Clinical and Translational Oncology (2022) 24:1–12

https://doi.org/10.1007/s12094-021-02669-8

REVIEW ARTICLE

Ferroptosis: an iron‑dependent cell death form linking metabolism,

diseases, immune cell and targeted therapy
Shengxian Li1 · Yong Huang1

Received: 7 May 2021 / Accepted: 10 June 2021 / Published online: 23 June 2021
© Federación de Sociedades Españolas de Oncología (FESEO) 2021

Abstract
Compared with the traditional forms of cell death—apoptosis, necrosis and autophagy, ferroptosis is a novel form of iron-
dependent programmed cell death forms which is different from the above traditional forms of cell death. Brent R Stockwell,
a Professor of Columbia University, firstly proposed that this from of cell death was named ferroptosis in 2012. The main
characteristics of ferroptosis is increasing iron loading and driving a lot of lipid peroxide generated and ultimately lead to
cell death. In this paper, the mechanism of ferroptosis, relationship between ferroptosis and common diseases and immune
state of body are reviewed, and the inhibitors and inducers related to ferroptosis that have been found are summarized to
provide medicine exploration targeted of ferroptosis and reference for the research in the future.

Keywords Ferroptosis · Common clinical diseases · Tumor · Immune cells · Targeted therapy

Introduction it does not depend on the Caspase9 family, but is closely

related to lipid metabolism, amino acid metabolism, iron
Cell death is definitely concern about mammalian growth, metabolism and gene regulation in vivo. Due to ferroptosis
homeostasis regulation and development of various diseases. in recent years has been more and more gotten the atten-
As is known to all, cell autophagy, apoptosis and necrosis tion of people, through deep researches in mechanism of
are the traditional form of regulating cell death, in addi- ferroptosis, it was found ferroptosis and a variety of human
tion, ferroptosis is a fresh mode of iron-dependent death diseases have inseparable relationship, including cardiac
induced by small molecules such as Erastin and RSL3 pro- ischemic disease, kidney disease, liver damage, and degen-
posed by Dixon in 2012, whose morphology, mechanism, erative disease, for example, ferroptosis of tumor cells can
induction and inhibition is different from traditional form of be induced to achieve the purpose of tumor treatment, and
cell death [1]. The morphology of ferroptosis mainly shows ferroptosis is also closely related to immunotherapy. There-
that smaller mitochondria appear in the fine structure of the fore, more and more drugs with ferroptosis as the therapeutic
cell, and the mitochondrial membrane is shrunk, the mito- target can be studied. The compounds Erastin discovered
chondrial cristae is reduced or disappeared, and the outer by Dolma et al. [2] as early as 2003 are equivalent to the
membrane is broken, but the morphological changes in the new compounds RSL3 and RSL5 that have similar func-
nucleus are not obvious. In the mechanism of occurrence, tions to Erastin found in 2008 by Yang et al. [3], Yang et al.
[3] also found that ferroptosis chelating agents, DFOM and
vitamin E could inhibit this non-apoptotic cell death mode-
* Shengxian Li ferroptosis. In this paper, mechanism of ferroptosis and its
L914694127@126.com relationship with diseases and human immune state are
* Yong Huang described in detail, and the inhibitors and activators target-
huangyong503@126.com ing of ferroptosis that have been found so far are summa-
1 rized, hoping to provide a new perspective for the study of
National Center for International Research of Bio‑Targeting
Theranostics, Guangxi Key Laboratory of Bio‑Targeting ferroptosis and explore other target medicine as a potential
Theranostics, Collaborative Innovation Center for Targeting therapeutic target.
Tumor Diagnosis and Therapy, Guangxi Talent Highland
of Bio-Targeting Theranostics, Guangxi Medical University,
Nanning 530021, Guangxi, China

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Mechanism of ferroptosis NADPH reduction reaction in its cytoplasm. Therefore, Glu-

