. TF and TFR1 have been shown to be the specific markers and key regulators of ferroptosis in recent studies [14, 15].

Fig. 1
figure 1

The core regulatory mechanisms and defense systems of ferroptosis. Ferroptosis is characterized by iron-dependent lipid peroxidation and overproduction of ROS. Fe3+ binds to TF and is transported to into the cell by TFR1. Ferritin (FTH1, FTL) is the main protein that regulates the storage and utilization of intracellular iron. The excess Fe2+ can be oxidized to Fe3+ and exported by FPN. Increased iron uptake, decreased iron storage, and inadequate iron efflux can lead to the increase of LIP and subsequent initiation of ferroptosis. The free PUFAs are catalyzed by ACSL4 and LPCAT3 to form PUFA-PLs. In addition, some membrane proteins (such as COXs, NOXs, and LOXs) can accelerate the process of lipid peroxidation. The GPX4-GSH antioxidant system is the main cellular defense mechanism against ferroptosis, which is initiated by System Xc− comprised of SLC3A2 and SLC7A11. Several GPX-independent defense systems have been identified, including the FSP1-CoQH2 system, the DHODH-CoQH2 system, and the GCH1-BH4 system. ACSL4, acyl-CoA synthetase long-chain family member 4; BH4, tetrahydrobiopterin; CoQ10H2, ubiquinol; CoQ10, coenzyme Q10; COXs, cyclooxygenases; DHODH, dihydroorotate dehydrogenase; FPN, Ferroportin; FSP1, ferroptosis suppressor protein 1; FTH, ferritin heavy chain; FTL, ferritin light chain; GCL, glutamate-cysteine ligase; GSS, glutathione synthetase; GSSG, oxidized glutathione; GPX4, glutathione peroxidase 4; GCH1, guanosine triphosphate cyclohydrolase 1; GSH, glutathione; LIP, labile iron pool; LOXs, lipoxygenases; LPCAT3, lysophosphatidylcholine acyltransferase 3; NOXs, NADPH oxidases; PUFA, polyunsaturated fatty acid; PUFA-PL, polyunsaturated fatty acid-containing phospholipid; ROS, reactive oxygen species; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; TF, transferrin; TFR1, transferrin receptor 1

Full size image

Lipid peroxidation

The main feature of ferroptosis is lipid peroxidation, mainly due to the peroxidation of polyunsaturated fatty acid (PUFA) containing bis-allylic carbons [16]. The free PUFAs, including arachidonic acid (AA), are ligated with coenzyme A (CoA) catalyzed by acyl-CoA synthetase long chain family member 4 (ACSL4) [17]. The esterification of PUFA-CoAs is subsequently catalyzed by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to form PUFA-containing phospholipids (PUFA-PLs) [18], which are oxidized to lipid peroxides (PL-PUFA-OOH) and eventually activate ferroptosis. Therefore, suppression of ACSL4 or LPCAT3 expression may be an effective way to inhibit ferroptosis. Current evidence suggests that inhibition of ACSL4 by either pharmacologic inhibitors or gene knockout can prevent ferroptosis, but it seems that knockout of LPCAT3 does not exhibit the expected blocking effect of ferroptosis [17]. In addition to autoxidation driven by the Fenton reaction [19], the peroxidation of PUFA-PLs can be accelerated by some membrane proteins, such as cyclooxygenases (COXs) [20], NADPH oxidases (NOXs) [21], and lipoxygenases (LOXs) [22]. Toxic lipid peroxides and their decomposition products including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) cause rapid and irreversible damage to the cell membrane, ultimately leading to cell death.

Failure of antioxidant systems

The failure of antioxidant system is one of the important causes of ferroptosis. Among several ferroptosis defense systems that have been identified so far, the GPX4-glutathione (GSH) system is the most critical and has been widely studied. GPX4, the only phospholipid peroxidase, belongs to selenoprotein family that converts PL hydroperoxides to PL alcohols, and thus acts as a core inhibitor of ferroptosis [23]. Genetic or pharmacologic inhibition of GPX4 induces lipid peroxidation and results in ferroptosis in various models [24,25,26]. GPX4 is regulated by its cofactor GSH, which is synthesized from cysteine, glycine, and glutamate [27]. Importantly, GSH production is dependent on the System Xc−, an antiporter on the cell membrane consisting of solute carrier family 3 member 2 (SLC3A2) and solute carrier family 7 member 11 (SLC7A11) [28]. The System Xc− transports cystine into the cell for subsequent GSH production catalyzed by glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS). GSH can be converted to oxidized glutathione (GSSG) catalyzed by GPX4, and conversely GSSG can be reduced to GSH to maintain homeostasis. Previous studies have shown that either cystine deficiency or pharmacologic inhibition of System Xc− (such as erastin, sorafenib, and sulfasalazine) activates ferroptosis. In addition, there are several GPX-independent defense systems, including the ferroptosis suppressor protein-1 (FSP1)-CoQH2 system, the dihydroorotate dehydrogenase (DHODH)-CoQH2 system, and the GTP cyclohydroxylase-1 (GCH1)-tetrahydrobiopterin (BH4) system [29].

Ferroptosis and infection

Various types of RCDs have been recognized as defense strategies for host against pathogenic infections. In turn, the pathogens interfere with RCDs to ensure their propagation and survival [30]. Pathogen-induced cell death promotes the release of progeny and contributes to severe inflammation and injury of host [31]. On the other hand, some pathogens can escape host sanction by inhibiting cell death in the early stage of infections, which helps their reproduction [32]. A growing body of evidence suggests the close correlation between ferroptosis and various infections such as viruses, bacteria, or fungi [33]. However, currently only a limited number of studies have reported the occurrence of ferroptosis in viral-infected pigs (Table 1) while ferroptosis caused by prevalent bacterial infections in pigs has not been reported.

