Ferroptosis and Its Role in Chronic Diseases

Ferroptosis, which has been widely associated with many diseases, is an iron-dependent regulated cell death characterized by intracellular lipid peroxide accumulation. It exhibits morphological, biochemical, and genetic characteristics that are unique in comparison to other types of cell death. The course of ferroptosis can be accurately regulated by the metabolism of iron, lipids, amino acids, and various signal pathways. In this review, we summarize the basic characteristics of ferroptosis, its regulation, as well as the relationship between ferroptosis and chronic diseases such as cancer, nervous system diseases, metabolic diseases, and inflammatory bowel diseases. Finally, we describe the regulatory effects of food-borne active ingredients on ferroptosis.


Introduction
The term 'ferroptosis', first proposed in 2012, refers to a programmed cell death resulting from iron-dependent lipid peroxidation accumulation. Ferroptosis is distinct from other previously established regulated cell deaths and has specific morphological, biochemical, and genetic characteristics. The regulation of ferroptosis is associated with multiple signal pathways, and there is increasing evidence to suggest its participation in the regulation of numerous diseases. In this paper, we describe the basic features and the regulation mechanisms of ferroptosis, and analyze the application of ferroptosis in chronic diseases such as cancer, nervous system diseases, metabolic diseases, and inflammatory bowel diseases. We also describe the regulatory effects of food-borne active ingredients on ferroptosis.

Morphological Features
Ferroptosis has morphological, biochemical, and genetic features that are unique in comparison with apoptosis, autophagy, necroptosis, and pyroptosis (Table 1) [1][2][3]. Cells that undergo ferroptosis generally show a necrosis-like morphological transformation, including cell membrane rupture, cytoplasmic swelling, and moderate chromatin condensation [4]. At the ultrastructural level, ferroptotic cells usually present mitochondrial shrinkage, an increase in membrane density, reduced or absent cristae, and rupturing of the outer membrane [2]. Since autophagy promotes ferroptosis, autophagy-related ultrastructures, such as double-membrane autophagosomes and various lysosome-related vesicles, are often seen in ferroptotic cells or tissue [5].  Figure 1. Ferroptosis regulatory pathways. Ferroptosis regulatory pathways can be roughly classified into three types: The first involve iron metabolism, including the nuclear receptor coactivator 4 (NCOA4) regulation of ferritin degradation, and the Nrf2-HO-1 pathway, which affects iron. The second is the GSH/GPX4 pathway, including system Xc-inhibition, the transsulfuration pathway, mevalonate pathway (MVA pathway), glutamine pathway, and p53. The third type is that of lipid metabolism, including ACSL4, P53/SAT1/ALOX15, TPD52, and lipophagy, which are related to lipid regulation and ferroptosis, as well as the FSP1-CoQ10-NAD(P)H pathway synergies with GPX4 and GSH, which reduce phospholipid peroxidation and ferroptosis. In addition, endoplasmic reticulum (ER) stress facilitates ferroptosis via ATF4-induced CHAC 1 expression.

Iron Metabolism
Iron in food is principally Fe 3+ , which combines with transferrin (TF) in serum and is then identified by TFR1 in the cell membrane. Once absorbed by TFR1, Fe 3+ is reduced to Fe 2+ through the STEAP3 metalloreductase in the endosome, which is subsequently released from the endosome into the cytosol via solute carrier family 11 member 2 (SLC11A2/DMT1) [4]. The iron-storage protein ferritin plays an antiferroptosis role, including those of ferritin light chain and FTH1, and lysosomes can degrade ferritin to increase free iron levels. NCOA4-mediated ferritinophagy increases the degradation of ferritin by lysosomes, reduces iron storage, and promotes ferroptosis [12]. Finally, the iron-efflux protein FPN exports iron out of cells. Blocking the iron release pathway in cell membranes increases sensitivity to ferroptosis.

Lipid Metabolism
The absorption of free PUFAs such as arachidonic acid (AA) or adrenoxyl (AdA) is mediated by fatty acid translocase (FAT) and fatty acid transport protein (FATP) [13]. ACSL4 facilitates the incorporation of PUFAs into cell membranes and ferroptosis. Ferroptosis regulatory pathways can be roughly classified into three types: The first involve iron metabolism, including the nuclear receptor coactivator 4 (NCOA4) regulation of ferritin degradation, and the Nrf2-HO-1 pathway, which affects iron. The second is the GSH/GPX4 pathway, including system Xc-inhibition, the transsulfuration pathway, mevalonate pathway (MVA pathway), glutamine pathway, and p53. The third type is that of lipid metabolism, including ACSL4, P53/SAT1/ALOX15, TPD52, and lipophagy, which are related to lipid regulation and ferroptosis, as well as the FSP1-CoQ10-NAD(P)H pathway synergies with GPX4 and GSH, which reduce phospholipid peroxidation and ferroptosis. In addition, endoplasmic reticulum (ER) stress facilitates ferroptosis via ATF4-induced CHAC 1 expression.