tamate (GSH) is a key target for controlling ferroptosis, and
Ferroptosis, metabolic cell death form mediated by amino its synthesis processes (cysteine, GCLC enzyme and GSS
acid metabolism, iron metabolism, and lipid metabolism, is enzyme), uptake processes (transporters system Xc -), and
complicated, and its complete mechanics are described in transport processes (GPX4) can regulate ferroptosis.
detail below and illustrated in Fig. 1. Sulfur REDOX protein (TXN)—In 1994, it was proposed
that TXN reductase, the second most important substance in
Amino acid metabolism the mercaptan dependent antioxidant system [4], can cata-
lyze the reduction of cystine to cysteine so as to maintain
Glutathione (GSH)—Glutamate (GSH) is compounding the activity of GPX4. SLC7A11 and TXN enzyme systems
from cysteine and glycine under the catalyze of GCLC can synergistically supplement GSH. The TXN enzyme sys-
enzyme and GSS enzyme, Glutathione peroxidase 4 (GPX4) tem of malignant tumor cell lines is usually very active, and
oxidizes hydroperoxide and two molecules of reducing glu- inhibition of GSH and TXN pathways can effectively trig-
tathione (GSH) into lipid alcohols and oxidizing glutathione ger tumor cell death. Therefore, TXN is also one of the key
(GSSG), acting as an antioxidant and free radical scavenger targets for regulating ferroptosis.
which can inhibit ferroptosis. Intracellular cysteine, a key Glutamine metabolism—Glutamine is converted to gluta-
substrate of synthesizing of GSH, can be obtained by de mate in response to GSL1 and GSL2, if extracellular gluta-
novo synthesis or by recovery through protein degradation, mate levels are high, the system Xc − is unable to transport
most of the cancer cells using cystine transporters system intracellular glutamate out of the cell and unable to transport
Xc − to get cystine from extracellular environment, and extracellular cysteine into the cell, which will inhibit glu-
cysteine, which can be used in the synthesis of glutathione tathione synthesis and finally induce ferroptosis, so inhibit-
(and other biological molecules), is then produced through ing glutamine metabolism can inhibit ferroptosis [5].

Fig. 1  Mechanism of ferroptosis

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Clinical and Translational Oncology (2022) 24:1–12 3

+
Glutathione peroxidase 4 (GPX4)—GPX4 is a sele- is stored in Ferritin. As the most important protein in
noprotein [6]. As we all known, decoding selenocysteine cells, Ferritin can maintain intracellular iron homeostasis
requires special tRNA—selenocysteine tRNA (sec-tRNA), and reduce oxidative stress caused by Fenton reaction,
and synthesis of the isoprene group of sec-tRNA requires the so as to achieve the purpose of protecting cells [3, 17,
intermediate isoprene pyrophosphate (IPP) from the MVA 18]. Xuexian Fang et al. [19] clarified the physiological
pathway, because IPP is one of the most significant products effect of Ferritin inhibiting cardiac ferroptosis under iron
of the MVA approach [7]; hence, inhibitors of the MVA overload. ­Fe 2 +, which is stored in the ferritin, can also
pathway can induce ferroptosis by inhibiting the synthe- be mediated iron autophagy auxiliary by nuclear recep-
sis of GPX4. Zhang et al. [8] found that GPX4 was largely tors activated factor 4 (NCOA4) and released into the
expressed in tumor in comparison with normal tissues, and cytoplasm [20], Gao et al. [21] knockout fibrosarcoma
high expression of GPX4 was not conducive to the prognosis cells, pancreatic cells and other cells NCOA4 genes, the
of patients. ferroptosis were significantly inhibited, and excess of ­Fe2
System ­xc−—System ­xc− is made up of subunit SLC7A11 +
will participate in fenton reaction to generate hydroxyl
and subunit SLC3A2 [9], it transfers glutamate extracellu- free radicals to induce ferroptosis, or induces ferroptosis
lar and cystine intracellular for GSH synthesis. Ferroptosis by activating an enzyme that contains iron (e.g., lipoxy-
occurs when System XC − is inhibited, for example, Erastin genase) [22, 23].
induced ferroptosis through inhibiting the physical activity In addition, iron metabolism in the body is precisely
of System XC − [10]. A variety of regulatory factors can regulated by hepcidin. Ferroportin1 (FPN1, SLC40A1),
regulate ferroptosis by regulating SLC7A11, NFE2L2 [11] an iron channel, can transport iron from iron storage cells
positively regulates SLC7A11, and tumor suppressor genes to extracellular and circulatory systems to maintain iron
such as TP53 [12], BAP1 [13] and BECN1 [14] negatively homeostasis in cells [24, 25]. Hepcidin promotes the endo-
regulate SLC7A11. Another alternative pathway for synthe- cytic degradation of FPN1 by binding to the membrane
size cysteine, the trans-sulfur pathway, synthesis cysteine by surface, thereby inhibiting iron uptake by intestinal epi-
methionine, also can inhibits ferroptosis. thelium and iron reuse by macrophages in aging RBC [26].
Other—Other intracellular anti-ferroptosis systems Hepcidin, as a hormone secreted by the liver, is regulated
include coenzyme Q10 (CoQ10) produced by AIFM2, tet- by multiple pathways: serum iron and intracellular iron of
rahydrobiopterin (BH4) produced by GCH1 and the mem- the liver upregulate Hepcidin through the BMP6/ Smad4
brane repair system of EscRTIII, which play a critical part pathway [27]. Oxidative stress, hematopoiesis and energy
in anti-ferroptosis. metabolism downregulated Hepcidin through their respec-
Briefly, SLC7A11-GSH-GPX4 pathway is identified as tive pathways, respectively. In the process of pathogen
the most upstream process of regulating ferroptosis. The infection and inflammatory response, many inflammatory
mechanism of amino acid metabolism regulating ferroptosis factors upregulate the expression of Hepcidin through the
is mainly that cystine absorbed by System XC − is involved JAK2/STAT3 pathway [28]. Excess hepcidin leads to iron
in the synthesis of glutathione (GSH), and GSH is reduced retention in macrophages and decrease of free iron content
to GSSG under the action of GPX4 thereby restrain ferrop- in the circulatory system, which is one of the important
tosis. The current targeted reagents of ferroptosis are mainly mechanisms of the body against pathogen infection.
through target SLC7A11- GSH- GPX4 pathway, in addition, In a word, the mechanism of iron metabolism regulat-
by adjusting the armor hydroxyl pentanoic acid pathway, ing ferroptosis is mainly that the TF-(Fe3 +)2-TFR1 com-
sulfur transfer way, sulfur TXN REDOX proteins and glu- plex is formed under the action of transferrin—transfer-
tamine metabolism to some extent, can also play the role of rin receptor and enters into the cell lysosome, under the
regulating ferroptosis. action of iron reductase (STEAP3), it is reduced to ­Fe2 +
and stored in Ferritin. Excess F ­ e2 + oxidize lipids through
Iron metabolism Fenton reaction to produce ROS and lipid peroxides ulti-
mately bring about ferroptosis. Therefore, the expression
As an indispensable trace element, Iron can adjust the of iron overload, transferrin, transferrin receptor, ferritin
occurrence of ferroptosis. Outside the cell, transferrin and nuclear receptor coactivator4 ( NCOA4) can all be
(TF) transport two ­Fe3 + to transferrin receptor 1 (TFR1) used as targets for regulating ferroptosis, ALOX or eGln
and form TF—(Fe3 +) 2—TFR1 compounds [15] into lys- proline hydroxylase (also known as PHD) are taking effect
osomes in the cell, Basuli et al. [16] has shown that this for the activity of lipid peroxidation and iron homeostasis,
process is significant increase in ovarian cancer, breast expression of hepcidin and FPN1 can also act as targets
cancer and other cancers. After degradation of F ­ e3 + into to regulate ferroptosis. Therefore, iron metabolism is one
­Fe under the action of iron reductase (STEAP3), ­Fe 2
2+
of the important pathways to inhibit or induce ferroptosis.