Table 1 Induction or inhibition of ferroptosis by porcine viruses
Full size table

Porcine viral infectious diseases threaten the global pork industry and public health, which are characterized by rapid spread and widespread prevalence [39, 40]. In general, the host executes a series of defense responses against viral infection, including immune responses and RCDs [41,42,43]. For example, porcine deltacoronavirus (PDCoV) and porcine epidemic diarrhea virus (PEDV) have been found to activate the ferroptosis signaling pathway, and thus host inhibits virus replication by performing ferroptosis [34, 35]. However, the activation of ferroptosis does not affect the adhesion, invasion, and release of PEDV [35]. It is reported that swine influenza virus (SIV) infection can also cause intercellular iron overload and suppression of system Xc−/GPX4 axis activation, and ultimately induce ferroptosis. But unlike PDCoV and PEDV, ferroptosis acts as an aid rather than a blocker in SIV replication and virus-induced inflammatory responses [9]. It is worth noting that SIV-induced ferroptosis is attributed to labile iron accumulation, ROS release as well as lipid peroxidation, while SIV is considered sensitive to ROS and inhibition by them [44, 45]. Besides, the inhibition of PEDV by (1S,3R)-RSL3, a ferroptosis pathway downstream target activator, was observed earlier than its induction of ROS accumulation [36]. Therefore, although the important role of ROS in viral pathogenesis has been widely reported, it seems that the regulation of virus replication by ferroptosis cannot simply be attributed to ROS. In addition to ROS, iron and lipids are also closely related to the impact of ferroptosis on viral replication [46, 47], and the specific mechanism by which ferroptosis affects viral replication needs to be explored. In existing reports about swine viruses, only swine acute diarrhea syndrome coronavirus (SADS-CoV) was found to inhibit ferroptosis during the early stage of infection, thereby favoring its proliferation and survival [37]. Interestingly, the previous study showed that SADS-CoV induced apoptosis in the late stage of infection [48], suggesting that the virus mediates conversion of RCDs in the process of virus replication. Although the current literature on the association between swine virus infection and ferroptosis is very limited, these studies are sufficient to suggest the critical role of ferroptosis in the course of viral infection.

Excitingly, chemical inhibitors or activators targeting ferroptosis can significantly affect viral replication and the associated cell damage and inflammation. Additionally, Brequinar, a highly effective broad-spectrum antiviral molecule, inhibits African swine fever virus (ASFV) replication by activating ferroptosis although ASFV does not induce ferroptosis [38]. Hence, ferroptosis may be a potential target for the interference of viral infection and the development of antiviral drugs. Because of the wide variety of swine viruses and the fact that the same class of viruses show inconsistent effects on ferroptosis in different hosts [37, 49], more comprehensive and systematic studies are needed to be carried out.

Ferroptosis and injury

A growing body of evidence reveals the important role of ferroptosis in a variety of tissue injuries and non-infectious diseases in humans, such as liver injury, kidney injury, cardiovascular disease, and cancer [50,51,52,53]. However, current research has mainly focused on medical studies and mouse models, and less research has been carried out on pigs. Among the existing studies on the involvement of ferroptosis in tissue damage in pigs, the gut and reproductive system are the most concerned (Table 2), while other organs are rarely involved, so here we mainly discuss the studies on these two tissues.

Table 2 Ferroptosis involved in gastrointestinal system and reproductive system injury of pigs
Full size table

Gastrointestinal system injury

So far, numerous evidence has shown that ferroptosis is involved in intestinal injury induced by a variety of adverse factors, such as iron overload, mycotoxins, and viral infections.

Gut, as the main place of absorption, is more likely to absorb excess iron from diet compared to other organs. Excessive amounts of intracellular iron result in mitochondrial dysfunction and ferroptosis of IECs, as well as intestinal barrier disruption, intestinal microbiota disorder, and increase the susceptibility to pathogen infection. IPEC-J2 cells treated with ferric ammonium citrate (FAC, an iron supplement) showed significant reductions in cell activity and antioxidant capacity, impairment of intestinal epithelial barrier, and disruption of mitochondrial function due to iron overload-induced ferroptosis [54]. Gu et al. [61] reported that the iron overload induced the colitis in mice by modulating ferroptosis and altered the microbiome composition in the feces.

Mycotoxin is another toxic substance easily absorbed by the intestinal from diet, which is more likely to cause intestinal damage in pigs than in other species. Liu et al. [55] reported that diet with deoxynivalenol (DON) at doses of 1.0 and 3.0 mg/kg increased oxidative stress markers MDA in the duodenum, jejunum and ileum of piglets, while ferroptotic gene (DMT1) was upregulated and anti-ferroptotic genes (FPN, FSP1 and CDGSH iron sulfur domain protein 1 (CISD1)) were downregulated. Furthermore, DON-induced damage in IEPC-J2 cells was mitigated by ferroptotic inhibitor deferiprone, confirming the role of ferroptosis in the gastrointestinal toxicity of DON. Apart from DON, the toxicological mechanisms of many other mycotoxins such as patulin, HT-2 toxin, aflatoxin B1 and zearalenone (ZEN) have been revealed to be closely related to ferroptosis in mouse model. However, direct evidence is lacking on whether enterotoxicity of mycotoxins other than DON to pigs is involved in ferroptosis. Therefore, relevant studies are worth exploring due to the prevalence of mycotoxins in pig feed.