Iron Metabolism
Iron in food is principally Fe 3+ , which combines with transferrin (TF) in serum and is then identified by TFR1 in the cell membrane. Once absorbed by TFR1, Fe 3+ is reduced to Fe 2+ through the STEAP3 metalloreductase in the endosome, which is subsequently released from the endosome into the cytosol via solute carrier family 11 member 2 (SLC11A2/DMT1) [4]. The iron-storage protein ferritin plays an antiferroptosis role, including those of ferritin light chain and FTH1, and lysosomes can degrade ferritin to increase free iron levels. NCOA4-mediated ferritinophagy increases the degradation of ferritin by lysosomes, reduces iron storage, and promotes ferroptosis [12]. Finally, the iron-efflux protein FPN exports iron out of cells. Blocking the iron release pathway in cell membranes increases sensitivity to ferroptosis.

Lipid Metabolism
The absorption of free PUFAs such as arachidonic acid (AA) or adrenoxyl (AdA) is mediated by fatty acid translocase (FAT) and fatty acid transport protein (FATP) [13]. ACSL4 facilitates the incorporation of PUFAs into cell membranes and ferroptosis. Lipoxygenases (ALOXs) mediate lipid peroxidation and cause ferroptosis. Tumor protein D52 (TPD52)-mediated lipid storage represses RSL3-induced lipid peroxidation and succedent ferroptosis [14]. Lipophagy, a process of autophagy, degrades lipid droplets (LDs), enhances the production of free fatty acids, and increases lipid peroxidation and ferroptosis [14]. Sterol carrier protein 2 promotes the transportation of peroxidized lipids to mitochondria and accelerates GPX4 depletion-mediated ferroptosis. Finally, acetyl-CoA carboxylase alpha is involved in fatty acid β-oxidation and biosynthesis, and promotes ferroptosis.

Amino Acid Metabolism
Amino acid metabolism is closely related to ferroptosis regulation. Cysteine availability restricts GSH biosynthesis, while cysteine starvation induces GSH depletion and ferroptosis. When the available cysteine is limited, some cells utilize the transsulfuration pathway to transform methionine to cysteine [15]. These cells do not require the cystine/glutamate antiporter system Xc-to import cystine and, therefore, are resistant to system Xc-inhibitor-induced ferroptosis. Glutamate is also an important regulator of ferroptosis. In high concentrations, it suppresses system Xc-and triggers ferroptosis. Glutamine degradation (via glutaminolysis) fuels the tricarboxylic acid (TCA) cycle and provides the basis for necessary biosynthetic processes, such as lipid biosynthesis. Cystine starvation and blocked cystine uptake cannot increase ROS accumulation, lipid peroxidation, and ferroptosis in the presence of glutamine deficiency or the inhibition of glutaminolysis [16].

GPX4
RSL3 represses GPX4 activity via covalent bonding with GPX4, resulting in the accumulation of lipid peroxides and, ultimately, ferroptosis. GSH is a co-factor in the catalysis of peroxides by GPX4 to produce alcohols; however, cysteine deprivation leads to GSH depletion, which directly inactivates GPX4, resulting in the subsequent induction of ferroptosis. Legumain has been shown to facilitate tubular ferroptosis via the promotion of chaperone-mediated GPX4 autophagy in acute kidney injury [27], while the selenium-GPX4 axis reduces the ferroptosis of follicular helper T cells [28]. Selenium is necessary for GPX4 to suppress hydroperoxide-induced ferroptosis [29,30]. FINO 2 promotes ferroptosis through GPX4 inactivation and iron oxidation [31]. The downregulation of GPX4 during myocardial infarction triggers ferroptosis in cardiomyocytes [32]. Dihydroartemisinin (DHA) induces ferroptosis in glioblastoma through the inhibition of GPX4 [33]. SIRT3activated autophagy promotes ferroptosis by increasing the AMPK/mTOR pathway and reducing GPX4 levels [34]. GPX4 maintains Treg cell activation and reduces antitumor immunity by inhibiting lipid peroxidation and ferroptosis [35]. Kaempferol protects from oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis via the upregulation of the Nrf2/SLC7A11/GPX4 axis [36]. Finally, the inactivation of GPX4 was found to trigger ferroptosis and acute renal failure in mice [37].

