Cell Biol Toxicol (2023) 39:827–851
https://doi.org/10.1007/s10565-022-09778-2
REVIEW
Ferroptosis: From regulation of lipid peroxidation
to the treatment of diseases
Yonghui Lv · Meiying Wu · Zhe Wang ·
Junqing Wang
Received: 28 June 2022 / Accepted: 11 November 2022 / Published online: 2 December 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022
Abstract Ferroptosis is a regulated cell death
mainly manifested by iron-dependent lipid peroxide
accumulation. The leading cause of ferroptosis is the
imbalance of intracellular oxidative systems (e.g.,
LOXs, POR, ROS) and antioxidant systems (e.g.,
GSH/GPx4, CoQ10/FSP1, ­BH4/GCH1), which is reg-
ulated by a complex network. In the past decade, this
metabolic network has been continuously refined, and
the links with various pathophysiological processes
have been gradually established. Apoptosis has been
regarded as the only form of regulated cell death for
a long time, and the application of chemotherapeutic
drugs to induce apoptosis of cancer cells is the main-
stream method. However, studies have reported that
cancer cells’ key features are resistance to apoptosis
and chemotherapeutics. For high proliferation, can-
cer cells often have very active lipid metabolism and
iron metabolism, which pave the way for ferroptosis.
Y. Lv · M. Wu (*) · J. Wang (*)
School of Pharmaceutical Sciences, Shenzhen Campus
of Sun Yat-Sen University, Shenzhen 518107, China
e-mail: wumy53@mail.sysu.edu.cn
J. Wang
e-mail: wangjunqing@mail.sysu.edu.cn
Y. Lv
e-mail: lvyh9@mail2.sysu.edu.cn
Z. Wang (*)
Department of Pathology, The Eighth Affiliated Hospital,
Sun Yat-Sen University, Shenzhen 518033, China
e-mail: wangzh379@mail.sysu.edu.cn
Interestingly, researchers found that drug-resistant or
highly aggressive cancer cells are more prone to fer-
roptosis. Therefore, ferroptosis may be a potential
strategy to eliminate cancer cells. In addition, links
between ferroptosis and other diseases, such as neu-
rological disorders and ischemia–reperfusion injury,
have also been found. Understanding these diseases
from the perspective of ferroptosis may provide new
insights into clinical treatment. Herein, the metabolic
processes in ferroptosis are reviewed, and the poten-
tial mechanisms and targets of ferroptosis in different
diseases are summarized.
Keywords Ferroptosis · Iron metabolism · Lipid
metabolism · Redox regulation · Diseases
Abbreviations
GPx4 Glutathione peroxidase 4
ACSL4 Acyl-CoA synthetase long chain
family member 4
LPCAT3 Lysophosphatidylcholine acyltrans-
ferase 3
LOXs Lipoxygenases
GSH Glutathione
PUFA Polyunsaturated fatty acid
MUFA Monounsaturated fatty acid
PUFA-PLs Polyunsaturated phospholipids
AA Arachidonic acid
AdA Adrenoyl acid
NADPH Nicotinamide adenine dinucleotide
phosphate
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HMGB1 High mobility group box 1
VDAC2/3 Voltage dependent anion channel-3/2
NOX Nitrogen oxides
TFR1 Transferrin receptor 1
LIP Labile iron pool
CARS Cysteinyl tRNA synthetase
SLC7A11 Solute carrier family 7 member 11
HSPB1 Heat shock protein family B (small)
member 1
Nrf2 Nuclear factor erythroid 2-related
factor 2
ROS Reactive oxygen species
NCOA4 Nuclear receptor coactivator 4
DMT1 Divalent metal transporter 1
FPN1 Ferroportin 1
OA Oleic acid
PA Palmitic acid
LA Linoleic acid
ALOXs Arachidonic acid lipoxygenases
G6PDH Glucose 6-phosphate dehydrogenase
GDH Glutamate dehydrogenase
PGDH 6-Phosphogluconate dehydrogenase
SCP2 Sterol carrier protein 2
DHA Docosahexaenoic acid
POR Cytochrome P450 reductase
CoQ10 Coenzyme Q10
AMPK AMP-activated protein kinase
ACC​ Acetyl-CoA carboxylase
LKB1 Serine/threonine-protein kinase 1
GLS Glutaminase
α-KG α-Ketoglutaric acid
OTUB1 Ubiquitin aldehyde binding 1
GSSG Oxidized glutathione
AIFM2/FSP1 Apoptosis inducing factor mitochon-
dria associated 2
ESCRT-III Endosomal sorting complex
BH4 Tetrahydrobiopterin
GCH1 GTP-cyclohydrolase 1
EMT Epithelial-mesenchymal transition
DAMPs Damage-associated molecular pattern
IRI Ischemia-reperfusion injury
Introduction
Cell death plays an essential role in various life pro-
cesses, such as proliferation, growth, development,
and immunity (Vaux and Korsmeyer 1999). Accord-
ing to the international standard proposed by the
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Cell Biol Toxicol (2023) 39:827–851
Nomenclature Committee on Cell Death, accidental
cell death (ACD) and regulated cell death (RCD) are
two modes of cell death (Kroemer et al. 2005). ACD
is considered a biologically uncontrolled death result-
ing from non-physiological stress. In contrast, RCD
is a gene-regulated cell suicide process that occurs in
multicellular organisms to meet development needs
and maintain homeostasis. RCD was first observed
during metamorphic development in amphibians
(Vogt and Vogt 1842). However, RCD was not widely
studied until the term “apoptosis” was proposed in
1972 (Kerr et al. 1972). Apoptosis has long been con-
sidered the only form of RCD in mammalian cells.
However, this view is continually challenged by the
discovery of the non-apoptotic form of RCD (e.g.,
pyroptosis, autophagy, necroptosis, ferroptosis). Fer-
roptosis has attracted much attention since Brent
R. Stockwell first proposed it in 2012 (Dixon et al.
2012). As the name suggests, iron plays an important
role in ferroptosis. Unlike caspase-mediated apop-
tosis, ferroptosis is associated with lipid peroxides
which lead to lethal disruption of the plasma mem-
brane. This process is highly dependent on intracellu-
lar iron levels (Cao and Dixon 2016). How to identify
ferroptosis? The following four criteria can generally
be used to determine whether cells undergo ferrop-
tosis (Stockwell et al. 2017). (1) Cell death caused
by cystine uptake inhibition should be eliminated by
β-mercaptoethanol. (2) Cell death caused by reactive
oxygen species should be prevented by iron chela-
tors (e.g., deferoxamine) and antioxidants (e.g., BHT,
vitamin E). (3) The morphological changes of cells
should be mainly mitochondria shrinkage and dam-
age and no other characteristic changes. (4) The cell
death process can be interrupted by ferroptosis inhibi-
tors (e.g., liproxstatin-1, ferrostatin-1) but not by
other RCD inhibitors.
Apoptosis has long been considered the only form
of RCD (Sauler et al. 2019). The application of chem-
otherapeutic drugs to induce apoptosis is one of the
important methods for cancer treatment. However,
previous studies have reported that cancer cells have
intrinsic or acquired resistance to apoptosis, which
is one of the key features of cancer (Mohammad
et al. 2015). Interestingly, drug-resistant or highly
aggressive cancer cells were highly susceptible to
ferroptosis (Viswanathan et al. 2017). Furthermore,
hyperproliferative cancer cells tend to be rich in iron
(Weinberg 1996), which causes cancer cells to be
Cell Biol Toxicol (2023) 39:827–851
sensitive to ferroptosis. Therefore, ferroptosis may
become a new strategy to eliminate cancer cells (Xu
et al. 2021a). Recent evidence suggests that ferrop-
tosis is also closely related to neurological disorders,
ischemia–reperfusion injury, immunity, and infection
(Qiu et al. 2020). The growing research on ferroptosis
reveals more potential therapeutic targets for clinical
applications. Here, we review the metabolic regula-
tion of ferroptosis and highlight the potential mecha-
nisms and targets of ferroptosis in various diseases.
Ferroptosis: a unique form of regulated cell death
Morphological and biochemical features of ferrop-
tosis are unique in RCD. Morphologically, the cell
membrane does not rupture and blister. The mito-
chondrial morphology changed significantly, mani-
fested as shrinkage, loss or reduction of mitochondrial
cristae, increased membrane density, and rupture of
the outer mitochondrial membrane. In addition, there
was no change in nuclear size and no chromatin con-
densation. Biochemically, a large amount of iron
and ROS are accumulated, and the MAPK pathway
is activated. Glutamate/cystine antiporter activity is
inhibited, resulting in the depletion of the intracel-
lular reducing agent GSH. In addition, the release
of arachidonic acid mediators is increased. Immuno-
logically, DAMPs are released to promote inflamma-
tory responses. Multiple ferroptosis regulators were
upregulated, including VDAC2/3, Ras, NOX, TFR1,
p53, and CARS. In contrast, anti-ferroptosis regula-
tors such as GPx4, SLC7A11, HSPB1, and Nrf2 were
downregulated (Xie et al. 2016). However, the mor-
phology of apoptotic cells has markedly different fea-
tures, including retraction of pseudopodia, membrane
blebbing, chromatin condensation, cell, nuclear vol-
ume reduction, and nuclear fragmentation. In addi-
tion, apoptotic cells have unique biochemical charac-
teristics, such as activation of caspases (Cohen 1997),
fragmentation of oligonucleosomal DNA, and phos-
phatidylserine eversion. Immunologically, apoptotic
cells often trigger anti-inflammatory responses and
immune silencing, while in some cases, they trigger
immune responses by releasing DAMPs. In apoptotic
cells, many key regulators are up-regulated, including
p53, Bax, Bak, etc. Simultaneously, it downregulated
multiple anti-apoptotic family proteins (Hengartner
2000). Pyroptosis, autophagy, and other RCD also
829
have different morphological and biochemical charac-
teristics, as detailed in Table 1.
Ferroptosis: redox homeostasis pushing
boundaries
Ferroptosis is a complex oxidative and antioxidant
regulatory network (Fig. 1) (Jiang et al. 2021; Stock-
well 2022). The introduction of PUFAs (mainly AA
and AdA) into the plasma membrane is mediated by
ACSL4/LPCAT3 (Doll et al. 2017). These polyun-
saturated phospholipids (PUFA-PLs) are important
substrates for generating lipid peroxides. Normally,
lipid peroxides are maintained at physiological levels
by intracellular antioxidant systems (e.g., GSH/GPx4,
CoQ10/FSP1, ­BH4/GCH1). However, these enzymes
are inhibited or downregulated in ferroptosis (Tang
and Kroemer 2020). Ferroptosis is iron-dependent.
In cells, iron is mainly stored in the form of ferritin.
Ferritinophagy increases the level of the intracellular
labile iron pool (LIP), which promotes the ROS gen-
eration through Fenton and Haber–Weiss reactions
(Kruszewski 2003). In addition, the enzymes that cat-
alyze lipid peroxidation are mostly heme or non-heme
iron enzymes.
Lipid peroxidation
Enzymatic oxidation
The ALOX family consists of six members, ALOX5,
ALOX12, ALOX12B, ALOX5, ALOX15B, and
ALOXE3, which are a class of non-heme iron dioxy-
genases (Yang et al. 2016). ALOX5 oxidizes AA to
5-hydroxyperoxyeicosatetraenoic acid (5-HPETE).
ALOX (12, 12B, 15, 15B) can catalyze AA to
15-HPETE and 12-HPETE with incomplete regi-
oselectivity (Fig. 2) (Gaschler and Stockwell 2017).
ALOX15 regulates RSL3-induced ferroptosis upon
binding to phosphatidylethanolamine-binding pro-
tein 1 (PEBP1). Zhou et al. found that inhibition of
ALOX12 alleviated GPx4 depletion-induced ferrop-
tosis in HT22 cells (Zhou et al. 2020). Probst and
colleagues showed that RLS3-induced ferroptosis
in acute lymphoblastic leukemia cells was inhibited
by nordihydroguaiaretic acid, a selective inhibitor
of ALOX12/15 (Probst et al. 2017). Furthermore,
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 Table 1  The characteristics of common RCD (Chen et al. 2021a; Li et al. 2020b; Nguyen et al. 2020; Xia et al. 2019; Xie et al. 2016)
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Type Ferroptosis Apoptosis Autophagy Pyroptosis Necroptosis