Recent research has revealed that porcine viruses interact closely with their hosts via the ferroptosis pathway. Among the swine viruses targeting gut, PDCoV, SADS-CoV, and PEDV have been reported to activate or inhibit ferroptosis, and chemical inhibitors or activators aimed ferroptosis can regulate virus replication and virus-induced intestinal damage [34, 36, 37].

Moreover, ferroptosis is also present in some intestinal pathological models. Previous studies in our laboratory showed that weaned piglets with intestinal oxidative damage induced by diquat significantly increased expression of TFR1 and decreased expression of GPX4 in jejunum and ileum, indicating that diquat activates the ferroptosis signaling pathway in IECs of piglets [56]. Kong et al. [57] reported that irradiation induced the downregulation of GPX4 and SLC7A11 in the intestine in the Göttingen minipig model of hematopoietic-acute radiation syndrome (H-ARS), which was consistent with conditions favoring ferroptosis.

Reproductive system injury

At present, the adverse factors that have been reported to activate ferroptosis in pig reproductive system mainly include mycotoxins, heat stress, and zinc (Zn) overload.

Mycotoxins not only cause serious damage to the gastrointestinal system of pigs, but also to the reproductive system. Fu et al. [58] revealed that ZEN-induced reproductive toxicity was due to the activation of ferroptosis in female pigs through RNA-seq analysis. Furthermore, it is confirmed that ZEN induced oxidative stress and ferroptosis in a glutathione-dependent manner and could be mitigated by melatonin supplementation in cell model and mouse model. However, up to date, it has not been reported whether other mycotoxin-induced damage to the reproductive system of pigs involves ferroptosis. Notably, in mouse models, a variety of mycotoxins have been reported to cause reproductive system toxicity by the activation of ferroptosis [62]. Although mice are excellent pathological models, similar studies in pigs are necessary.

Recently, Yang et al. [59] reported that heat stress reduced the protein expression of GPX4, TFR1, and Ferritin while increased the level of intracellular ROS in porcine Sertoli cells, which was consistent with the characteristics of ferroptosis, and the decline in cell vitality could be alleviated by Ferrostatin-1. These results confirmed the role of ferroptosis in heat stress-induced injury of porcine Sertoli cells. Mechanistically, heat stress significantly increased the expression of cytochrome P450 cyclooxygenase 2C9 and the content of epoxyeicosatrienoic acids, thus triggering the Ras-JNK signaling pathway and ultimately leading to the activation of ferroptosis of porcine Sertoli cells.

Zn is a critical microelement for physiological process, but excess Zn exposure can lead to testicular dysfunction. Recent study by Li et al. [60] reveals that ferroptosis is partly responsible for the reproductive toxicity caused by Zn overload, and Zn-induced ferroptosis in porcine testis cells is attributed to mitophagy.

In addition, ferroptosis may also be involved in embryonic development in pigs. FSP1 is a glutathione-independent ferroptosis inhibitory factor, which plays a crucial role in the regulation of mitochondrial function and ferroptosis. It has recently been reported to be involved in regulating the porcine early embryonic development and quality. Specifically, inhibition of FSP1 can impair blastocyst formation, lead to mitochondrial dysfunction and ferroptosis, and therefore impairing the quality of porcine early embryos [63].

Ferroptosis regulation by nutrients

According to the previous description, ferroptosis is closely related to dysregulated iron metabolism and lipid peroxidation. At present, there are few studies on the regulation of ferroptosis by nutrients, especially in livestock and poultry. Existing studies have shown that some nutrients or plant extracts with antioxidant effect play an important role in the regulation of ferroptosis (Table 3). Although only a few of these studies involve pigs, they can still provide references for us to regulate ferroptosis caused by various adverse factors in pig production by nutrients.

Table 3 Ferroptosis regulation by nutrients in pigs and some medical/mice models
Full size table

Selenium

Ferroptosis is mainly regulated by selenium (Se)-dependent pathway [85]. It is regulated by Se mainly due to GPX4, a unique selenoprotein that functions as a phospholipid peroxidase, thereby protecting cells from lipid peroxidation and ferroptosis. Dietary supplementation of Se is an effective strategy to increase intracellular selenium concentration and thus protect cells from ferroptosis. However, relevant studies are currently mainly focused on mouse models and cell models, and direct evidence is lacking in pigs. Fan et al. [64] revealed that dietary supplementation of Se increased the expression of GPX4, p-PI3K, and AKT, and decreased the level of 4-HNE in mice with DON-induced intestinal injury, inhibited DON-induced ferroptosis and thus improved intestinal barrier function. Se treatment apparently attenuated oxidative stress and inhibited iron accumulation in animal model and cell model of cerebral ischemia–reperfusion (I/R) injury [65]. Se mitigated the impairments in the nervous system of mice due to inhibition of ferroptosis by regulating the Nrf2/GPX4 pathway [66]. In addition to being a component of GPX4 synthesis, selenium can also augment the transcription of GPX4 via coordinated activation of the transcription factors TFAP2c and SP1 and thus alleviate haemorrhagic or ischaemic stroke [67]. Similarly, Se increased the expression of GPX4 and the transcription factors TFAP2c and SP1, and ameliorated histological and functional impairment caused by cadmium-induced ferroptosis in sheep kidney [86].