Figure 2.
Role of ferroptosis in chronic diseases. Ferroptosis participates in the regulation of many system disorders, including nervous system diseases, cardiovascular diseases, liver diseases, kidney diseases, lung diseases, pancreatic diseases, and intestinal diseases. Role of ferroptosis in chronic diseases. Ferroptosis participates in the regulation of many system disorders, including nervous system diseases, cardiovascular diseases, liver diseases, kidney diseases, lung diseases, pancreatic diseases, and intestinal diseases.

Liver Cancer
Liver cancer is the sixth most common malignancy and the third primary cause of cancer-related deaths worldwide [77]. Ferroptosis plays an important role in the regulation of hepatocellular carcinoma (HCC) (Figure 3). Sorafenib, which is a multikinase inhibitor used widely in the treatment of advanced HCC, induces ferroptosis by inhibiting SLC7A11;

Colorectal Cancer
Recent studies have reported that ferroptosis participates in the regulation of colorectal cancer (CRC), a common malignancy of the digestive system ( Figure 3). RSL3 is known to induce CRC ferroptosis by inactivating GPX4 and producing ROS [88]. Tagitinine C, a natural product, acts synergistically with erastin to induce ferroptosis in CRC cells via the PERK-Nrf2-HO-1 signaling pathway [48]. The benzopyran derivative IMCA induces ferroptosis by downregulating SLC7A11 and the AMPK/mTOR pathway in CRC [89]. Inhibit-

Breast Cancer
Breast cancer is the most common cancer among women. Sulfasalazine has been found to trigger breast cancer cell ferroptosis via the repression of GPX4 and SLC7A11 expressions and an increase in TFR1 and DMT1 expressions, particularly in cells with low estrogen receptor (ER) expression [96]. The combined treatment of siramesine and lapatinib triggers breast cancer cell ferroptosis by increasing TF expression and reducing FPN expression [97]. Metformin triggers ferroptosis via a reduction in the UFMylation of SLC7A11 in breast cancer [98]. Curcumin promotes the ferroptosis of breast cancer cells by increasing lipid ROS levels, lipid peroxidation end-product MDA accumulation, and intracellular free iron levels [99]. Targeted exosome-encapsulated erastin promotes the ferroptosis of triple-negative breast cancer (TNBC) cells [100]. The GSK3β/Nrf2 signaling pathway strengthens the ferroptosis of breast cancer induced by erastin [101]. Inhibiting GPX4 increases gefitinib-induced ferroptosis in TNBC cells [102], while simvastatin induces ferroptosis in TNBC cells [103]. Metformin promotes ferroptosis via the up-regulation of miR-324-3p and down-regulation of GPX4 in breast cancer [104]. Lidocaine induces the ferroptosis of ovarian and breast cancers by increasing miR-382-5p and decreasing SLC7A11 [105], while ketamine induces ferroptosis by targeting the KAT5/GPX4 axis in breast cancer cells [106].

Ovarian Cancer
Ovarian cancers are prevalent female malignancies, seriously affecting women's health and life quality in the world. Lidocaine promotes ferroptosis in ovarian and breast cancer cells by enhancing miR-382-5p and down-regulating SLC7A11 expression [105]. Stearoyl-CoA desaturase 1 (SCD1) suppresses ovarian cancer cell ferroptosis [107], while the inhibition of pharmaceutical SCD1 promotes ferroptosis in vitro and in vivo, and the combined treatment of SCD1 inhibitors and ferroptosis inducers significantly inhibits ovarian tumor growth [108]. SNAI2 knockdown promotes ferroptosis in ovarian cancer [109]. Sodium molybdate induces the ferroptosis of ovarian cancer cells via labile iron elevation and GSH depletion [110]. Ferroptosis inducers increase the sensitivity of BRCA-proficient ovarian cancer cells to PARP inhibitor by repressing SLC7A11 [25]. Human serum incubatedsuperparamagnetic iron oxides promote ferroptosis via p53 overexpression in ovarian cancer cells [111]. Superparamagnetic iron oxide nanoparticles increase oxidative stress, reduce autophagy, and activate ferroptosis in ovarian cancer stem cells [111]. GALNT14 induces ferroptosis in ovarian cancer via the EGFR/mTOR pathway [112]. MAP30 protein from Momordica charantia and cisplatin synergistically induce ferroptosis in ovarian cancer [113].