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Identification Regulated cell death is Apoptosis is a regulated Autophagy is a process that Pyroptosis mediated by Traumatic cell death due to
caused by the accumula- cell death mediated by engulfs self-cytoplasmic the gasdermin family physicochemical factors
tion of iron-dependent various proteases. It is proteins or organelles of proteins is a form of
lipid peroxides, which is characterized by the to form vesicles that regulated cell death that
morphologically and bio- cleavage of specific fuse with lysosomes for releases pro-inflammatory
chemically distinct from aspartate residues of degradation factors and lyses cells
other RCD target proteins by these
proteases
Morphological character- Plasma membrane without cell membrane blistering; Autophagosome formation Loss of membrane integ- Rupture in the plasma mem-
istics rupture and blebbing; Nuclei and cell size reduc- such as macroautophagy rity; brane;
Mitochondrial shrinkage; tion; and microautophagy Chromatin condensation; Decreased cell volume;
Increased mitochondrial Chromatin condensation; Bubbling; swelling; Cytoplasm and organelle
membrane density; Nuclear fragmentation Release inflammatory swelling;
Loss or reduction of mito- factors Mitochondrial cristae rupture
chondria crista; until disappearance;
Loss of mitochondrial outer Chromatin condensation
membrane integrity;
Normal nuclear volume
and without chromatin
condensation
Biochemical characteristics Accumulation of iron and Activation of pro-apoptotic Conversion of MAP1 Activation of CASP (1, 4, Decreased ATP levels;
ROS; Bcl-2 family and caspases LC3B-I to MAP1 LC3B- 5) and GSDMD; Activation of MLKL and
Activated MAPKs; proteins; II; Inflammasome; RIP (1, 3);
Inhibition of system XC − ; Oligonucleosomal DNA Substrate (e.g., p62) degra- GSDMD cleavage; DAMPs such as HMGB1 are
Increased GSH and fragmentation; dation; GSDMD-N-mediated pore released;
NADPH oxidation; Phosphatidylserine ever- Separation of Beclin-1 from formation; Overactive PARP1;
Δψm dissipation; sion; Bcl-2/XL; Release of IL1β and IL18 Cytosolic necrosome forma-
Arachidonic acid mediators Δψm dissipation Increased autophagic flux tion
such as 11-HETE and and lysosomal activity
15-HETE release;
Cannot be modulated by
inhibitors of other RCD,
such as caspase, cathep-
sin, calpain proteases,
RIPK1, and cyclophilin
D;
Cell Biol Toxicol (2023) 39:827–851
 Table 1  (continued)
Type Ferroptosis Apoptosis Autophagy Pyroptosis Necroptosis

Immune characteristics DAMPs such as HMGB1 Immune silent and anti-
are released inflammatory;
Under certain circum-
stances, the release of
DAMPs to elicit an
immune response
Key regulators Pro-ferroptosis: VDAC2/3, Proapoptotic: CARD8,
ACSL4, Ras, NCOA4, GZMB, CASP (2, 3,
Frequent inhibition of Pro-inflammatory Usually releases DAMPs to
inflammasome activation; promote inflammation;
Non-classical secretion of Under certain circumstances,
cytokines pro-inflamma- anti-inflammatory
tory in some cases;
Genes: ATG (1, 3–9) etc Regulators: CASP (1, 4, 5) Regulators: AURKA, RIP
Regulators: LC3, Beclin and GSDMD (1, 3), Ppm1b, MLKL,
Cell Biol Toxicol (2023) 39:827–851

NOX, CARS, TFR1, p53 6–10), p53, Bcl-2 family 1, ATG proteins family, LUBAC, ESCRT-III,
Anti-ferroptosis: GPx4, Anti-apoptotic: HSPA1B, mTOR, DRAM3, AMPK, cIAPs
SLC7A11, HSPB1, Nrf2, CARD6, Bcl-XL, NOX5 TFEB, ­Na+/K+-ATPase Genes: COL4A3BP, EDD1,
FSP1, RPL8, IREB2, CS, CD40, MPG, DCC1, CA9,
ATP5G3, TTC35, ACSL3 NPEPL1, SLC25A15,
SIRT5
Inducers GSH depletion: Erastin, Intrinsic apoptosis: DNA Rapamycin, Lithium, Metformin, DPP8/9 inhibi- TNF-α, Z-VAD-FMK
IKE, DPI2, BSO, BAY damage, Cytosolic C ­ a2+ Valproate, and Carbamaz- tor, Anthocyanin, Iron,
87–2243, SAS, Sorafenib, overload, etc epine DHA, α-NETA, DOX,
Glutamate, Cyst(e)inase Extrinsic apoptosis: FASL, Cisplatin, lobaplatin,
GPx4 inactivation: RSL3, UNC5B, DCC Paclitaxel, BI2536,
DPI (7/ML162, 10/ L61H10
ML210) DPI (12, 13,
17, 18, 19) Altretamine,
FIN56, Simvastatin, With-
aferin A, Lovastatin acid,
Fluvastatin;
Iron loading: F
­ INO2, Hemo-
globin, (NH4)2Fe(SO4)2,
Hemin, Salinomycin,
Lapatinib + Siramesine,
Amino acid deple-
tion + Cornell dots, BAY
11–7085;
Others: CIL (41, 56, 69,
70, 75, 79), Artemisinin
derivatives, Lanperisone

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 Table 1  (continued)
832

Type Ferroptosis Apoptosis Autophagy Pyroptosis Necroptosis

Inhibitors Antioxidants: Vitamin E, Apoptosis inhibitors: ILP- VPS34 inhibitors: PIK-III, CASP inhibitors: Wedelol- RIP1 inhibitors: Nec-1