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4 Clinical and Translational Oncology (2022) 24:1–12

Lipid metabolism (oxidative stress) to link ferroptosis with treatment of many human diseases.
Therefore, it is of great significance to link ferroptosis with
What are the products of lipid peroxidation mainly included? disease by targeting the mechanism of ferroptosis. The fol-
There is no doubt that lipid hydroperoxides(LOOHS), lowing sections will elaborate on some of the diseases that
malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) have been found so far and the association between the
are the most common products. Lipid peroxidation directly body’s immune status and ferroptosis.
damages cell membrane and organelle membrane phospho-
lipids, excessive reactive oxygen free radicals cause adverse
damage to cell components such as nucleic acids; therefore, Relationship between ferroptosis
lipid peroxides accumulation and excessive active free radi- and various diseases and immune cell
cals are the premise of ferroptosis [29].
The membrane and organelle membrane of living organ- The association between ferroptosis and tumor
isms are rich in PUFAs, which are substrates of lipoxygenase
(LOXs), only in the way that they occur oxidation reaction Studies pointed out that the use of the delta-2 agonist
and esterification reaction and turn into membrane phos- cimatinib and the tyrosine kinase inhibitor lapatinib in breast
pholipids, will they become the signal of ferroptosis [30]. cancer cell lines induces ferroptosis by increasing iron levels
Under the action of ACSL4 and LPCAT3, free PUFAs react [37]. Growing evidence revealed that the use of the rheuma-
with phosphatidylethanolamine (PES) to synthesize PUFAS- toid arthritis drug phenofen in human hepatoma cell lines
PES [30, 31]. Because PUFAS-PES contains easily extracted also induced ferroptosis and was saved by the ferroptosis-
diallyl hydrogen atoms, it is prone to lipid peroxidation. specific inhibitor FER-1 [38]. In addition, activated ­CD8+
Under the action of ACSL4, arachidonic acid (AA) and T cells can release IFN-γ, which will inhibit the expression
adrenal acid (ADA) bind with coenzyme A, respectively, of SLC7A11 in tumor cells through the JAK1-STAT1 path-
generate to AA-CoA and ADA-CoA, which are their acyl way, suggesting that targeted regulation of cysteine/cysteine
coenzyme A esters, then bind to membrane phospholipids levels in tumor cells may be a valid way of tumor immuno-
[30–33], it promotes the esterification of phosphatidyle- therapy [39]. For these reasons, one could envisage that the
thanolamine to form AA-PE or ADA-PE after the action relationship between ferroptosis and tumors is inextricably
of LPCAT3 and finally resulting in ferroptosis [30, 31]. In linked.
addition, arachidonic acid (AA) generates prostaglandin Ferroptosis exerts a major influence in the development
(PEG2) and thromboxin under the action of cyctoxidase and treatment of many tumors. Previous works have shown
(COXS), and arachidonic acid (AA) generates leukotriene ferroptosis sensitivity is significantly correlated with tumor
and hydroxy-eicosatetraenoicacid (Hetes) under the action gene mutations, such as RAS [40], TP53 mutation [41],
of lipoxygenase (LOX), Arachidonic acid (AA) generates HIF mutation, stress response pathways [42], epithelial-
Hetes under the action of cytochrome P450 family enzymes. mesenchymal-transformation(EMT) [43] and other signal-
Both PEG2 and Hetes are different types of arachidonic acid. ing pathways. On the one hand, ferroptosis inducers such as
NADPH oxidase (NOXS), cytochrome P450 oxidoreduc- Erastin can cause ferroptosis and thus inhibit progression of
tase (POR), and mitochondrial respiratory chain can produce tumor; on the other hand, ferroptosis can induce inflamma-
ROS and also participate in lipid oxidation of iron death tion-related immunosuppressive tumor microenvironment to
[34]. In addition, NADPH oxidase (NOXS), cytochrome promote tumor growth. It is well known that the content of
P450 oxidoreductase (POR), and mitochondrial respiratory iron and glutathione in tumor microenvironment is higher
chain can produce ROS and also participate in lipid oxida- than that in normal cells, so tumor cells should easily trig-
tion of ferroptosis [1, 35, 36]. ger ferroptosis. However, how do tumor cells regulate fer-
In conclusion, the ACSL4-LPCAT3-ALOXS axis can roptosis-sensitive microenvironment to protect themselves
promote lipid oxidation to form excessive lipid hydroper- from being cleared by immune cells? Certainly the extent
oxides and ROS, inducing cell membrane rupture and cell of ferroptosis’s influence on tumor biology remains to be
ferroptosis. In this metabolic process, GPX4, AA, ADA, further studied.
PUFA, ACSL4, LPCAT3, ALOXS, and COXs all play a
very important role and can be used as targets of ferroptosis Relationship between ferroptosis and MDS
to inhibit or induce ferroptosis. Therefore, lipid metabo- (Mitochondrial DNA depletion syndrome)
lism is also one of the important mechanisms for regulating
ferroptosis. MDS is caused by the reduction of DNA content by reason
Broadly speaking, deeply researching into the mechanism of the mutation of the nuclear gene that synthesizes mito-
of ferroptosis has led to the discovery that the causing of chondrial DNA, leading to the dysfunction of multiple tis-
resistance to previous treatments just because of the failure sues and organs, the affected organs usually include liver,