Amino acids and bioactive peptides

Glycine is one of the components used for the synthesis of endogenous antioxidants GSH, which is the cofactor of GPX4. The antioxidant effect of glycine has been widely reported. Previous studies in our laboratory reveals that dietary glycine supplementation can inhibit the occurrence of cell ferroptosis, thus effectively alleviating the liver and intestinal damage caused by diquat in weaned piglets [68, 69]. Glycine has also been reported to regulate ROS-induced lipid metabolism and further reduce ferroptosis, thereby promoting porcine oocyte maturation and early embryonic development [87]. Glutamate is also necessary to GSH synthesis, but supplementation with glutamate does not appear to inhibit ferroptosis. Instead, high concentrations of glutamate interfere cystine uptake by inhibiting the System Xc−, leading to intracellular glutathione depletion and resulting in ROS accumulation, and ultimately activating ferroptosis and inducing neuroexcitotoxicity [88]. Another antioxidant amino acid, L-citrulline, has been shown to have a variety of health benefits, such as improving immune system function, regulating blood sugar levels, and preventing cardiovascular disease. L-citrulline has recently been found to regulate iron metabolism and restrain ferroptosis, improve mitochondrial quality, and improve gut microbiota in mouse model, thereby alleviating intestinal damage caused by iron overload [54]. Mechanistically, L-citrulline activates AMPK pathway in IPEC-J2 cell model, thereby exerting antioxidation and protecting cells from oxidative stress damage.

In addition, some bioactive peptides have been reported to regulate ferroptosis by improving oxidative stress and regulating iron metabolism. For instance, fish skin gelatin peptides and Gly-Pro-Ala (GPA) peptide increase the expression of GSH and GPX4 by activating Nrf2, alleviating the toxicity and oxidative stress induced by DON in the mice and IPEC-J2 cells [70]. Lentil peptides derived protein reduces the mRNA levels of DMT1 and TFR, and increases iron bioavailability, suggesting its regulation of ferroptosis and the improvement of iron deficiency anemia [71].

Vitamin E

Vitamin E is well known for its excellent ability to scour free radicals and block lipid oxidation, making it one of the most effective and safe natural ferroptosis inhibitors. In several dietary vitamin E, tocopherol is more easily absorbed and utilized by the body, thus α-tocopherol is considered to be the main form of antioxidant activity of vitamin E in the body [89]. But tocotrienols appear to be more effective than tocopherols in protecting cells from ferroptosis because of their superior ability to inhibit LOXs, the key enzymes that regulate lipid peroxidation and subsequent ferroptosis [90]. Dietary supplementation of vitamin E has a promising effect in blocking ferroptosis. Although this has not been reported in pigs, the results in mice and cell models are supportive. Matsushita et al. [72] found that dietary supplementation of high dosage of vitamin E repaired the dysfunction of T cells due to Gpx4 deficiency and protected from acute lymphocytic choriomeningitis virus and Leishmania major parasite infections. Dietary supplementation of vitamin E in mice can improve iron-mediated oxidative damage to the liver by inhibiting the iron- and redox-sensing transcription factor Nrf2, enhancing liver iron efflux and restricting ferroptosis [73]. In addition, dietary supplementation of vitamin E during gestation improves fetal lethality caused by Gpx4 deficiency in mice [74]. This suggests that nutritional regulation of ferroptosis can be carried out during pregnancy to prevent ferroptosis-related diseases earlier.

Plant extracts

In recent years, many plant extracts, especially polyphenols and flavonoids, are well known for their anti-inflammatory and antioxidant properties [91, 92]. This suggests that plant extracts can be used to regulate ferroptosis. Our laboratory reported that holly polyphenols sourced from Ilex latifolia Thunb inhibited the activation of ferroptosis induced by diquat, thus alleviating the histological and functional injury of liver and intestine in weanling piglets [56, 75]. Li et al. [76] found that hesperidin, one of the major flavonoids in citrus fruits that has various biological activities, alleviated mitochondrial dysfunction and ferroptosis in the intestine of piglets exposed to DON. Actually, only the above studies have reported the regulation of ferroptosis by plant extracts in pigs. However, a variety of plant extracts have been found to regulate ferroptosis in medical models or in vitro experiments, which can also provide valuable references for the research and application in pigs. For example, quercetin, a plant polyphenol with anti-inflammatory and antioxidant properties, was reported to reverse DON-induced intestinal oxidative stress and ferroptosis in mouse model [77]. Another polyphenol, resveratrol, is a bioactive ingredient in wine and grape juice. It is an antitoxin secreted by plants under adversity or pathogen attack, and has subsequently been found to have a variety of beneficial effects such as immune regulation and anti-aging, and can be used as a dietary supplement for human health care and disease prevention. It can activate SIRT3 and GSH/GPX4 signaling to relieve ferroptosis of intestinal cells in I/R mice, and restrict DON-induced ferroptosis by activating SLC7A11-GSH-GPX4 signaling pathways in vitro [78, 79]. Lycopene, a carotenoid found in tomatoes, watermelons and other plant foods. It was recently reported to protect the intestine and nervous system by inhibiting mitochondrial damage and ferroptosis in mouse model [80, 81]. Glycyrrhetinic acid is the prominent constituent of glycyrrhize glabra, which has anti-inflammatory, anti-allergic and anti-bacterial effects. It inhibits nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and subsequent ferroptosis, as well as improving mitochondrial function [82]. Besides, epigallocatechin gallate and astragalus polysaccharide have also been confirmed to inhibit ferroptosis in mice [83, 84].

Conclusions and perspectives

The role of ferroptosis in injury and disease is multifaceted. It can be a strategy for host to maintain normal cell function and homeostasis, and can in turn be hijacked by viruses to promote viral proliferation. There is no doubt that the role of ferroptosis in porcine virus-induced injuries and other non-infectious injuries should not be ignored, although the relevant studies are still insufficient. Importantly, the effect of nutrients on ferroptosis in a large number of medical models is encouraging, which will have important implications for us to use nutrients to prevent and treat various diseases in pig production. Therefore, more comprehensive and in-depth studies on the mechanism of ferroptosis and its regulation in pigs are needed.