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Trolox, U0126 2, XIAP, c-IAP (1, 2), Vps34-In1, SAR 405 actone, Ac-YVAD-CMK, MLKL inhibitors: NSA
ROS inhibitors: SRS (8–72, Bruce/Apollon, ML-IAP/ PI3K inhibitors: Methy- VX765, Z-YVAD (OMe)- RIPK3 inhibitors: GSK872,
11–92, 12–45, 13–37, LIVIN, NAIP, Survivin ladenine, Wortmannin, FMK HS-1371
16–86), Ferrostatin-1 Caspase inhibitors: Z-VAD/ LY294002 NLRP3 inhibitors:
Iron chelators: DFO, Sola- IETD/DEVD-FMK, ULK1 inhibitors: MRT MCC950, CY-09, Isoli-
mine, Ciclopirox olamine, Emricasan, Q-DEVD/ (68,921, 67,307), SBI- quiritigenin, Oridonin,
2, 2- Bipyridyl LEHD/VD-OPh, Ivachtin, 0206965 Glybenclamide
Others: β-mercaptoethanol, Ac-DEVD-CHO Beclin1 inhibitors: Spau- GSDMD cleavage: Ac-
Cycloheximide, Ebselen, tin-1 FLTD-CMK
Aminooxyacetic acid H+-ATPase inhibitors:
Bafilomycin A1, Con-
canamycin A
Lysosome inhibitors: Chlo-
roquine, Hydrochloroquin
MAPKs mitogen-activated protein kinases, HETE hydroxyeicosatetraenoic acids, CASP caspase, GSDMD gasdermin D, RIP receptor-interacting protein, MLKL mixed lineage
kinase domain-like, PARP1 poly (ADP-ribose) polymerase 1, CARS cysteinyl-tRNA synthetase, FSP1 ferroptosis suppressor protein 1, RPL8 ribosomal protein L8, IREB2 iron
response element binding protein 2, CARD8 caspase recruitment domain-containing protein 8, GZMB granzyme B, UNC5B unc-5 netrin receptor B, ATG​autophagy, LC3 micro-
tubule-associated protein light chain 3, DRAM3 damage-regulated autophagy modulator 3, TFEB transcription factor EB, mTOR mammalian target of rapamycin, cIAPs inhibitor
of apoptosis proteins, LUBAC linear ubiquitin chain assembly complex, Ppm1b protein phosphatase 1B, AURKA aurora kinase A, MPG N-methylpurine-DNA glycosylase, CA9
carbonic anhydrase 9, SIRT5 sirtuin 5, NPEPL1 aminopeptidase like 1, DPI2 diphenylene iodonium 2, DPP8 dipeptidyl peptidase 8, NAIP neuronal apoptosis inhibitor protein
Cell Biol Toxicol (2023) 39:827–851
Cell Biol Toxicol (2023) 39:827–851
Fig. 1  The regulatory network of ferroptosis. The conver-
sion of PUFAs to PUFA-PLs sensitizes cells to ferroptosis.
In contrast, MUFA-PLs inhibit ferroptosis by reducing the
abundance of PUFA-PLs. Under energy stress, PUFA produc-
tion is reduced due to the activation of the LKB1-AMPK-ACC
pathway. Glutamine, on the one hand, promotes ferroptosis by
increasing ROS production; on the other hand, it inhibits fer-
roptosis by promoting cystine uptake. The iron-transferrin
buthionine sulfoximine-induced intracellular GSH
depletion was lethal in wild-type cells but not in
ALOX12/15-deficient cells (Hamilton and Wedner
1985). Cytochrome p450 reductase (POR) is a class
833
complex is taken up into cells by TFR1-mediated endocytosis.
Iron overload promotes ferroptosis by accelerating Fenton and
Haber–Weiss reactions. GSH/GPx4, CoQ10/FSP1, and ­BH4/
GCH1 are the three major antioxidant metabolic axes. GPx4
inhibits lipid peroxidation in the presence of GSH. Ubiquinol
and ­BH4 can neutralize hydroxyl and alkoxy radicals to inhibit
lipid peroxide accumulation
of ER-localized oxidoreductase. Tang et al. reported
that in clear cell renal cell carcinoma and mela-
noma cells, POR could promote the peroxidation
of PUFA-PLs, resulting in cancer cell death in an
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Fig. 2  Arachidonic acid
undergoes peroxidation
under the catalysis of differ-
ent lipoxygenases to gener-
ate various peroxides
ALOXs-independent manner (Tang and Kroemer
2020). Yan et al. reported that in Hela cells, POR
could promote the production of hydrogen peroxide
by transferring electrons from NADPH to oxygen,
which promotes ferroptosis (Yan et al. 2021).
Free radical oxidation
Non-enzymatic oxidation is mainly initiated by fer-
rous iron. Ferrous iron in LIP catalyzes the produc-
tion of hydroxyl radicals from hydrogen peroxide
through Fenton and Haber–Weiss reactions (Fig. 3a)
(Kruszewski 2003; Ou et al. 2022). Subsequently, the
radical chain reaction introduces oxygen molecules
into the polyunsaturated acyl chains of phospholipids
to form lipid hydroperoxides. These lipid hydroper-
oxides are further catalyzed by ferrous iron, resulting
in the continuous expansion of lipid peroxidation in
the plasma membrane, ultimately triggering ferropto-
sis. Specifically, the radical chain reaction is divided
into three stages (Fig. 3b) (Doll and Conrad 2017). (i)
Chain initiation: PUFA-PLs (labeled RH) is attacked
by hydroxyl radical, which leads to the loss of one
hydrogen atom and becomes an alkyl radical (R·). An
oxygen molecule is introduced into R· to form lipid
peroxy radicals (ROO·). (ii) Propagation: The gener-
ated ROO· reacts with other RH to produce new lipid
hydroperoxide (ROOH) and R·, which indicates that
free radicals propagate between different phospho-
lipid molecules. Then, ROOH is catalyzed by fer-
rous to form alkoxy radical (RO·). RO· attacks other
phospholipids (RH) to produce more R·. The gener-
ated R· repeats the above process continuously, which
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leads to the destruction of RH on the plasma mem-
brane. (iii) Termination: While the radical chain reac-
tion spreads, some ROO· will react with other ROO·
to produce R = O, lipid alcohol, and oxygen. Alter-
natively, in the presence of a free radical scavenger
(·Astabilized), ROO· is converted to ROOA.
Lipid antioxidation
GSH/GPx4
As one of the major intracellular antioxidant enzymes,
GPx4 is a GSH-dependent enzyme with the ability
to inhibit the accumulation of lipid hydroperoxide
(ROOH) (Forcina and Dixon 2019). The inactivation
of GPx4 leads to rapid accumulation of intracellular
lipid peroxides, which induces ferroptosis (Fig. 1).
Hangauer et al. reported that drug resistance of cancer
cells is related to GPx4 activity (Hangauer et al. 2017).
Cancer cells overexpressing GPx4 are resistant to
treatment with buthionine sulfoximine and hypericin.
Induction of GPx4 expression in breast cancer cells
that do not express GPx4 results in increased cancer
cell drug resistance (Zhang et al. 2020). Cao and col-
leagues showed that Iron chelators or antioxidants
could attenuate cell death caused by GPx4 inactiva-
tion (Cao and Dixon 2016). This further confirms that
GPx4 activity is critical for ferroptosis. Furthermore,
in erastin-induced ferroptosis, HSP90 degrades GPx4
through a chaperone-mediated autophagy process.
Application of the HSP90 inhibitor CDDO or knock-
down of the HSP90 subunit can inhibit erastin-induced
Cell Biol Toxicol (2023) 39:827–851
Fig. 3  The oxidation of phospholipids. a Oxygen is con-
verted into superoxide radicals (·O2−) under the catalysis of
various enzymes in the cell, such as CYP, and NOX. Hydro-
gen peroxide produced under the catalysis of superoxide dis-
mutase is converted into hydroxyl radicals through the Fen-
ton and Haber–Weiss reactions. PUFA-PLs (RH) react with
oxygen under the catalysis of LOXs to generate lipid perox-
ferroptosis (Chen et al. 2021e). System XC- is a
sodium-independent transporter with the ability to
uptake cystine and efflux glutamate. SLC7A11, a
multichannel transmembrane protein, is one of the
two subunits that make up system XC- (Fig. 1). Lew-
erenz et al. have reported that SLC7A11 promotes
GSH biosynthesis by increasing cystine uptake (Lew-
erenz et al. 2013). Upregulated GSH can increase the
activity of GPx4 to inhibit ferroptosis. The inactiva-
tion of ACSL4 can partially abolish ferroptosis caused
by the inactivation of SLC7A11 or GPx4 (Koppula
et al. 2021). Liu et al. described that OTUB1 deubiq-
uitinates SLC7A11 to increase SLC7A11 stability,
resulting in the suppression of ferroptosis (Liu et al.
2019). In addition, tumor suppressor genes (e.g., p53,
BAP1) and proto-oncogene (KRAS) can also induce
SLC7A11 expression to inhibit ferroptosis. However,
it is worth noting that not all tumors had elevated lev-
els of SLC7A11 expression. For example, ARID1A-
deficient tumors or tumors with gain-of-function
mutations in p53 show reduced levels of SLC7A11
expression (Sasaki et al. 2020).
835
ides (ROOH). The ROOH either participates in Fenton and
Haber–Weiss reactions to generate alkoxy radicals (RO·) or
is reduced to lipid alcohol (ROH) by GPx4. b Under the ini-
tiation of hydroxyl radicals, RH undergoes radical chain reac-
tions, including chain initiation, chain propagation, and chain
termination
CoQ10/AIFM2
Coenzyme Q10 is an endogenous retinoid compound