Pancreatic Cancer
Pancreatic cancer, one of the most fatal of all cancers, is seen mainly in males and the older population (40-85 years) [114]. The inhibition of cytosolic aspartate aminotransaminase promotes pancreatic cancer cell ferroptosis by repressing mitochondrial metabolism and promoting a catabolic state [115]. The natural compound artesunate induces ferroptosis in pancreatic cancer cells [116]. Cysteine depletion promotes the ferroptosis of pancreatic tumor cells in mice [117]. Ruscogenin, a saponin found in the root of Ophiopogon japonicus, increases intracellular ferrous iron and ROS, thereby inducing ferroptosis in pancreatic cancer cells [118]. The abrogation of ADP ribosylation factor 6 promotes RSL3induced ferroptosis in pancreatic cancer cells [119]. DHA acts synergistically with cisplatin to trigger ferroptosis in pancreatic ductal adenocarcinoma (PDAC) by regulating iron metabolism [120]. Combining artesunate with GRP78 inhibition facilitates ferroptosis in KRAS mutant PDAC [121]. Chrysin enhances pancreatic cancer sensitivity to gemcitabine by inducing autophagy-dependent ferroptosis via the targeting of human carbonyl reductase 1 [122]. Ponicidin suppresses pancreatic cancer growth by inducing ferroptosis [123], while piperlongumine induces ferroptosis in human pancreatic cancer cells by suppressing the gamma-glutamyl cycle and regulating the metabolism of PUFAs [124].

Stroke
Stroke is one of the leading causes of death and disability in the world. Selenium activates homeostatic transcription to protect neuron cells from ferroptosis and treat stroke [125]. ACSL4 enhances ischemic stroke by inducing neuronal ferroptosis-related brain injury and neuroinflammation [126], while the inhibition of ACSL4 improves neurological functioning after stroke via the suppression of ferroptosis [127]. Reducing NCOA4 inhibits the ferritinophagy-mediated ferroptosis of neurons, and thus can be used to treat ischemic stroke [63]. The hemin-induced hemorrhagic stroke model is one of classic neuronal ferroptosis [128]. Intracerebral hemorrhage (ICH) is a type of severe stroke, the pathology of which is closely related to ferroptosis. Curcumin nanoparticles inhibit ferroptosis and enhance ICH treatment [129], and baicalin can also suppress ferroptosis in ICH [130]. Tau-mediated iron export inhibits ferroptosis after ischemic stroke [131]. Supplementing lactoferrin reduces the ferroptosis of nerve cells after diabetic ICH [132], while crocin reduces ICH-induced neuronal ferroptosis by increasing Nrf2 expression and nuclear translocation [133]. Dauricine represses nerve cell ferroptosis and brain injury after ICH by up-regulating GPX4 expression [134], while pyridoxal isonicotinoyl hydrazone, a lipophilic iron-chelating agent, alleviates hemorrhage stroke by decreasing ferroptosis and inflammation [135].

Huntington's Disease
Huntington's disease (HD) is an autosomal dominant and fatal neurodegenerative disease resulting from abnormal cytosine-adenine-guanine repetition in the huntingtin gene [160], for which there is currently no effective treatment. A few ferroptotic characteristics have been observed in HD animal models and patients, such as iron accumulation, oxidative stress, GSH depletion, and reduced GPX activity [161], which suggests the participation of ferroptosis in the regulation of HD pathogenesis. Several ferroptosis regulators have also been found to take effect in HD models. For instance, Fer-1 suppressed oxidative lipid damage and ferroptosis in HD cellular models [162], while the intraventricular delivery of the iron chelator DFO led to motor phenotype improvement in R6/2 HD mice [163].