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Clinical and Translational Oncology (2022) 24:1–12 5

brain, muscle, etc. As the main iron storage organ in the SLC39A14 in liver induced ferroptosis of liver chymal cells
human body, the liver is the first to be attacked when iron by absorbing non-transferrin Bound Iron (NTBI), thus lead-
overload occurs. Mitochondrial DNA deletion widely exists ing to the occurrence of liver fibrosis. Several recent stud-
in aging, degenerative diseases and other genetic diseases, so ies have shown that, ferroptosis not only well elucidates the
it has a wide range of potential pathological and therapeutic pathological mechanism of liver diseases, but also provides
significance [44]. At least nine genetic mutations have been a research basis of new drugs targeting diseases related to
identified that cause MDS [45]. Deoxyguanosine kinase abnormal iron metabolism. As an important mechanism
(DGUOK) role is largely synthetic purine nucleotide in the of liver fibrosis and an important target for the control and
mitochondria, the mutation type most often lead to bone therapy of liver fibrosis, it provides ideas for the prevention
MDS [46], patients often died of severe liver failure within of liver injury caused by iron overload in clinical practice.
a year, in addition to liver transplantation, there is no other Ultimately, it is demonstrated that ferroptosis, as a new tar-
effective treatments [47], its important clinical phenotype is get for liver fibrosis, will bring good results.
liver iron deposit, serological examination showed elevated
serum ferritin and transferrin [48]. Studies have shown that Associations between ferroptosis and degenerative
hepatocytes of MDS patients are more sensitive to ferrop- diseases
tosis caused by iron deposition, first, mitochondrial DNA
deletion in hepatocytes leads to mitochondrial dysfunction, Alzheimer’s disease (AD). Alzheimer’s disease (AD) is the
decreased mitochondrial ATP synthesis, increased reactive most common neurodegenerative disease among the elderly,
oxygen species and glutathione depletion, and the iron in in which the loss of synapses and neurons leads to mem-
ferritin is released into the cytoplasm, causing lipid peroxi- ory loss. Current studies have shown that there is an exact
dation to increase reactive oxygen species (ROS), and finally relationship between excess iron accumulation in the brain
leading to ferroptosis of liver cells. Therefore, the regulation and the occurrence and development of AD and learning
of iron metabolism pathway can provide a blueprint for the and memory disorders [53]. There are many pathological
future development of therapeutic target for MDS liver fail- changes associated with ferroptosis in AD patients and ani-
ure, which is a novel pathological mechanism and potential mal models, such as increased liposome oxidation, downreg-
therapeutic strategy. ulation of GPX4, accumulation of iron ions, and increased
extracellular glutamate concentration [22, 54]. Bao Wd et al.
Association of ferroptosis with cardiac ischemic [55] for the first time systematically elucidates the charac-
disease (ischemia reperfusion injury) teristics of ferroptosis in hippocampal neurons in a mouse
model of AD and identifies pathologic down regulation of
Xuexian Fang et al. [49] found that Ferrostatin 1 (FER-1) Ferroportin (FPN) in both AD patients and mice, it has been
significantly reduced cardiotoxicity induced by doxorubicin, confirmed that FPN deficiency can induce ferroptosis and
HMOX1 is a key regulatory gene of ferroptosis in adriamy- lead to learning and memory impairment, restoration of
cin cardiomyopathy; therefore, unlike previous approaches FPN expression can improve ferroptosis characteristics of
of preventing and treating cardiomyocytes, ferroptosis could neurons and learning and memory impairment. The role of
be a promising therapeutic target. Marcus Conrad et al. [50] ferroptosis in neurodegenerative diseases has been widely
showed that the characteristics of cardiomyocyte is related concerned.
to ferroptosis. A variety of examples demonstrated that it is Parkinson’s disease. Clinically, patients with Parkinson
clear that ferroptosis provides promising new ideas and new present with a large increase in iron and lipid peroxides,
strategies of heart disease prevention and treatment, such as which are also the characteristics of ferroptosis. The unsatu-
clinical myocardial infarction. rated fatty acid chain of phospholipid in biofilm is continu-
ously oxidized and repaired, if the repair is not timely, the