that not only participates in the mitochondrial respira-
tory chain but can also neutralize various free radicals
to exert a powerful antioxidant effect (Crane 2001).
Ubiquinol is the reduced form of coenzyme Q10,
which can prevent lipid peroxidation. Apoptosis-
inducing factor mitochondria-associated 2 (AIFM2,
also known as FSP1) can mediate ubiquinol produc-
tion (Fig. 1) (Dai et al. 2020). Different subcellular
localizations of AIFM2 have different cellular regu-
latory roles. Membrane AIFM2 can reduce coen-
zyme Q10 to ubiquinol under the action of NADPH,
thereby inhibiting ferroptosis (Bersuker et al. 2019).
Notably, although iFSP1 can inhibit the activity of
AIFM2, treatment with iFSP1 alone does not induce
ferroptosis (Zheng et al. 2021). Nawarskas et al.
described that statin could increase the sensitivity of
cells to ferroptosis by inhibiting the production of
coenzyme Q10 (Fig. 1) (Nawarskas 2005). In addi-
tion, Kuang et al. reported that exogenous coenzyme
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Q10 analogs idebenone also inhibit ferroptosis
(Kuang et al. 2020). The ESCRT-III-dependent mem-
brane repair mechanism mediated by CHMP5 and
CHMP6 may be activated with the accumulation of
AIFM2 in the cell membrane, which inhibits ferrop-
tosis (Liu et al. 2021).
BH4/GCH1
Tetrahydrobiopterin ­(BH4) is an active cofactor
involved in redox processes. ­ BH4 has antioxidant
properties both in vitro and in vivo. Kraft and co-
workers revealed that overexpression of GCH1 ­(BH4
synthesis rate-limiting enzyme) abrogates lipid per-
oxidation and shows strong protection against IKE-
induced ferroptosis independent of other ferropto-
sis-related antioxidant systems (Kraft et al. 2019).
­ H4/GCH1 path-
Soula et al. also proposed that the B
way is a GPx4-independent antioxidant system. The
accumulation of NADP and GSSG was found in
­BH4-deficient cells, while elevated levels of CoQ10
were found in GCH1-overexpressing cells (Soula
et al. 2020). Furthermore, GCH1 has no protec-
tive effect against apoptosis induced by apoptosis-
inducing agents (Wei et al. 2020). This indicates that
GCH1 can act as a selective target of ferroptosis.
NADPH
NADPH is a major intracellular reducing agent which
can maintain intracellular redox homeostasis (Fig. 1).
NADPH can be produced through the pentose phos-
phate pathway (PPP) (Stincone et al. 2015). The
silencing of the G6PDH and PGDH genes sensitizes
HCC cells to ferroptosis-inducing agents. Yan et al.
documented that NADPH can regulate ferroptosis
in several ways. NADPH-cytochrome p450 reduc-
tase (POR) and NADH-cytochrome b5 reductase
(CYB5R1) can promote the production of lipid perox-
ides. Occasionally, hydrogen peroxide is produced by
POR and CYB5R1, transferring electrons to ambient
oxygen. The hydrogen peroxide then promotes fer-
roptosis through Fenton and Haber–Weiss reactions
(Yan et al. 2021). As a major reducing agent, NADPH
assists glutathione reductase in reducing GSSG to
glutathione GSH (Kaneko et al. 2002). The regen-
eration of ­BH4 requires the participation of NADPH
(Thöny et al. 2000). NADPH also inhibits ferropto-
sis by reducing coenzyme Q10 to ubiquinol through
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Cell Biol Toxicol (2023) 39:827–851
FSP1 (Doll et al. 2019). In addition, NADPH can also
promote cystine uptake by SLC7A11 and elevate the
production of GSH (Koppula et al. 2021). Overall,
NADPH can enhance the antioxidant capacity of cells
through multiple pathways and reduce susceptibility
to ferroptosis.
The metabolic regulation of ferroptosis
Labile iron pool
The occurrence and development of ferroptosis
require the participation of iron. Although the exact
mechanism between ferroptosis and iron metabolism
is unclear, the critical role of iron metabolism in fer-
roptosis is beyond doubt (Doll and Conrad 2017).
For example, (1) ferroptosis can be terminated by the
iron chelator. (2) LIP mediates the production of ROS
by Fenton and Haber–Weiss reactions (Kruszewski
2003). (3) The enzymes related to lipid peroxidation
(e.g., LOXs) are mainly heme and non-heme iron
enzymes.
The transport of extracellular iron into the LIP
is mediated by various enzymes (TFR1, STEAP3,
DMT1) (Fig. 1) (Dunn et al. 2007). Ferrous iron in
LIP can convert peroxides into free radicals, the main
reactive oxygen species in cells, through the Fenton
and Haber–Weiss reactions (Dixon and Stockwell
2014; Kruszewski 2003). Gao et al. demonstrated that
ferroptosis induced by erastin could be prevented by
gene knockout of TFR1 (Gao et al. 2015). Zhang et al.
reported that miR-222 could inhibit TFRC-induced
ferroptosis in LX-2 cells (Zhang et al. 2022a). Intra-
cellular iron is either used to synthesize iron-con-
taining enzymes or stored as ferritin. Autophagic
degradation of ferritin (ferritinophagy) elevates the
intracellular LIP, sensitizing cells to ferroptosis.
NCOA4 is a key enzyme mediating the above process
(Mancias et al. 2014).
Solute carrier family 40 member 1 (SLC40A1/
FPN1) can mediate the export of non-heme iron
across the membrane (Fig. 1) (Donovan et al. 2005).
FPN1 overexpression increases cellular resistance to
ferroptosis, which is a negative regulator. Hepcidin
antimicrobial peptide (HAMP), a peptide hormone
secreted by the liver, can induce the internalization
and degradation of FPN1 (Liu et al. 2005). Ferritin
is released extracellularly as exosomes mediated by
Cell Biol Toxicol (2023) 39:827–851
prominin-2, which inhibits ferroptosis (Brown et al.
2019). Brown et al. have shown that RSL3 can selec-
tively induce the overexpression of prominin-2 in
ferroptosis-insensitive cells but not in ferroptosis-sen-
sitive cells (Brown et al. 2019). This suggests that the
knockdown of prominin-2 may promote ferroptosis.
Other iron‑related proteins
Other iron-related proteins that can regulate fer-
roptosis include PCBP1, heat shock protein family
B small member 1 (HSPB1), and heme oxygenase
(HMOX1). Philpott et al. have shown that loss of
PCBP1 in mouse hepatocytes increases the LIP,
leading to ferroptosis (Philpott et al. 2020). A pre-
vious study reported that HSPB1 expression was
increased in erastin-induced ferroptosis cells (Sun
et al. 2015). Furthermore, HSPB1 can counter-
act ferroptosis by inhibiting TFR1-mediated iron
uptake (Fig. 1) (Chen et al. 2006). HMOX1 has a
dual role in ferroptosis. For one, HMOX1 can pro-
mote ferroptosis, as the HMOX1 inhibitor zinc
protoporphyrin IX prevents erastin-induced fer-
roptosis. Conversely, the HMOX1 inducer heme
promotes erastin-induced ferroptosis. In addition,
CO generated by HMOX1 decomposing heme can
also promote erastin-induced ferroptosis (Kwon
et al. 2015). Notably, heme/hemoglobin-induced
ferroptosis is ERK1/2-independent in hemorrhagic
stroke, which differs from erastin-induced ERK1/2-
dependent ferroptosis (Zille et al. 2022). Second,
HMOX1 can inhibit ferroptosis under certain con-
ditions. For example, the knockdown of HMOX1
increased erastin-induced ferroptosis in renal proxi-
mal tubular cells (Adedoyin et al. 2018).
PUFAs/MUFAs
The different types of fatty acids play different
regulatory roles in ferroptosis (Das 2019). Polyun-
saturated fatty acids (PUFAs) refer to straight-chain
fatty acids with two or more double bonds. Treat-
ment with exogenous PUFAs increases the sensitiv-
ity of cells to ferroptosis (Magtanong et al. 2019).
The activation of lipophagy can increase endogenous
PUFAs and promote ferroptosis (Chen et al. 2021e).
However, deuterated-PUFAs, in which the hydrogen
atom at the bisallyl position is replaced by deuterium
atom make cells resistant to ferroptosis (Magtanong
837
et al. 2019). Monounsaturated fatty acids (MUFAs)
are fatty acids with only one double bond. Unlike
PUFAs, MUFAs (e.g., OA) have inhibitory effects
on ferroptosis (Magtanong et al. 2019). Why do dif-
ferent types of fatty acids have opposite effects on
ferroptosis? Probably because PUFAs are impor-
tant substrates for unsaturated phospholipids syn-
thesis. The type of unsaturated phospholipids in the
cell membrane determines how sensitive the cell is
to ferroptosis. Furthermore, vertebrates cannot syn-
thesize ω6 and ω3 PUFAs de novo due to the lack
of Δ12 and Δ15 (Fig. 4). Therefore, 18:2n-6 and
18:3n-3 must be obtained from the diet (Henderson
1996; Tocher 2003). In addition to de novo synthe-
sis, PUFAs or MUFAs can be taken up by fatty acid
transporter (FATP), fatty acid translocase (CD36),