Cardiovascular Diseases
Cardiovascular diseases are those involving the heart and blood vessels, such as atherosclerosis, peripheral vascular diseases, and cerebrovascular diseases. Ferritin plays a key role in inhibiting cardiac ferroptosis and succedent heart failure, while cardiac ferritin H loss promotes cardiomyopathy by increasing SLC7A11-mediated ferroptosis [23]. Mitochondria-dependent ferroptosis plays an important role in doxorubicin-induced cardiomyopathy [164]. ENPP2, a lipid kinase participating in lipid metabolism, reduces erastin-induced ferroptosis in cardiomyocytes by regulating GPX4, ACSL4, and Nrf2 expression and increasing AKT signaling [165]. The inhibition of ferroptosis alleviates atherosclerosis by reducing lipid peroxidation and endothelial dysfunction [9]. Rapamycin plays a key role in reducing excess iron and ferroptosis in cardiomyocytes [166]. MSC exosomes derived from human umbilical cord blood inhibit ferroptosis and attenuate myocardial injury, possibly by inhibiting the expression of DMT1 by miR-23a-3p [167]. GPX4 down-regulation during myocardial infarction results in ferroptosis in cardiomyocytes [32]. TRIM21 ablation alleviates cardiotoxicity of the chemotherapeutic agent doxorubicin by suppressing ferroptosis [168].

Liver Diseases
Increasing evidence indicates that the suppression of ferroptosis may slow the development of several liver diseases, including alcoholic liver injury, nonalcoholic steatosis hepatitis (NASH), and fibrosis [177]. Intestinal SIRT1 deficiency attenuates alcoholic liver injury via the mitigation of hepatic ferroptosis in mice [178]. Ginkgolide B, a primary ingredient of Ginkgo biloba extracts, alleviates nonalcoholic fatty liver disease in obese mice by inhibiting ferroptosis, possibly through the Nrf2 signaling pathway [179]. Ferroptosis inhibitors reduce methionine/choline-deficient diet-induced NASH by inhibiting liver lipotoxicity [180]. (+)-Clausenamide, an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, alleviates drug-induced liver injury by suppressing hepatocyte ferroptosis. The radical oxidation of n-6 PUFAs promotes ferroptosis and APAP-induced acute liver failure [181]. Ferroptosis plays a dual role in liver fibrosis. Some evidence suggests the pathogenic role of ferroptosis in iron-overload-induced liver fibrosis, and inhibiting ferroptosis potently prevents liver fibrosis. Hepatic TF plays a role in maintaining liver function and preventing ferroptosis-induced liver fibrosis [182]. Artesunate relieves liver fibrosis via downregulation of the ferroptosis signaling pathway [183]. Fibroblast growth factor 21 reduces iron-overload-induced liver injury and fibrosis by suppressing ferroptosis [184]. Activation of hepatic stellate cells (HSCs); that is, transdifferentiation into matrix-producing myofibroblasts, is considered the central driver of hepatic fibrosis [185]. Recent studies demonstrate the potential of inducing ferroptosis in HSCs as a therapeutic strategy designed to alleviate the development of liver fibrosis. Artemether relieves carbontetrachloride-induced liver fibrosis and inhibits HSCs activation through p53-dependent ferroptosis induction [186]. Sorafenib suppresses liver fibrosis by inducing HSCs ferroptosis via the inactivation of the HIF-1α/SLC7A11 pathway [187]. Moreover, certain regulators of ferroptosis in HSCs, including p53 [186], ELAV-like protein 1 (ELAVL1) [188], and zinc finger protein 36 (ZFP36) [189], have been reported as potential targets for the treatment of liver fibrosis.

Inflammatory Bowel Diseases
Inflammatory bowel disease is a chronic relapsing disease mainly affecting the intestinal tract, and includes ulcerative colitis (UC) and Crohn's disease (CD). Ferroptosis participates in intestinal epithelial cell death in UC [209]. The suppression of ferroptosis ameliorates DSS-induced UC by suppressing the Nrf2/HO-1 signaling pathway [49]. Curculigoside protects against ferroptosis in UC by inducing GPX4 [210]. Fer-1 reduces TNBS-induced colitis by inhibiting ferroptosis [211]. Furin inhibits the DSS-induced ferroptosis of epithelial cells and reduces experimental colitis via Nrf2-GPX4 signaling pathway activation [212]. Astragalus polysaccharide was shown to inhibit ferroptosis in a murine model of experimental colitis and human Caco-2 cells by blocking the Nrf2/HO-1 pathway [213]. Dietary lipids are a trigger of GPX4-restricted enteritis resembling CD [214].

Regulatory Effects of Food-Borne Active Ingredients on Ferroptosis
A large number of studies have reported that food-borne active ingredients, such as polyphenols, can regulate ferroptosis (Figure 4). model of experimental colitis and human Caco-2 cells by blocking the Nrf2/HO-1 pathway [213]. Dietary lipids are a trigger of GPX4-restricted enteritis resembling CD [214].