Ferroptosis and hepatocellular injury disease accumulation of phospholipid peroxides may lead to fer-
roptosis of cells. Calcium-independent phospholipase A2β
Fu D.Wang et al. [51], whose study about that iron can (IPLA2β, corresponding gene name pNPLA9), a Sn-2 acyl
induce ferroptosis in liver parenchymal cells and bone mar- binding protein that specifically hydrolyzes phospholipids,
row macrophages, is the first study to be conducted in the take effect in the removal of oxidized phospholipids and the
world, and ferroptosis inhibitor (FEV-1) can effectively remodeling of phospholipids. One of the important patho-
alleviates liver fibrosis and other indexes of liver injury logical mechanisms, the accumulation of phospholipid oxi-
by inhibiting ferroptosis. Yingying Yu et al. [52] for the dation in dopaminergic neurons, is caused by the loss of
first time clarified the physiological effect and molecular IPLA2β. Kagan VE et al. [33] found that 15-Lox can anchor
mechanism of Transferrin inhibiting liver fibrosis by regu- to cell membrane under the action of companion molecule
lating ferroptosis, and found that the metal ion transporter PEBP1, specifically oxidize phosphatidylethanolamine

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6 Clinical and Translational Oncology (2022) 24:1–12

(PE) to produce oxidized phosphatidylethanolamine (ox- Influence and application of ferroptosis in immune
PE), among which PE oxidation product 15-HPET-PE is cells and inflammatory diseases
an important signal molecule for ferroptosis of cells. The
anti-ferroptosis function of IPLA2β is mainly through scav- Last several years, vast research evidences have shown that
enging ferroptosis signaling molecule 1-SA-2–15-HPET-P. influence and application of ferroptosis in immune cells
The mutation of IPLA2β makes it conformational and can- becomes more and more important, a summary of relation-
not bind to the phospholipids of the cell membrane, thus ship of them is explained more in detail below.
reducing the enzymatic hydrolysis and oxidative capacity
of the phospholipids.
The role of ferroptosis in T cell‑mediated
immunotherapy
Brain trauma and ferroptosis
CD8 + T cells can improve the antitumor effect in tumor
In TBI patients, we can found iron content changes, sug- cells by inducing ferroptosis. Interferon γ (INFγ) released
gesting that disruption of iron homeostasis may be an by CD8 + T cells may activate the JAK1-STAT1 pathway
important pathophysiological process of TBI [56]. As an to inhibit the expression of SLC7A11, sequentially reduc-
important biomarker, ferritin can be used to predict the time ing the absorb of cystine by tumor cells and leading to
of injury after TBI and is associated with patient survival ferroptosis of tumor cells [39], so Interferon γ (INFγ) can
[57]. Tongyu Rui et al. [58] illustrated the time-history of be used as a target for regulating ferroptosis.
ferroptosis-related protein expression and iron deposition In addition, activated T cells have a high demand for
after traumatic brain injury, found xCT, Cox2, Tfr1, Nox2 iron, and the lack of iron inhibits the proliferation of T
and Fpn protein expression is at its peak in 12 h to 24 h cells, iron overload leads to an imbalance in the proportion
after trauma, then declining gradually close to or slightly of CD4 and CD8 T cells, and iron overload also increases
lower than normal, and Alexandra bohne Fth, Ftl and 4 the ROS level in T cells and causes DNA damage [60]. In
HNE protein expression increases in 3 days after trauma terms of molecular mechanism, iron can adjust the gen-
obviously, slightly down from 3 to 14 d, Pruslan staining eration of cytokines such as GM-CSF after transcription,
confirmed a significant increase in iron deposition 7 days negatively regulate DNA methylation through Tet protein,
after trauma. After treatment with melatonin and ferroptosis and regulate mitochondrial function of T cells through the
inhibitor Liproxstatin 1 respectively, the expression levels REDOX process of cytochrome C [61, 62].
of ferroptosis and iron metabolism-related proteins can be Therefore, targeting T cell iron metabolism and inter-
significantly reversed. Therefore, the anti-ferroptosis effect feron γ metabolism are potential strategies to raise effi-
is supposed to be a newfound target for the brain injury treat- ciency of T cell immunotherapy. The role of ferroptosis in
ment and provide a resultful means for the clinical treatment T cell-mediated immunotherapy is shown in Fig. 2.
of brain injury.