and fatty acid-binding protein (FABP) (Fig. 1)
(Bonen et al. 2007).
ACSL4/LPCAT3
ACSLs are responsible for introducing fatty acids
into the plasma membrane, which have five members
in humans (ACSL1, ACSL3, ACSL4, ACSL5, and
ACSL6). They have different substrate preferences
and tissue specificities in fatty acid metabolism (Quan
et al. 2021). ACSL3 is biased to catalyze the produc-
tion of OA-CoA, while ACSL4 is biased to catalyze
the formation of AA-CoA and AdA-CoA (Kuwata
and Hara 2019). Particularly, ACSL4 is selectively
expressed in different cancer cells. The expression
level of ACSL4 was significantly higher in ferropto-
sis-sensitive cells than in ferroptosis-resistant cells
(Doll et al. 2017). The overexpression of ACSL4 was
observed in ferroptosis of hepatocellular carcinoma
induced by sorafenib (Feng et al. 2021). ACSL3 is
often associated with ferroptosis inhibition. ACSL3
tends to catalyze the production of MUFA-CoA (e.g.,
OA-CoA), which remodels the plasma membrane,
reducing phospholipid peroxidation (Doll et al. 2017).
Exogenous MUFAs can inhibit erastin or RSL3-
induced ferroptosis, which is ineffective in ACSL3-
deficient cells (Magtanong et al. 2019). LPCAT is
responsible for incorporating fatty acid acyl chains
into phosphatidylcholine. As a downstream protease
of ACSL4, LPCAT3 tends to incorporate AA-CoA
and AdA-CoA into the plasma membrane to pro-
mote ferroptosis (Hashidate-Yoshida et al. 2015). In
addition, SCP2 promotes ferroptosis by transporting
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 838
Fig. 4  The biosynthesis
of long-chain PUFAs. Δ4,
Δ5, Δ6, Δ8, Δ9, Δ12, Δ15,
fatty acyl desaturases; FAS,
fatty acid synthase; ACC,
acetyl-CoA carboxylase;
ELOVL, very long-chain
fatty acid elongase; β, per-
oxisomal β-oxidation
phospholipids (including lipid peroxides) between
different organelle membranes (Kriska et al. 2010).
Mitochondrial respiratory chain
Glucose is metabolized in different ways in tumor
and normal cells. Unlike most normal cells, tumor
cells tend to ferment glucose to lactate, even in a
condition of oxygen sufficient to support oxida-
tive phosphorylation. This way of metabolism in
tumors is called aerobic glycolysis (WARBURG
1956). Compared with oxidative phosphorylation,
aerobic glycolysis is far less efficient in generat-
ing ATP. To meet ATP demand, tumor cells absorb
large amounts of glucose and undergo high rates
of aerobic glycolysis. Simultaneously, a lot of
NADPH is produced. NADPH possesses the ability
to maintain cellular redox homeostasis and inhibit
ferroptosis (see above). The normal progress of
the mitochondrial respiratory chain produces a
lot of ROS. However, the abnormal accumulation
of ROS can cause cellular damage (Poljsak et al.
2013). In addition, ferroptosis inducer erastin can
inhibit the binding of tubulin and mitochondrial
voltage-dependent anion channels (VDACs), keep-
ing VDACs open and enhancing mitochondrial res-
piration, which in turn increases ROS production
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Cell Biol Toxicol (2023) 39:827–851
(Zhao et al. 2020). It is worth mentioning that
mitophagy can maintain the number of mitochon-
dria. SLC25A37 and SLC25A28 are degraded
and activated through the PINK1-PRKN pathway,
resulting in mitochondrial iron accumulation. How-
ever, the effect of mitophagy on ferroptosis remains
mysterious (Chen et al. 2021e).
AMPK
Under energy stress, tumor cells activate the AMPK
pathway to increase ATP production. However,
AMPK can also phosphorylate and inhibit ACC,
the rate-limiting enzyme for de novo fatty acid syn-
thesis (Fig. 1) (Park et al. 2002). The inhibition of
ACC in ferroptosis-sensitive tumor cells results in
a significant reduction in the abundance of PUFAs,
which reduces ferroptosis sensitivity (Lee et al.
2020). In addition, AMPK can supplement NADPH
supply by enhancing fatty acid oxidative metabo-
lism, further reducing ferroptosis sensitivity (Jeon
et al. 2012).
Glutamine
The non-essential amino acid glutamine is mainly
absorbed through SLC1A5 and SLC38A1 (Fig. 1).
Cell Biol Toxicol (2023) 39:827–851
Glutamine is converted to α-KG by GLS and GDH
(Xiao et al. 2016). α-KG accelerates the generation
of ROS through the tricarboxylic acid cycle and
oxidative phosphorylation, which promotes ferrop-
tosis. In addition, intracellular glutamate can also
promote the uptake of extracellular cystine through
system XC-, which reduces ferroptosis sensitivity
(Lewerenz et al. 2006).
The ferroptosis in diseases
Generally, cancer cells have more active iron metab-
olism and higher levels of reactive oxygen species
than normal cells (Weinberg 1996). Many cancer-
related genes (e.g., p53, BAP1, and KRAS) are
also associated with ferroptosis. The activation of
the cancer canonical signaling pathway RAS-RAF-
MEK-ERK is required for erastin-induced ferropto-
sis (Dolma et al. 2003). Cancer cells that are highly
aggressive and resistant to conventional chemother-
apeutics are more prone to ferroptosis (Viswanathan
et al. 2017). Studies have reported that some neu-
rological disorders are associated with intracellular
iron accumulation, GPx4 inactivation, GSH deple-
tion, and abnormal lipoxygenase activity (Weiland
et al. 2019). In addition, the link between ferroptosis
and ischemia–reperfusion injury, infection, etc. has
also been reported. This suggests that ferroptosis
therapy may be a potential treatment for human dis-
ease. The key mechanisms and targets of ferroptosis
in human disease are summarized in Table 2. Below,
several common diseases linked to ferroptosis are
reviewed.
Cancer
Breast cancer
Breast cancer is notorious for being difficult to treat
and metastasizes frequently. Breast cancer metas-
tasis is closely related to the EMT of cancer stem
cells (CSCs) (Takebe et al. 2011). The mesenchy-
mal phenotype epithelioid transformation (MET)
is the inverse process of EMT and is associated
with tumor cell “homing” and proliferation (Brab-
letz 2012). Breast cancer can be transformed into
CSCs by transforming growth factor-β (TGF-β) or
839
fibronectin, thereby increasing invasiveness and drug
resistance. By targeting EMT-MET and CSCs, breast
cancer cells have the potential to induce ferroptosis.
Ma et al. showed that cancer cell death induced by the
co-administration of siramesine and lapatinib could
be inhibited by vitamin E (Ma et al. 2016). Ironomy-
cin (AM5) induces ferritinophagy in CSCs, leading to
iron overload and induction of ferroptosis (Mai et al.
2017). The diterpenoid natural product pleuromutilin
promotes ferroptosis in breast cancer cells by inhibit-
ing thioredoxin (Llabani et al. 2019).
Lung cancer
Lung cancer originating from the bronchial mucosa
or lung glands is one of the malignant tumors that
pose the greatest threat to human health (Barta et al.
2019). Currently, cisplatin combination therapy is
commonly used to treat lung cancer. However, it has
been reported that lung cancers are resistant to cispl-
atin in some cases (Ashrafizadeh et al. 2021). There-
fore, new therapeutic strategies need to be explored
urgently. Zhang et al. pointed out that drug-resistant
lung cancer cells tend to have higher expression lev-
els of GPx4. The combination of GPx4 inhibitor and
cisplatin can not only induce non-small cell lung can-
cer (NSCLC) cell death but also effectively inhibit
tumor growth in xenograft animal models. Mecha-
nistically, GPx4 inhibitors and cisplatin may overload
cancer cells with iron and trigger ferroptosis through
ferritinophagy (Zhang et al. 2020). In addition, cispl-
atin-based chemotherapeutics can activate the Nrf2/
xCT pathway in NSCLC cells, leading to drug resist-
ance. When cisplatin was combined with erastin or
sorafenib to treat NSCLC, the upregulated Nrf2/xCT
pathway was inhibited, reducing cell resistance to
cisplatin-based chemotherapy (Li et al. 2020a). Over-
all, co-administration of ferroptosis inducers may be a
potential strategy for treating cisplatin-resistant lung
cancer.
Colorectal cancer
It has been confirmed that TP53 plays an important
role in colorectal cancer cells. TP53 can inhibit dipep-
tidyl peptidase 4 (DPP4). Silencing the TP53 gene
promotes DPP4-dependent lipid peroxidation, which
leads to ferroptosis in colorectal cancer cells (Xie
et al. 2017). Pagliara et al. showed that 5-fluorouracil
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 Table 2  The ferroptosis in human diseases
840