Data availability

Not applicable.

Abbreviations

AA:

Arachidonic acid

ACSL4:

Acyl-CoA synthetase long chain family member 4

AMPK:

AMP-dependent protein kinase

ASFV:

African swine fever virus

BH4 :

Tetrahydrobiopterin

CISD1:

CDGSH iron-sulfur domain-containing protein 1

CoA:

Coenzyme A

CoQH2 :

Ubiquinol

COX:

Cyclooxygenase

DHODH:

Dihydroorotate dehydrogenase

DMT1:

Divalent metal transporter-1

DON:

Deoxynivalenol

FAC:

Ferric ammonium citrate

FPN:

Ferroportin

FSP1:

Ferroptosis suppressor protein-1

FTH:

Ferritin heavy chain

FTL:

Ferritin light chain

GCH1:

GTP cyclohydroxylase-1

GPX4:

Glutathione peroxidase 4

GSH:

GPX4-glutathione

GCL:

Glutamate-cysteine ligase

GSS:

Glutathione synthetase

GSSG:

Oxidized glutathione

H-ARS:

Hematopoietic-acute radiation syndrome

HNE:

Hydroxynonenal

I/R:

Ischemia-reperfusion

IEC:

Intestinal epithelial cell

LIP:

Labile iron pool

LOX:

Lipoxygenase

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

MDA:

Malondialdehyde

NCOA4:

Nuclear receptor coactivator 4

NOX:

NADPH oxidase

PDCoV:

Porcine deltacoronavirus

PEDV:

Porcine epidemic diarrhea virus

PL:

Phospholipids

PUFA:

Polyunsaturated fatty acid

RCD:

Regulated cell death

ROS:

Reactive oxygen species

SADS-CoV:

Swine acute diarrhea syndrome coronavirus

Se:

Selenium

SIRT3:

Silent information regulator 3

SIV:

Swine influenza virus

SLC3A2:

Solute carrier family 3 member 2

SLC7A11:

Solute carrier family 7 member 11

TF:

Transferrin

TFR1:

TF receptor 1

ZEN:

Zearalenone

Zn:

Zinc

References

  1. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25(3):486–541.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zhou SY, Cui GZ, Yan XL, Wang X, Qu Y, Guo ZN, et al. Mechanism of ferroptosis and its relationships with other types of programmed cell death: insights for potential interventions after intracerebral hemorrhage. Front Neurosci-Switz. 2020;14:589042.

    Article  Google Scholar 

  3. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Stockwell BR. Ferroptosis: death by lipid peroxidation. Free Radical Bio Med. 2018;120:S7–S7.

    Article  Google Scholar 

  5. Miyake S, Murai S, Kakuta S, Uchiyama Y, Nakano H. Identification of the hallmarks of necroptosis and ferroptosis by transmission electron microscopy. Biochem Bioph Res Co. 2020;527(3):839–44.

    Article  CAS  Google Scholar 

  6. Jiang XJ, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Bio. 2021;22(4):266–82.

    Article  Google Scholar 

  7. Wang YM, Wu S, Li Q, Sun HY, Wang HQ. Pharmacological inhibition of ferroptosis as a therapeutic target for neurodegenerative diseases and strokes. Adv Sci. 2023;10(24):e2300325.

    Article  Google Scholar 

  8. Qi YG, Zhang XL, Wu ZH, Tian M, Chen F, Guan WT, et al. Ferroptosis regulation by nutrient signalling. Nutr Res Rev. 2022;35(2):282–94.

    Article  CAS  PubMed  Google Scholar 

  9. Cheng JH, Tao J, Li BQ, Shi Y, Liu HL. Swine influenza virus triggers ferroptosis in A549 cells to enhance virus replication. Virol J. 2022;19(1):104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Luan PX, Sun Y, Zhu Y, Qiao SQ, Hu G, Liu Q, et al. Cadmium exposure promotes activation of cerebrum and cerebellum ferroptosis and necrosis in swine. Ecotox Environ Safe. 2021;224:112650.

    Article  CAS  Google Scholar 

  11. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014;10(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  12. Sukhbaatar N, Weichhart T. Iron regulation: macrophages in control. Pharmaceuticals-Base. 2018;11(4):137.

    Article  CAS  Google Scholar 

  13. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 2020;30(10):3411–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gao MH, Monian P, Quadri N, Ramasamy R, Jiang XJ. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59(2):298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–8.

    Article  CAS  PubMed  Google Scholar 

  17. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, IngoId I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91–8.

    Article  CAS  PubMed  Google Scholar 

  18. Jain S, Zhang XL, Khandelwal PJ, Saunders AJ, Cummings BS, Oelkers P. Characterization of human lysophospholipid acyltransferase 3. J Lipid Res. 2009;50(8):1563–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shah R, Shchepinov MS, Pratt DA. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. Acs Central Sci. 2018;4(3):387–96.

    Article  CAS  Google Scholar 

  20. Fitzpatrick FA. Cyclooxygenase enzymes: regulation and function. Curr Pharm Design. 2004;10(6):577–88.

    Article  CAS  Google Scholar 

  21. Yao LS, Ban FF, Peng SR, Xu D, Li HB, Mo HZ, et al. Exogenous iron induces NADPH oxidases-dependent ferroptosis in the conidia of aspergillus flavus. J Agr Food Chem. 2021;69(45):13608–17.