The relationship between ferroptosis

and Spontaneous intracerebral hemorrhage (ICH)

After intracerebral hemorrhage, the spilled hemoglobin

degrades, releasing large amounts of iron ions which accu-
mulate in the brain tissue around the hematoma. This excess
iron accumulation can lead to increased oxidative stress,
inducement of impaired cell function, and ultimately neu-
ronal death. Bao WD et al. [59] systematically explained the
regulatory effect of miR-124/Ferroportin signaling pathway
on iron deposition and neuronal death in intracerebral hem-
orrhage, and revealed the influence of this signaling pathway
on perifocal neuronal apoptosis and ferroptosis pathway. The
regulation of ferroptosis can provide a suitable target of this
disease, and it is definitely important in the study of the
signaling pathway of iron ion regulation in the brain under
the pathological state. Fig. 2  The role of ferroptosis in T cell-mediated immunotherapy

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Clinical and Translational Oncology (2022) 24:1–12 7

The role of ferroptosis in different B cell‑mediated

immunotherapies

Different B cell subsets showed different sensitivities to fer-

roptosis. The knockout of GPX4 gene in B1 and MZ B cells
will trigger ferroptosis by inducing lipid peroxidation, finally
affecting the immune response of B cells; however, deletion
of GPX4 does not induce ferroptosis in follicular B cells (Fo
B). The possible mechanism is that the content of fatty acid
transporter CD36 in the plasma membrane of B1 and MZ
B cells is significantly higher than that of Fo B cells, which
leads to more acid and lipid droplets in B1 and MZ B cells,
and thus more prone to lipid peroxidation [63].
Activated B cells also have a higher demand for iron.
Iron supplementation can ameliorate the impaired prolif-
eration and weakened antibody response of B cells that are Fig. 4  The role of ferroptosis in Fo B cells
deficient in iron. Studies have shown that iron ion regulates
the expression of Cyclin E1 by regulating the activity of
demethylase JMJC, thereby regulating the proliferation of expression of ferroptosis-related target genes ZEB1 [65,
B cells and antibody production [64]. 66] and SLC7A11 [67] by activating SMAD signaling tran-
All in all, inhibition of the fatty acid transporter CD36 on scription, and SLC7A11 gene deletion promotes iron over-
the plasma membrane of B1 and MZ B cells is an important load induced ferroptosis in macrophages. In other words,
target for regulating ferroptosis, and iron supplementation ferroptosis can be regulated by adjusting the expression of
is also a feasible strategy for regulating ferroptosis. Figure 3 TGFβ1 in macrophages. He Rongrong’s team [68] found
is a description of the role of ferroptosis in B1 and MZ B that macrophages can recognize the oxidized phospholipids
cells, and Fig. 4 is a description of the role of ferroptosis in (SAPE-OOH) on the surface of ferroptosis cells through the
Fo B cells. membrane receptor TLR2 (Toll-like receptor 2), which is a
key signal for macrophages to recognize ferroptosis cells,
The role of ferroptosis in different thereby mediating the phagocytes to clear ferroptosis cells.
macrophage‑mediated immunotherapies Iron content can regulate inflammatory cytokines in
macrophages, but the direction and way of regulation are
D. Wang and his team demonstrated that iron citrate can not unique. In Salmonella-infected macrophages, iron accu-
induce ferroptosis in macrophages derived from bone mar- mulation has been reported to decrease the generation of
row [51]. TGFβ1 secreted by macrophages regulates the pro-inflammatory factors, which may be due to a fact that
iron promotes the production of anti-inflammatory factors
[69]. However, in vivo and in vitro experiments have shown
that the gather of iron in macrophages facilitates the pro-
inflammatory polarization and arises the expression of pro-
inflammatory factors through the TLR4/TRIF pathway [70].
In addition, iron has also been reported to regulate the TCA
cycle in macrophages, thereby regulating the production of
cytokines [71].Based on the pro-inflammatory effect of iron,
iron oxide nanoparticles have been reported to inhibit tumor
growth by promoting the polarization of pro-inflammatory
macrophages. That is to say, increasing the iron content in
macrophages can achieve the effect of killing tumor cells.
In addition, similar to B cells, different subsets of mac-
rophages have different sensitivities to ferroptosis. The
content of inducer nitric oxide synthase (iNOS) in pro-
inflammatory M1 macrophages is more than that in anti-
inflammatory M2 macrophages, so there are higher nitric
oxide free radicals in M1 cells, thus inhibiting lipid per-
Fig. 3  The role of ferroptosis in B1 and MZ B cells oxidation. On the contrary, due to the low content of iNOS