Category Diseases Key mechanisms Targets Regulators Ref

Cancer Breast cancer Iron overload; TFR1, SLC40A1, CISD1/2, HO-1, Lapatinib, MOF-Fe2+, Neratinib, Lin et al. (2021)

13
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Pancreatic cancer
Lung cancer
Hepatocellular carcinoma
Gastric cancer
Colorectal cancer
Clear cell renal cell carcinoma
Adrenocortical carcinoma
Ovarian cancer
Melanoma
Head and neck cancer
Brain cancer
Blood cancer Acute lymphoblastic leukemia
Acute myeloid leukemia
Ferritinophagy; ACSL1, ACSL4, SCL7A11, GPx4, Artesunate, α-eleostearic acid, Erastin,
Increased ACSL1 and ACSL4 expression; Nrf2, HMGCR​ Sulfasalazine, Metformin, RSL3,
Decrease SLC7A11, GPx4, and HMGCR protein levels; Fluvastatin
Lysosomal iron-dependent ROS induced; ROS, L-cyst(e)ine, PDK, HSPA5, Artesunate, Cotylenin A and PEITC, Chen et al. (2021d)
Autophagy-dependent ferroptosis induced; SLC7A11, mTOR, GPx4, POLG, Cyst(e)inase, Dichloroacetate, EGCG,
L-cysteine and GSH depleted TFAM, NUPR1 IKE, Piperlongumine, Rapamycin,
Pyruvate oxidation and fatty acid synthesis are induced; RSL3, Ruscogenin, Zalcitabine,
Inhibition of GPx4 activity; ZZW-115
Induction of STING1-dependent autophagy;
NUPR1-LCN2-mediated iron depletion is inhibited;
Inhibition of K
­ RASG12C, GPx4, GCLC, PRIM2-SLC7A11, NFE2L2- KRAS, GPx4, GSH, ROS, SLC7A11, Adagrasib, BSO, Cisplatin, Curcumin, Wu et al. (2021b)
SLC7A11, USP14, FAF2, and NFE2L2-HMOX1 CaM, USP14 Erastin, Ginkgetin, Orlistat, Par-
Induction of lipid peroxidation, C
­ a2+/CaM signaling, and PINK1/ acetamol, PdPT, RSL3, Sorafenib,
Parkin-dependent mitosis; Sulforaphane, Zinc
Activation of autophagy;
Up-regulation of LC3-II/LC3-I, TP53, and BECN1;
Depletion of GSH
Inhibition of system XC-, Nrf2, GPx4, NUPR1, and S1R System XC-, Nrf2, GPx4, NUPR1, S1R Sorafenib, Quiescin Sulfhydryl Oxidase, Bekric et al. (2022), Su et al. (2020)
Artesunate, Erastin, RSL3, Solasonine,
ZZW-115, Haloperidol, Heteronemin
Inhibition of CD01; c-Myb/CD01 Erastin, SASP Hao et al. (2017)
Upregulation of GPx4;
Inhibition of GPx4, DPP4 GPx4, DPP4, TMEM16F, ACSL4, RSL3, Cisplatin, β-elemene, Vitamin C, Xu et al. (2021b)
Activation of TMEM16F; SLC7A11, TP53, NCOA4, ACADSB Resibufogenin, IMCA, Bromelain, MiR-
Upregulation of ROS, DR5, and ACSL4; NAs, Erastin, Artesunate, Sorafenib,
Downregulating SLC7A11, TP53, and GSH; FeOOH nanospindles
Scavenging endogenous hydrogen sulfide (H2S);
Altered iron homeostasis
Inhibition of GSH, system XC − , NCOA4, EMP1-NOX4, and GPx4; VHL/HIF-2α, HILPDA, System XC-, Buthionine sulfoximine, Sorafenib, Artesu- Cosialls et al. (2021), Wang et al. (2021),
Upregulation of FTH, FTMT, and ROS levels; NCOA4, GPx4, NOX4, FTH, FTMT, nate, FINO2 Zhao et al. (2021a)
Enhancing DPP4 activity DPP4
Upregulation of GPx4 and ACSL4 Unknown Unknown Weigand et al. (2020)
Iron overload; TFR1, TAZ/NOX, GPx4 Erastin, Artesunate, Altretamine Bebber et al. (2020), Lin et al. (2020), Zuo
Reduce the depletion of NADPH; et al. (2020)
Inhibition of GPx4
Inhibition of SLC7A11, GPx4, and NEDD4 SLC7A11, GPx4, GCL, NEDD4 Buthionine sulfoximine Chen et al. (2021b), Tsoi et al. (2018), Yang
et al. (2020)
Inhibition of CISD2, SLC7A11, LKB1, and antioxidant proteins; CISD2, SLC7A11, LKB1, Nrf2 Pioglitazone, Sulfasalazine, MiR-100-3p Figueroa-González et al. (2020), Kim et al.
(2018), Yu et al. (2019)
Downregulation of GSH; VDACs, system XC-, Iron, Cystine, Erastin, Sulfasalazine, Sorafenib, t-BHP, Qiu et al. (2020), Weiland et al. (2019)
Inhibition of GPx4; KEAP1, GPx4 Withaferin A, β-mercaptoethanol,
Iron overload; Zinc, CS
Upregulation of cystine uptake
Overactivation of heme oxygenase-1;
Increased ferritinophagy, depletion of GSSG, GSH, and inactivation
of system XC-
Promoting the production of ROS LOXs RSL3 Zhang et al. (2022b)
Iron overload; Iron, System XC-, GPx4, GSH, ROS, APR-246, ATPR, TYP, DHA, CircK- Zhao et al. (2021b)
Inhibition of SLC7A11, GPx4, and ALDH3A2Upregulation of ROS TFR1, P53, HMGB1, ALDH3A2, DM4C
and P53; Hsa-let-7b-5p
Downregulation of TFR1 and HMGB1
Cell Biol Toxicol (2023) 39:827–851
 Table 2  (continued)
Category Diseases Key mechanisms Targets Regulators Ref

Nervous system disease Parkinson’s Disease Iron overload; Iron, System XC-, GPx4, GSH, Lipid Sulfasalazine, Sorafenib, RSL3, FINO2, Weiland et al. (2019)
Ferritinophagy; peroxidation, Protein synthesis ART, t- BHP, DPI2, BSO, DFO, Fer-1,
Upregulation of DMTI expression and ROS; Vitamin E, Cp
Downregulation of SLC7A11, GSH, and CoQ10;
Inhibition of GPx4;

Alzheimer’s disease Depletes GSH System XC-, GPx4, Lipid peroxidation, Sulfasalazine, RSL3, FINO2, ART, BSO, Weiland et al. (2019)
Inhibition of GPx4; GSH, Protein synthesis Fer-1, Vitamin E, Cp, RPL13, CS
Upregulation of ROS;
Inhibition of ROS;

Huntington’s disease Depletes GSH; System XC-, GPx4, Lipid peroxidation, Sulfasalazine, RSL3, FINO2, ART, BSO, Weiland et al. (2019)
Directly inhibits GPx4, accumulation of lipid hydroperoxides GSH, LOXs Fer-1, Vitamin E, Zileuton
Cell Biol Toxicol (2023) 39:827–851

FINO2 inhibits GPx4 function and oxidizes iron;

ART interacts with lysosomal iron and generates ROS;
Inhibition of ROS;
Blocks LOX-induced lipid peroxidation;

Stroke Prevents cystine import; System XC-, GPx4, ROS, Iron, Seleno- Erastin, RSL3, Ferrostatins, Liproxstatins, Liu et al. (2022)
Inhibition of GPx4 and LOXs proteins Trolox, N-Acetylcysteine, Deferoxam-
Accumulation of ROS; ine, Ceruloplasmin, Selenium
Blocks lipid peroxidation;
Neutralizes toxic lipids;
Depletes iron;
Increases abundance of selenoproteins;

Traumatic brain injury Iron overload; Cyt C/CL, GSH, LOXs, GPx4, HIF-PHD Fer-1, Baicalein, N-acetylcysteine, JP4- Anthonymuthu et al. (2018), Karuppa-
Accumulation of ROS; 039, Adaptaquin gounder et al. (2016), Yao et al. (2021)
Upregulation of transferrin, LOXs, and ACSL4;
Inhibition of GPx4;
Ischemia–reperfusion Myocardial ischemia–reperfu- Accumulation of ROS; ER stress, SIRT1-p53/SLC7A11, p53/ Liproxstatin-1, Deferoxamine, USP22, Yang and Lin (2022)
injury sion injury Ferritinophagy; TfR1, AMPK, NOX2, ACSL4, GPx4, USP7, Lip-1, ELAVL1, Etomidate,
Downregulation of GPx4; VDAC1, GSH, Iron, MDA, Nrf2, Baicalin, Cyanidian-3-glucoside
Activation of the p53/TFR1 pathway, NOX2-related PCD; NCOA4, LC3II/LC3I, FTH1
Upregulation of VDAC1 levels;
Acute kidney injury Downregulation of GPx4 and GSH GPx4, SLC7A11, GSH, HO-1 Ferrostatin 1 or 16–86, PANX1 deletion, Li et al. (2021), Wu et al. (2021a)
Upregulation of HO-1, MDA, 4-HNE, and ROS MIF, Pachymic acid, XJB-5–131, Irisin
Immunity Unknown System XC-, GSH, HMGCR, Nrf2, ROS, Sulfasalazine, Glutamate, Sorafenib, Tang et al. (2020)
Ferrous Statins, Trigonelline, Artesunate, Iron,
Doxorubicin
Infection Unknown ALOXs Baicalein, Ferrostatin-1 Chen et al. (2021c)
Inflammation Inhibition of GPx4; ER stress, GPx4 ferrostatin-1, GSK2606414, Curculigoside, Chen et al. (2021c)
Upregulation of ROS; Liproxstatin-1, DFP, ROSI
Emancipation of HMGB1