    Article  CAS  Google Scholar 

  22. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 2016;113(34):E4966–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radical Bio Med. 2019;133:144–52.

    Article  CAS  Google Scholar 

  24. Angeli JPF, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16(12):1180–91.

    Article  PubMed Central  Google Scholar 

  25. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li J, Tian XG, Liu JM, Mo YY, Guo XY, Qiu Y, et al. Therapeutic material basis and underling mechanisms of Shaoyao Decoction-exerted alleviation effects of colitis based on GPX4-regulated ferroptosis in epithelial cells. Chin Med. 2022;17:96.

    Article  Google Scholar 

  27. Forman HJ, Zhang HQ, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 2009;30(1–2):1–12.

    Article  CAS  PubMed  Google Scholar 

  28. Koppula P, Zhuang L, Gan BY. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12(8):599–620.

    Article  CAS  PubMed  Google Scholar 

  29. Lei G, Zhuang L, Gan BY. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gao J, Wang QB, Tang YD, Zhai JB, Hu W, Zheng CF. When ferroptosis meets pathogenic infections. Trends Microbiol. 2023;31(5):468–79.

    Article  CAS  PubMed  Google Scholar 

  31. Jorgensen I, Rayamajhi M, Miao EA. Programmed cell death as a defence against infection. Nat Rev Immunol. 2017;17(3):151–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tummers B, Green DR. The evolution of regulated cell death pathways in animals and their evasion by pathogens. Physiol Rev. 2022;102(1):411–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen X, Kang R, Kroemer G, Tang DL. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021;218(6):e20210518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang GZ, Cao YA, Xu C, Zhang SS, Huang YJ, Zhang S, et al. Comprehensive transcriptomic and metabolomic analysis of porcine intestinal epithelial cells after PDCoV infection. Front Vet Sci. 2024;11:1359547.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhang HL, Li YG, Yang RM, Xiao L, Dong SM, Lin JX, et al. Erastin inhibits porcine epidemic diarrhea virus replication in Vero cells. Front Cell Infect Mi. 2023;13:1142173.

    Article  CAS  Google Scholar 

  36. Li YG, Bao YW, Li Y, Duan XX, Dong SM, Lin JX, et al. RSL3 inhibits porcine epidemic diarrhea virus eeplication by activating ferroptosis. Viruses-Basel. 2023;15(10):2080.

    Article  CAS  Google Scholar 

  37. Zeng SY, Peng OY, Hu FY, Xia Y, Geng R, Zhao Y, et al. Metabolomic analysis of porcine intestinal epithelial cells during swine acute diarrhea syndrome coronavirus infection. Front Cell Infect Mi. 2022;12:1079297.

    Article  CAS  Google Scholar 

  38. Chen Y, Guo YC, Chang H, Song ZB, Wei Z, Huang Z, et al. Brequinar inhibits African swine fever virus replication in vitro by activating ferroptosis. Virol J. 2023;20(1):242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guo JH, Liu ZM, Tong X, Wang ZX, Xu SE, Chen Q, et al. Evolutionary dynamics of type 2 porcine reproductive and respiratory syndrome virus by whole-genome analysis. Viruses-Basel. 2021;13(12):2469.

    Article  CAS  Google Scholar 

  40. Li ZY, Chen WX, Qiu ZL, Li YW, Fan JD, Wu KK, et al. African swine fever virus: a review. Life-Basel. 2022;12(8):1255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tang DL, Kang R, Vanden Berghe T, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29(5):347–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Koren E, Fuchs Y. Modes of regulated cell death in cancer. Cancer Discov. 2021;11(2):245–65.

    Article  CAS  PubMed  Google Scholar 

  43. Peng F, Liao MR, Qin R, Zhu SO, Peng C, Fu LL, et al. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Tar. 2022;7:286.

    Article  CAS  Google Scholar 

  44. Wang RF, Zhu YX, Lin X, Ren CW, Zhao JC, Wang FF, et al. Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production. Autophagy. 2019;15(7):1163–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu ZZ, Ge YZ, Ding LX, Zhang ZM, Qu Y, Jin CY, et al. Synthesis and evaluation of alkoxy-substituted enamides against influenza A virus in vitro and in vivo. Bioorg Chem. 2023;139:106712.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang S, Cao YN, Yang Q. Transferrin receptor 1 levels at the cell surface influence the susceptibility of newborn piglets to PEDV infection. Plos Pathog. 2020;16(7):e1008682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cochrane RA, Dritz SS, Woodworth JC, Huss AR, Stark CR, Saensukjaroenphon M, et al. Assessing the effects of medium-chain fatty acids and fat sources on PEDV infectivity. Transl Anim Sci. 2019;4(2):txz179.

    PubMed  Google Scholar 

  48. Zhang JY, Han YR, Shi HY, Chen JF, Zhang X, Wang XB, et al. Swine acute diarrhea syndrome coronavirus-induced apoptosis is caspase- and cyclophilin D- dependent. Emerg Microbes Infec. 2020;9(1):439–56.

    Article  CAS  Google Scholar 

  49. Kung YA, Chiang HJ, Li ML, Gong YN, Chiu HP, Hung CT, et al. Acyl-coenzyme a synthetase long-chain family member 4 Is involved in viral replication organelle formation and facilitates virus replication via ferroptosis. MBio. 2022;13:e0271721.

  50. Chen JY, Li XP, Ge CD, Min JX, Wang FD. The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 2022;29(3):467–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ni LH, Yuan C, Wu XY. Targeting ferroptosis in acute kidney injury. Cell Death Dis. 2022;13(2):182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fang XX, Ardehali H, Min JX, Wang FD. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Nat Rev Cardiol. 2023;20(1):7–23.