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8 Clinical and Translational Oncology (2022) 24:1–12

in M2 macrophages, less nitric oxide free radicals are pro-

duced, and the inhibition effect on lipid peroxidation is less
[72].
In some cases, ferroptosis process and immune response
may exist at the same time and interact with each other.
And ferrroptosis can induce inflammation-related immu-
nosuppressive tumor microenvironment to promote tumor
growth. In conclusion, ferroptosis is extremely relevant to
the immune state of the body, and exploring the relation-
ship between ferroptosis and immunity is conducive to the
development of more effective treatment strategies for many
diseases, which is a very promising research direction. Fig-
ures 5 and 6 are respectively about the role of ferroptosis in
M1 macrophages and M2 macrophages.
Overall, from the perspective of the biological molecular
mechanism and occurrence mechanism of ferroptosis, it can
well explain the onset and progression of many common
diseases and the close relationship between the immune state
of the body and ferroptosissy, systematically elucidating Fig. 6  The role of ferroptosis in M2 macrophages
the molecular mechanism of ferroptosis, the functions and
mechanisms of ferroptosis in various diseases and immune
cells and immunotherapy, will be an extremely promising sorafenib, salazopyridine, etc. At the same time, there are
research in a fashion that provide a blueprint for the future many kinds of ferroptosis inhibitors that can be used to
development of new treatment strategies for many diseases. inhibit ferroptosis, such as iron chelator, ferropstain-1, vita-
In addition, it also provides a way of thinking for the use min E, GSH, liproxstatin 1, etc. A summary of ferroptosis
of the inducers and inhibitors of ferroptosis that have been activators and inhibitors that have been found is respectively
discovered at present; therefore, it is necessary to summarize shown in Tables 1 and 2. Through a detailed review of the
the existing inducers and inhibitors of ferroptosis. mechanism offerroptosis and its inhibitors and inducers, we
hope to screen out targeted drugs that can effectively inter-
Ferroptosis inhibitors and inducers vene ferroptosis to treat common human diseases.

Since ferroptosis has been studied, many substances have

been found to induce ferroptosis, such as erastin, RSL3, Conclusion and perspectives

Ferroptosis is regulated by multiple pathways such

as amino acid metabolism, lipid metabolism and iron
metabolism, it is a new cell death mode that leads to lipid
peroxidation of cell membrane by accumulating of lipid
peroxides, the mechanism of ferroptosis, the various com-
pounds that induce and inhibit ferroptosis, the correlation
between ferroptosis and the onset and progression of vari-
ous diseases and the immune state of the body have been
thoroughly studied, but the existing reports on ferroptosis
is still infantile and not profound enough, the study of cell
death mode is still an important work to solve the problem
of treating common human diseases. It is expected that
there will be more and more related studies in the future,
which will provide new ideas for the treatment plan with
ferroptosis as the therapeutic target, and also will provide
references for the development of more ferroptosis inhibi-
tors and inducers. In addition, it will be a meaningful
work to screen targeted drugs that regulate the metabo-
Fig. 5  The role of ferroptosis in M1 macrophages lism of amino acids, lipids, reactive oxygen species and

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Clinical and Translational Oncology (2022) 24:1–12 9