HO-1 heme oxygenase-1, PDK pyruvate dehydrogenase kinases, POLG DNA polymerase gamma, TFAM mitochondrial transcription factor A, NUPR1 nuclear protein 1, CaM
calmodulin, S1R sigma-1 receptor, TMEM16F transmembrane protein 16F, HILPDA hypoxia-inducible lipid droplet-associated protein, FTMT mitochondrial ferritin, VDACs
voltage-dependent anion channels, KEAP1 kelch-like ECH-associated protein 1, ALDH3A2 aldehyde dehydrogenase 3 family member A2, MDA malondialdehyde, HMGCR​
hydroxymethylglutaryl-coenzyme A reductase, MOF-Fe2+ ­Fe2+-based metal–organic framework, RSL3 RAS-selective lethal, PEITC phenethyl isothiocyanate, EGCG​ epigallo-
catechin gallate, IKE imidazole ketone erastin, BSO buthioninesulfoximine, PdPT palladium pyrithione complex, SASP sulfasalazine, t-BHP tert-butyl hydroperoxide, APR-246
eprenetapopt, ATPR 4-amino-2-trifluoromethyl-phenyl retinate, TYP typhaneoside, ART​ artesunate, DPI diphenylene iodonium, DFO deferoxamine, Cp ceruloplasmin, CS citrate
synthase, Fer-1 ferrostatin-1, USP ubiquitin-specific protease, Lip-1 liproxstatin-1, ELAVL1 embryonic lethal-abnormal vision like protein 1, PANX1 pannexin1, MIF macrophage
migration inhibitory factor, DFP deferiprone, ROSI rosiglitazone, FTH1 ferritin heavy chain 1, GCL glutamate cysteine ligase, HIF-PHD hypoxia-inducible factor prolyl hydroxy-