    Article  PubMed  Google Scholar 

  53. Yu TT, Xu-Monette ZY, Yu L, Li Y, Young KH. Mechanisms of ferroptosis and targeted therapeutic approaches in lymphoma. Cell Death Dis. 2023;14(11):771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhao D, Gao Y, Chen YQ, Zhang YS, Deng Y, Niu S, et al. L-citrulline ameliorates iron metabolism and mitochondrial quality control via activating AMPK pathway in intestine and improves microbiota in mice with iron overload. Mol Nutr Food Res. 2024;68(6):e2300723.

    Article  PubMed  Google Scholar 

  55. Liu M, Zhang L, Mo YX, Li JH, Yang JC, Wang J, et al. Ferroptosis is involved in deoxynivalenol-induced intestinal damage in pigs. J Anim Sci Biotechno. 2023;14:29.

    Article  CAS  Google Scholar 

  56. Xu X, Wei Y, Hua HW, Jing XQ, Zhu HL, Xiao K, et al. Polyphenols sourced from Ilex latifolia Thunb. relieve intestinal injury via modulating ferroptosis in weanling piglets under oxidative stress. Antioxidants-Basel. 2022;11(5):966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Horseman T, Rittase WB, Slaven JE, Bradfield DT, Frank AM, Anderson JA, et al. Ferroptosis, inflammation, and microbiome alterations in the intestine in the Göttingen minipig model of hematopoietic-acute radiation syndrome. Int J Mol Sci. 2024;25(8):4535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fu W, Dai C, Ma ZF, Li Q, Lan DL, Sun CP, et al. Enhanced glutathione production protects against zearalenone-induced oxidative stress and ferroptosis in female reproductive system. Food Chem Toxicol. 2024;185:114462.

    Article  CAS  PubMed  Google Scholar 

  59. Yang H, Cai XQ, Qiu MJ, Deng CC, Xue HY, Zhang JJ, et al. Heat stress induces ferroptosis of porcine Sertoli cells by enhancing CYP2C9-Ras- JNK axis. Theriogenology. 2024;215:281–9.

    Article  CAS  PubMed  Google Scholar 

  60. Li QW, Yang QW, Guo P, Feng YH, Wang SF, Guo JY, et al. Mitophagy contributes to zinc-induced ferroptosis in porcine testis cells. Food Chem Toxicol. 2023;179:113950.

    Article  CAS  PubMed  Google Scholar 

  61. Gu K, Wu AM, Yu B, Zhang TT, Lai X, Chen JZ, et al. Iron overload induces colitis by modulating ferroptosis and interfering gut microbiota in mice. Sci Total Environ. 2023;905:167043.

    Article  CAS  PubMed  Google Scholar 

  62. Yang X, Chen YH, Song WX, Huang TY, Wang YS, Chen Z, et al. Review of the role of ferroptosis in testicular function. Nutrients. 2022;14(24):5268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang YQ, Qu HX, Dong YW, Qi JJ, Wei HK, Sun H, et al. Inhibition of FSP1 impairs early embryo developmental competence in pigs. Theriogenology. 2024;214:257–65.

    Article  CAS  PubMed  Google Scholar 

  64. Fan SJ, Chen JY, Tian HH, Yang XT, Zhou LZ, Zhao QY, et al. Selenium maintains intestinal epithelial cells to activate M2 macrophages against deoxynivalenol injury. Free Radical Bio Med. 2024;219:215–30.

    Article  CAS  Google Scholar 

  65. Shi YY, Han LJ, Zhang XX, Xie LL, Pan PL, Chen F. Selenium alleviates cerebral ischemia/reperfusion injury by regulating oxidative stress, mitochondrial fusion and ferroptosis. Neurochem Res. 2022;47(10):2992–3002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu HM, Luan Y, Wang HZ, Zhang PF, Liu SJ, Wang P, et al. Selenium inhibits ferroptosis and ameliorates autistic-like behaviors of BTBR mice by regulating the Nrf2/GPx4 pathway. Brain Res Bull. 2022;183:38–48.

    Article  CAS  PubMed  Google Scholar 

  67. Alim I, Caulfield JT, Chen YX, Swarup V, Geschwind DH, Ivanova E, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. 2019;177(5):1262–79.

    Article  CAS  PubMed  Google Scholar 

  68. Xu X, Wei Y, Hua HW, Zhu HL, Xiao K, Zhao JC, et al. Glycine alleviated intestinal injury by inhibiting ferroptosis in piglets challenged with diquat. Animals-Basel. 2022;12(22):3071.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Hua HW, Xu X, Tian W, Li P, Zhu HL, Wang WJ, et al. Glycine alleviated diquat-induced hepatic injury via inhibiting ferroptosis in weaned piglets. Anim Biosci. 2022;35(6):938–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Deng Z, Yu HC, Yang ZP, Hu LL, Liu Q, Wang YN, et al. Gly-Pro-Ala peptide and FGSHF3 exert protective effects in DON-induced toxicity and intestinal damage via decreasing oxidative stress. Food Res Int. 2021;139:109840.

    Article  CAS  PubMed  Google Scholar 

  71. Evcan E, Gulec S. The development of lentil derived protein-iron complexes and their effects on iron deficiency anemia. Food Funct. 2020;11(5):4185–92.