Table 1  Ferroptosis activators

Classification Compound/drug Target/function

Activators Cisplatin (CDDP) Destroy DNA

Erastin VDAC2/VDAC3
Gallic acid hydrate COX-2
RSL3 ((1S,3R)-RSL3) GPX4
TBHQ Nrf2
Hemin HO-1
Simvastatin (MK 733) HMG-CoA reductase
Pifithrin-α hydrobromide P53
Lovastatin HMG-CoA reductase
PRIMA-1Met P53; TrxR1
BAY 11–7085 (BAY 11–7083) NF-κB; IκBα
Atorvastatin hemicalcium salt (CI-981) HMG-CoA reductase
Sulfasalazine (NSC 667,219) NF-κB
Artesunate STAT-3;EX1 (EXP1)
L-Buthionine-(S,R)-sulfoximine G-glutamylcysteine synthetase
ML-210 GPX4
iFSP1 FSP1 (AIFM2)
Piperlongumine ERK1/2 signaling pathway
Artemisinin (Qinghaosu) Akt signaling pathway
Brusatol (NSC 172,924) Nrf2
Fluvastatin sodium HMG-CoA reductase
Withaferin A NF-Kb; vimentin; EPCR
Pravastatin sodium (CS-514 sodium) HMG-CoA reductase
DL-Buthionine-(S,R)-sulfoximine Glutamylcysteine synthetase
Matrine (Matridin-15-one) Kappa opioid agonist
Gallic acid COX-2
L-Glutamic acid monosodium salt Glutamate receptor
(−)-Epicatechin COX-1; iNOS
Siramesine hydrochloride The sigma-2 receptor agonist
(S)-Glutamic acid Glutamate receptors
PD146176 (NSC168807) 15-LO
PRIMA-1 (NSC-281668) TP53
L-Cystine Cellular regulation
Pseudolaric Acid B T lymphocytes
DL-Buthionine-(S,R)-sulfoximine hydrochloride Glutamylcysteine synthetase
Trigonelline Nrf2
Chrysosplenetin MDR1 and p-gp
(E)-Ferulic acid Remove ROS and inhibit lipid peroxidation
Arteannuin B Anti-SARS-CoV-2
Cerivastatin sodium HMG-CoA reductase
Siramesine(Lu 28–179) Sigma-2 receptor agonist
Cerivastatin HMG-CoA reductase
Dihydroartemisinic acid (Dihydroqinghao acid) A natural product isolated from Artemisia annua

iron for the treatment of common human diseases such as and provide reference for the future research and explora-
tumor and heart disease. Through a detailed review of the tion of ferroptosis. It may also be a meaningful work that
mechanism of ferroptosis and its inhibitors and inducers, combining drug therapy with common treatments such as
we hope to screen out targeted drugs that can effectively chemotherapy and radiation is a promising job.
intervene ferroptosis to treat common human diseases,

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10 Clinical and Translational Oncology (2022) 24:1–12

Table 2  Ferroptosis inhibitors Classification Compound/drug Target/function

Inhibitor Ferrostatin-1 Prevent membrane lipid damage

SP600125 JNK
Acetylcysteine (N-Acetylcysteine) ROS; Cysteine
Deferoxamine mesylate Free iron
Necrostatin-1 (Nec-1) RIP1 kinase; IDO
Rosiglitazone (BRL 49,653) PPARγ agonist; TRPC5 and TRPM3
SB 202,190 P38 and p38β2
Curcumin (Diferuloylmethane) NF-κB and MAPKs
(−)-Epigallocatechin Gallate EGFRse;OXPHOS
U-73122 Phospholipase C;
5-lipoxygenase (5-LO)
Bardoxolone methyl Nrf2 and NF-κB
Trolox vitamin E
L-Glutathione reduced Scavenge oxygen free radicals
Pioglitazone (U 72,107) PPARγ
Deferiprone Iron chelator
Troglitazone PPARγ agonists
Baicalein Xanthine oxidase inhibitor
Coenzyme Q10 Electron transport chain
Deferasirox (ICL 670) Chelating excess iron ions
α-Vitamin E (( +)-α-Tocopherol) Fat-soluble antioxidant
Zileuton 5- lipoxygenase
L-Glutamine Metabolic processes
(L-Glutamic acid 5-amide)
Deferasirox Iron ion chelating
Vildagliptin (LAF237) DPP-IV
Nordihydroguaiaretic acid 5LOX
Idebenone Coenzyme Q10
Pioglitazone hydrochloride PPARγ agonists
Ciclopirox olamine Antifungal agent
(Ciclopirox ethanolamine)
Rosiglitazone maleate (BRL 49653C) PPARγ;TRPM2;TRPM3 and TRPC5
Dp44mT Iron Chelator
Eugenol Antioxidant
DL-alpha-Tocopherol Antioxidant
Deferasirox Fe3 + chelate Chelator of iron ions
D-Glutamine D—type stereoisomer of a cell per-
meable Glutamine
Butylated hydroxytoluene Antioxidant
Docebenone (AA 861) 5-LO
Vildagliptin dihydrate (LAF237 dihydrate) DPP-IV
Pioglitazone D4 (U 72,107 D4) PPARγ
Curcumin D6 (Diferuloylmethane D6) HATS; NF-κB and MAPKs

Funding support This review was supported by the National Natu- Declarations
ral Science Foundation of China (No. 82072340), the Major National
Science and Technology Projects–Major New Drug Creation Competing interests The authors have declared that no competing
(2019ZX09301-132); Changjiang Scholars and Innovative Research interest exists.
Team in University (No. IRT_15R13); Guangxi Science and Technol-
ogy Base and Talent Special Project (No. AD17129003).

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Clinical and Translational Oncology (2022) 24:1–12 11

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