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lase domain
841
 842
could induce the activation of ribosomal protein L3
(RPL3) in TP53-deficient colorectal cancer cells by
inhibiting the expression of cystathionine-β-synthase,
which may affect the level of cysteine in cancer cells
(Pagliara et al. 2016). In addition, it has been reported
that RPL3 reduces the expression of system XC- and
induces ferroptosis in TP53 mutant lung cancer cells
(Russo et al. 2017). The co-administration of albizi-
abioside A and cisplatin can promote ferroptosis by
inactivating GPx4 in colon cancer cells (Wei et al.
2018). Bromelain can upregulate the expression of
ACSL4 in KRAS-mutated colorectal cancer cells to
promote ferroptosis (Park et al. 2018). Therefore, tar-
geting TP53 or ACSL4 to induce ferroptosis in colo-
rectal cancer has potential clinical applications.
Clear cell renal cell carcinoma
Clear cell renal cell carcinoma (CCRCC) is a com-
mon renal cell carcinoma closely associated with
mutations in the von Hippel Lindau (VHL) gene.
CCRCC is highly sensitive to GSH depletion-induced
ferroptosis due to mutations in the VHL gene. In
addition, mutations in the VHL gene lead to persis-
tent stabilization of hypoxia-inducible factor (HIF).
Zou et al. pointed out that HIF2α specifically enriches
PUFAs in CCRCC, thereby increasing susceptibility
to ferroptosis (Zou et al. 2018). The use of PT2385
(HIF inhibitor) can slightly improve the survival rate
of CCRCC patients, but prolonged use can lead to
acquired resistance (Courtney et al. 2020). In addi-
tion to VHL genes, p53 and BAP1 are also frequently
deleted or mutated in CCRCC. The inactivation of
BAP1 leads to the upregulation of SLC7A11, which
inhibits ferroptosis (Han et al. 2021). Furthermore,
CCRCC is highly sensitive to intracellular glutamate
and cystine levels. CCRCC neutralizes intracellular
lipid peroxides mainly through the GSH/GPx4 path-
way. It has been found that ferroptosis in CCRCC can
be effectively induced by inhibiting the GSH biosyn-
thetic pathway (Miess et al. 2018).
Melanoma
Melanoma is one of the most serious skin cancers.
Generally, the MAPK pathway is hyperactivated due
to alterations in the BRAF, RAS or NF1 genes, which
promote melanoma cell survival. In melanoma cells,
BRAF can inhibit oxidative metabolism, and BRAF
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inhibitors can enhance the dependence on oxidative
phosphorylation. This metabolic switch promotes fer-
roptosis in melanoma cells (Haq et al. 2013; Schöckel
et al. 2015). The application of exogenous PUFAs
can increase the sensitivity of melanoma cell lines
to ferroptosis. The expression level of SLC7A11 was
decreased in BRAFV600E melanoma cells during
vemurafenib or trametinib treatment (Osrodek et al.
2019), and SLC7A11 is considered a marker of fer-
roptosis-susceptible melanoma cells. In addition, the
sensitivity of melanoma cells to ferroptosis is also
related to GPx4. Knockout of the GPx4 gene was
lethal in drug-resistant A375 melanoma cells but did
not affect non-resistant A375 melanoma cells. More
importantly, the lethality of GPx4 knockout in drug-
resistant A375 melanoma cells could be terminated
with the ferroptosis inhibitor ferrostatin-1 (Hangauer
et al. 2017). In addition, the Nrf2 gene also plays an
important role in melanoma. Upregulation of Nrf2
induces the expression of CHAC1 and AKR in mela-
noma cells, thereby degrading lipid peroxides and
inhibiting ferroptosis (Gagliardi et al. 2019).
Nervous system diseases
Parkinson’s disease (PD) is characterized by neuronal
death in the substantia nigra pars compacta (SNpc),
which causes motor dysfunction (Phani et al. 2012).
Bharath et al. showed that iron accumulation, GSH
depletion, and elevated ROS levels are common in
SNpc neurons (Bharath et al. 2002). Guiney et al.
pointed out that ferroptosis is the major cell death
pathway for dopaminergic neurons (Guiney et al.
2017). Zeng et al. indicated that motor function was
improved in the PD animal model with the treatment
of iron chelators (Zeng et al. 2021). Astrocytes have
a strong iron storage capacity and the ability to pre-
vent neuronal iron overload. Furthermore, astrocytes
can provide neurons with antioxidants, such as the
glutathione S-transferase Mu2 (Fernandez-Fernan-
dez et al. 2012). Therefore, the lack of interaction
between neuronal cells and astrocytes may be respon-
sible for their ferroptosis.
A typical feature of Alzheimer’s disease (AD) is
neuronal degeneration related to learning and mem-
ory (Yankner 1996). Xie and co-works have shown
that lipid peroxidation and iron dysregulation are fre-
quently present in neuronal cells of AD patients (Xie
Cell Biol Toxicol (2023) 39:827–851
et al. 2014). Intracellular iron levels in neurons are
often inversely correlated with cognitive performance
in AD patients. The main cause of ferroptosis is the
imbalance of iron metabolism and lipid redox homeo-
stasis. Therefore, ferroptosis provides a new perspec-
tive for understanding the pathological mechanism of
AD. Hambright et al. showed that knocking out GPx4
in hippocampal neurons caused significant cognitive
impairment in mice, which could be ameliorated by
ferroptosis inhibitor liproxstatin-1 (Hambright et al.
2017). Treatment of animal models with the anti-
oxidants MitoQ and SOD2 also improved cognitive
impairment. Furthermore, treatment with alpha-lipoic
acid (ALA) ameliorated AD symptoms in the P301S
tau murine model (Zhang et al. 2018).
Huntington’s disease (HD) is characterized by
chorea movement, an autosomal dominant neurode-
generative disorder (Berardelli et al. 1999). Wu et al.
showed that lipid peroxidation, iron accumulation,
and reduced GPx4 activity were found in neurons of
HD patients and animal models (Wu et al. 2018). In
addition, the application of iron chelators can improve
cognitive function in HD model animals (Ward et al.
2015).
Ischemia–reperfusion injury
Iron overload is a major cause of myocardial I/R
injury. In the early stage of I/R, iron from ferritin
degradation promotes the Fenton reaction, which
accelerates ROS production. Gao et al. reported
that the inhibition of glutaminolysis attenuated
I/R-induced cardiac injury (Gao et al. 2015). Fang
et al. reported that Ferristatin-1 and iron chelators
could attenuate I/R-induced heart failure (Fang
et al. 2019). Chen et al. showed that the adminis-
tration of deferoxamine before reperfusion rapidly
ameliorated oxidative stress (Chan et al. 2012). In
addition, intravenous infusion of deferoxamine can
reduce ROS production during coronary artery
bypass grafting and protect the myocardium from
I/R injury (Paraskevaidis et al. 2005). Shan et al.
pointed out that Cyanidin-3-glucoside can effec-
tively alleviate I/R-induced myocardial injury by
reducing oxidative stress and iron overload (Shan
et al. 2021). A study in a rat I/R model showed that
baicalin attenuated myocardial ischemia–reperfu-
sion injury by inhibiting the expression of ACSL4
843
(Fan et al. 2021). Dabkowski et al. reported that
mitochondrial GPx4 overexpression in cardiomyo-
cytes could alleviate cardiac ischemia–reperfu-
sion injury (Dabkowski et al. 2008). Furthermore,
DMT1 appears to have an important role in AMI.
Song et al. reported that myocardial injury can
be alleviated in AMI mice by targeting DMT1
expression with exosomes from human umbilical
cord blood-derived MSCs (Song et al. 2021). Fer-
rostatin-1 and iron chelators improve acute and
chronic IRI-induced heart failure (Li et al. 2021).
I/R-related cardiac injury can also be alleviated by
promoting GSH production (Ou et al. 2021). This
suggests that ferroptosis may be a new strategy for
preventing and treating myocardial disease.
IRI is also one of the leading causes of acute renal
failure (Grynberg et al. 2021). Scindia et al. reported
that renal IRI is closely related to iron metabolism
(Scindia et al. 2015). Erastin-induced proximal tubule
cell death can be prevented by ferrostatin 1 and defer-
oxamine (Linkermann 2016). GPx4 also has a vital
role in renal IRI. For example, knockout of GPx4
resulted in renal failure in model mice, which was
ameliorated by ferroptosis inhibitors (Friedmann
Angeli et al. 2014). Furthermore, the inhibition of
ACSL4 activity with thiazolidinediones also partially
prevented the death of GPx4 knockout mice (Doll
et al. 2017).
For neuronal I/R injury, iron overload is criti-
cal. For example, deferoxamine reduces infarct size
after cerebral reperfusion (Hanson et al. 2009). Guan
et al. indicated that the learning and memory abili-
ties of I/R-injured gerbils could be enhanced by the
application of galangin, which inhibits ferroptosis
by up-regulating SLC7A11 and GPx4 (Guan et al.
2021). In addition, Carvacrol can attenuate I/R dam-
age in hippocampal neurons by increasing the expres-
sion of GPx4 (Guan et al. 2019). Ferroptosis has also
been considered a potential therapeutic target for
hepatic IRI. The ratio of aspartate aminotransferase
to alanine aminotransferase and the percentage of the
necrotic area was reduced in a liproxstatin-1-treated
mouse model of liver I/R injury (Angeli et al. 2014).
Fer-1 and α-tocopherol reduced ROS production and
down-regulated Ptgs2 in a mouse model of liver IRI
(Yamada et al. 2020). In other organs, liproxstatin-1
or rosiglitazone can ameliorate intestinal I/R injury
by regulating the expression of GPx4 and Ptgs2 (Li
et al. 2019).
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Immunity
It has been reported that IFN-γ produced by ­CD8+ T
cells can inhibit the expression of system XC- (Zitvo-
gel and Kroemer 2019). It is suggested that the induc-
tion of cell death by immune cells may be related
to ferroptosis. Uderhardt et al. reported that IL-4
and IL-13 could promote the expression of ALOXs,
while reducing the expression level of GPx4, result-
ing in the production of a lot of arachidonic acid
pro-inflammatory factors (Uderhardt et al. 2012).
For macrophages, ferroptosis inducers can promote
the release of HMGB1, which is required for mac-
rophage inflammation in response to ferroptotic cells
(Wen et al. 2019). Xu et al. pointed out that ferrop-
tosis plays a dual role in immune cells. On the one
hand, ferroptosis leads to the inactivation of ­CD4+
and ­CD8+ T cells. On the other hand, the differen-
tiation of peripheral blood mononuclear cells can be
promoted by ferroptosis (Xu et al. 2021c). However,
its underlying mechanism remains unclear.
Infection
In response to the invasion of pathogenic microor-
ganisms, host cells recognize pathogen-associated
molecular patterns (PAMPs) through multiple pat-
tern recognition receptors (PRRs) (Amarante-Mendes
et al. 2018). PRRs interact with PAMPs to generate
a large amount of ROS, mainly from the mitochon-
drial respiratory chain and NADPH oxidase complex
(Boller and Felix 2009). For one, the generated ROS
are crucial for the clearance of pathogenic microor-
ganisms. Second, a lot of ROS can cause oxidative
stress in host cells. It has been shown that pathogenic
microorganisms capable of producing lipoxygenase
can attack lipid components on the host cell mem-
brane and induce ferroptosis in host cells. For exam-
ple, although Pseudomonas aeruginosa does not have
arachidonic acid-phosphatidylethanolamine in its
cell membrane, it can convert arachidonic acid into
15-HETE on the host cell membrane (Vance et al.
2004). Consistently, Dar et al. showed that bacteria
lacking lipoxygenase were unable to induce ferrop-
tosis in human bronchial epithelial cells (Dar et al.
2019). In addition, Mycobacterium tuberculosis-
induced macrophage death also has ferroptosis fea-
tures such as inhibition of the GSH/GPx4 antioxidant
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Cell Biol Toxicol (2023) 39:827–851
axis and increased free iron and lipid peroxides. Iron
chelators and ferroptosis inhibitors can reduce the
death of macrophages infected with M. tuberculosis
(Amaral et al. 2019). This suggests that ferroptosis
is closely related to the pathological process of some
infections.
Conclusions and perspectives
Over the past decade, ferroptosis has received grow-
ing attention from researchers. As continuous efforts
are made, research progress in this field is constantly
updated. The understanding of ferroptosis has shifted
from disruption of cellular function to a complex net-
work of redox regulation. However, many questions
related to ferroptosis remain unanswered. First of all,
what is the point of ferroptosis? One possible hypoth-
esis is that ferroptosis is a compromise between the
benefits and risks of introducing PUFAs into cell
membranes. In short, the introduction of PUFAs into
the plasma membrane can confer additional func-
tions on cells (e.g., altering membrane fluidity). How-
ever, this simultaneously increases the sensitivity of
the plasma membrane to intracellular ROS. Under
the catalysis of oxidase and iron, PUFA-PLs in the
plasma membrane continuously react with ROS to
generate lipid peroxides, which trigger ferroptosis
after exceeding the cellular antioxidant capacity. If
this hypothesis holds, what is the threshold for lipid
peroxide-induced ferroptosis? Second, why is iron
irreplaceable in ferroptosis? Although copper and
cobalt can catalyze the Fenton and Haber–Weiss reac-
tions, only iron-mediated reactions can cause cellular
ferroptosis. Why iron? The free radicals generated
by Fenton and Haber–Weiss reactions are not spe-
cific for DNA, lipid, and protein damage, which is
inconsistent with the essential characteristics of RCD.
Perhaps, the activation of iron-containing enzymes
such as LOXs may be a breakthrough in answering
this question. In apoptosis, caspases and other pro-
apoptotic proteins are activated. In autophagy, MAP1
LC3B-I is converted to MAP1 LC3B-II, and Beclin-1
is dissociated from Bcl-2/XL. Compared to this, what
are the exact executioners and biomarkers of ferrop-
tosis? Iron-dependent lipid peroxide accumulation
may be an intermediate event in ferroptosis rather
than effector molecules. Peroxidation of PUFA-PLs
is currently considered to be the terminal event in
Cell Biol Toxicol (2023) 39:827–851
ferroptosis. There are several possibilities for lipid
peroxides to induce ferroptosis: (1) Destruction of a
phospholipid bilayer (e.g., pore formation). (2) Dis-
ruption of plasma membrane function. (3) Destruc-
tion of important components in cells. Finally, as an
emerging field, the current experimental methods
for ferroptosis research are still flawed. Most of the
mechanistic studies of ferroptosis are based on fluo-
rescent reporter molecules that detect lipid peroxides.
However, whether this method can truly and accu-
rately reflect the lipid peroxides produced by ferrop-
tosis remains questioned.
As mentioned above, there is a close connection
between ferroptosis and the pathological process
of various diseases. Cancer cells have abnormally
active iron metabolism and lipid metabolism, so it
has an innate advantage of inducing ferroptosis in
drug-resistant and highly aggressive cancer cells.
Ferroptosis in various neurodegenerative diseases is
also gradually recognized and provides a new per-
spective for further understanding of the underly-
ing pathological mechanisms. Thus, the application
of ferroptosis in treating human disease has poten-
tial clinical advantages. However, current ferrop-
tosis inducers or inhibitors are still not suitable for
clinical application. Identification and validation of
ferroptosis biomarkers are critical for developing
applicable ferroptosis drugs. The discovery of fer-
roptosis biomarkers will not only help to uncover
the intrinsic link between ferroptosis and specific
diseases but also evaluate the efficacy of ferroptosis
drugs. Although the link between ferroptosis and the
pathological process of various diseases has been
established, the link to the physiological process is
still lacking. As an ancient RCD, does ferroptosis
have a specific physiological significance? Such as
affecting aging and immunity. Iron accumulation has
been observed in Caenorhabditis elegans adulthood
and later life. Inhibition of iron accumulation signif-
icantly reduces age-related cell death and prolongs
the lifespan of C. elegans (Jenkins et al. 2020). For
immunity, γ-interferon produced by immune cells
can sensitize tumor cells to ferroptosis, indicating
a molecular basis for the body to use ferroptosis to
prevent disease.
In conclusion, the research related to ferroptosis
is still in its early stage, and some of its mechanisms
remain unclear. We believe that through the continu-
ous exploration of the above problems, researchers
845
will gradually reveal the original appearance of fer-
roptosis, which will ultimately become the corner-
stone for targeting ferroptosis in human diseases.
Author contribution Y.L. and J.W. wrote the main manu-
script text, Z.W. prepared figures, and M.W. prepared tables.
All authors reviewed the manuscript.
Funding This work was supported by the National Natural
Science Foundation of China (82001887 to JW and 81900105
to ZW), in part by a horizontal project of Sun Yat-sen Univer-
sity (K21-75110–007), Shenzhen Science and Technology Pro-
gram (JCYJ20210324115003009), and the Guangdong Basic
and Applied Basic Research Foundation (2019A1515110326).
Data availability Not applicable.
Declarations
Competing interests The authors declare no competing inter-
ests.
Ethics approval Not applicable.
Consent to participate Written informed consents were col-
lected from all participants before enrollment.
Consent for publication All contributing authors agree to the
publication of this article.
Human ethics Not applicable.
Conflict of interest The authors declare no conflict of inter-
est.
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