    Article  CAS  PubMed  Google Scholar 

  72. Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015;212(4):555–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Baratz E, Protchenko O, Jadhav S, Zhang DL, Violet PC, Grounds S, et al. Vitamin E induces liver iron depletion and alters iron regulation in mice. J Nutr. 2023;153(7):1866–76.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U, et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol. 2016;9:22–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. He PW, Hua HW, Tian W, Zhu HL, Liu YL, Xu X. Holly (Ilex latifolia Thunb.) polyphenols extracts alleviate hepatic damage by regulating ferroptosis following diquat challenge in a piglet model. Front Nutr. 2020;7:604328.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Li X, Lin Q, Gou FY, Zhu J, Yu MJ, Hong QH, et al. Effects of hesperidin on mitochondrial function, mitochondria-associated endoplasmic reticulum membranes and IP3R-MCU calcium axis in the intestine of piglets exposed to deoxynivalenol. Food Funct. 2024;15(12):6459–74.

    Article  CAS  PubMed  Google Scholar 

  77. Ye YR, Jiang MZ, Hong XY, Fu YW, Chen YC, Wu HP, et al. Quercetin alleviates deoxynivalenol-induced intestinal damage by suppressing inflammation and ferroptosis in mice. J Agr Food Chem. 2023;71(28):10761–72.

    Article  CAS  Google Scholar 

  78. Wang XJ, Shen TL, Lian J, Deng K, Qu C, Li EM, et al. Resveratrol reduces ROS-induced ferroptosis by activating SIRT3 and compensating the GSH/GPX4 pathway. Mol Med. 2023;29:137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang PJ, Yao Q, Zhu D, Yang XS, Chen QJ, Lu QR, et al. Resveratrol protects against deoxynivalenol-induced ferroptosis in HepG2 cells. Toxicology. 2023;494:153589.

    Article  CAS  PubMed  Google Scholar 

  80. Lin J, Zuo CG, Liang TZ, Huang Y, Kang P, Xiao K, et al. Lycopene alleviates multiple-mycotoxin-induced toxicity by inhibiting mitochondrial damage and ferroptosis in the mouse jejunum. Food Funct. 2022;13(22):11532–42.

    Article  CAS  PubMed  Google Scholar 

  81. Zhu SY, Jiang JZ, Lin J, Liu L, Guo JY, Li JL. Lycopene ameliorates atrazine-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus of mice. Food Chem Toxicol. 2023;174:113655.

    Article  CAS  PubMed  Google Scholar 

  82. Jiang JZ, Zhou XT, Chen H, Wang X, Ruan YB, Liu XH, et al. 18β-Glycyrrhetinic acid protects against deoxynivalenol-induced liver injury via modulating ferritinophagy and mitochondrial quality control. J Hazard Mater. 2024;471:134319.

    Article  CAS  PubMed  Google Scholar 

  83. Yang CJ, Wu AM, Tan LQ, Tang DD, Chen W, Lai X, et al. Epigallocatechin-3-gallate alleviates liver oxidative damage caused by iron overload in mice through inhibiting ferroptosis. Nutrients. 2023;15(8):1993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen YJ, Wang JY, Li JT, Zhu JH, Wang RQ, Xi QH, et al. Astragalus polysaccharide prevents ferroptosis in a murine model of experimental colitis and human Caco-2 cells via inhibiting NRF2/HO-1 pathway. Eur J Pharmacol. 2021;911:174518.

    Article  CAS  PubMed  Google Scholar 

  85. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172(3):409–22.

    Article  CAS  PubMed  Google Scholar 

  86. Wang L, Yang F, Hu MW, Chen GP, Wang Y, Xu HT, et al. GPX4 utilization by selenium is required to alleviate cadmium-induced ferroptosis and pyroptosis in sheep kidney. Environ Toxicol. 2023;38(4):962–74.

    Article  CAS  PubMed  Google Scholar 

  87. Gao LP, Zhang C, Zheng YY, Wu DY, Chen XY, Lan HA, et al. Glycine regulates lipid peroxidation promoting porcine oocyte maturation and early embryonic development. J Anim Sci. 2023;101:skac425.

    Article  PubMed  Google Scholar 

  88. Fan GH, Liu ML, Liu J, Huang YH. The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: glutamate accumulation. Front Mol Neurosci. 2023;16:1113081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Muñoz P, Munné-Bosch S. Vitamin E in plants: biosynthesis, transport, and function. Trends Plant Sci. 2019;24(11):1040–51.

    Article  PubMed  Google Scholar 

  90. Kagan VE, Mao GW, Qu F, Angeli JPF, Doll S, St Croix C, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81–90.

    Article  CAS  PubMed  Google Scholar 

  91. Gessner DK, Ringseis R, Eder K. Potential of plant polyphenols to combat oxidative stress and inflammatory processes in farm animals. J Anim Physiol Anim Nutr. 2017;101(4):605–28.

    Article  CAS  Google Scholar 

  92. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J. 2013;2013:162750.

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to all the members who edited and reviewed the manuscript.

Funding

This study was supported by National Natural Science Foundation of China (U22A20517).

Author information

Authors and Affiliations

  1. Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan, 430023, China

    Bei Zhou, Junjie Guo, Kan Xiao & Yulan Liu

Authors
  1. Bei Zhou
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Junjie Guo
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Kan Xiao
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Yulan Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

LYL and ZB conceptualized the review. ZB wrote the manuscript. ZB and GJJ collected the data. XK corrected the language. LYL and XK revised and finalized the manuscript. LYL supervised the review. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yulan Liu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, B., Guo, J., Xiao, K. et al. The multifaceted role of ferroptosis in infection and injury and its nutritional regulation in pigs. J Animal Sci Biotechnol 16, 29 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40104-025-01165-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40104-025-01165-1

Keywords

Journal of Animal Science and Biotechnology

ISSN: 2049-1891