Regulatory Effects of Food-Borne Active Ingredients on Ferroptosis
A large number of studies have reported that food-borne active ingredients, such as polyphenols, can regulate ferroptosis (Figure 4).  Quercetin (QCT), a natural flavonoid found commonly in fruits and vegetables, alleviates T2DM by inhibiting the ferroptosis of pancreatic β cells via the upregulation of GSH and GPX4, and by increasing mitochondria membrane-associated protein VDAC2, which functions as an antioxidant [169]. QCT also reduces AKI by repressing ferroptosis via a reduction in MDA and lipid ROS levels and an increase in GSH [190]. QCT can suppress the erastin-induced ferroptosis of bone-marrow-derived mesenchymal stem cells, probably via the antioxidant pathway [215]. QCT triggers p53-mediated cancer cell ferroptosis by promoting lysosome-dependent ferritin degradation and ROS generation [216]. Dihydroquercetin reverses cigarette-smoke-induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease by up-regulating the Nrf2-dependent pathway [217].
Gallic acid (GA) is a natural polyhydroxy phenolic compound seen in various foods, such as edible mushrooms, fruits, and vegetables. GA triggers cancer cell death via the activation of apoptotic, ferroptotic, and necroptotic pathways [218]. Preirradiation therapy followed by GA treatment inhibits the survival of cancer cells more effectively than GA treatment alone via the apoptosis and ferroptosis cell death mechanisms [219].
Curcumin, a polyphenol compound extracted from the turmeric plant, enhances the treatment effect of NSCLC by activating autophagy-dependent ferroptosis [70]. Curcumin decreases rhabdomyolysis-related renal damage by reducing ferroptosis, and mechanistic studies have shown that curcumin downregulates the TLR4/NF-κB axis and activates HO-1 [220]. Since curcumin nanoparticles suppress ferroptosis, they can be used to strengthen the treatment of ICH [129]. Curcumin also induces the ferroptosis of breast cancer cells by upregulating SLC1A5 [99].
Epigallocatechin gallate (EGCG), a major polyphenol in green tea, protects against radiation-induced intestinal injury by scavenging ROS and repressing apoptosis and ferroptosis via the Nrf2 signal pathway [221]. EGCG pretreatment reduces doxorubicin cardiotoxicity-induced ferroptosis by increasing AMPKα2 and promoting adaptive autophagy [222]. Apigenin is a flavonoid found in green leafy herbs and vegetables, including celery, parsley, spinach, chamomile, green pepper, and eggplant, as well as oranges and red wine [223]. Apigenin is able to alleviate myeloperoxidase-mediated oxidative stress and repress ferroptosis in neuronal cells [224].
Resveratrol is a polyphenol that exists commonly in various vegetables and fruits, such as grapes. Resveratrol alleviates ferroptosis-induced myocardial ischemia/reperfusion injury, reduces TfR1 expression, and increases the expressions of FTH1 and GPX4 [225]. Resveratrol nanoparticles can repress erastin-induced ferroptosis in HT22 mouse hippocampal cells [226], and also inhibits acrolein-induced ferroptosis and insulin secretion disorder via the ER-stress-related PERK pathway in mouse pancreatic β cells [227]. Nobiletin, a critical active flavonoid in citrus fruits, was found to reduce ferroptosis-related renal injury, inflammation, and fibrosis in a unilateral ureteral obstruction mouse model [228]. Nobiletin triggers the ferroptosis of human skin melanoma cells via the GSK3β-mediated Keap1/Nrf2/HO-1 signaling pathway [229].

Conclusions
Ferroptosis is a recently identified type of programmed cell death that results from iron-dependent lipid peroxide accumulation. Scientific research developments have revealed the participation of ferroptosis in the pathophysiological processes of numerous diseases, creating the potential for novel approaches to treat these diseases. The induction of ferroptosis can inhibit tumor progression, while its inhibition can alleviate nervous system diseases, metabolic diseases, and inflammatory bowel diseases. A large number of studies have reported that food-borne active ingredients, such as polyphenols, can regulate ferroptosis, either inhibiting it and thereby alleviating chronic conditions, or triggering ferroptosis in cancer cells and thereby inhibiting cancer. To define more precise relationships between ferroptosis and health effects, the following issues need to be addressed in the future:

•
The relationship between ferroptosis and other types of cell death still needs to be defined; • The final executors of ferroptosis downstream of lipid peroxidation remain to be identified; • In addition to polyphenols, other food-borne active ingredients that regulate iron death remain to be investigated.

Conflicts of Interest:
The authors declare no conflict of interest.