Ferroptosis: machinery and regulation

Figures & data

Figure 1. Core mechanism of ferroptosis. System x_c⁻-mediated cystine uptake and subsequent GSH production and GPX4 activation play a central role in protecting cells from ferroptosis. Alternatively, AIFM2 inhibits ferroptosis by catalyzing the production of CoQ10H2 from CoQ10 or promoting ESCRT-III–dependent membrane repair. Ferritinophagy and lipophagy provide the substrates Fe²⁺ and FA, respectively, for the execution of lipid peroxidation during ferroptosis. This process is accompanied by ACSL4-catalyzed arachidonic acid-CoA formation, followed by LPCAT3-mediated arachidonic acid-CoA esterification to phospholipids (PL). Several ROS-producing enzymes (e.g., ALOXs, POR, and NOXs) are also involved in the induction of lipid peroxidation. The red text and blue text indicate ferroptosis inducers and inhibitors, respectively. Abbreviations: 2ME, beta-mercaptoethanol; AA, arachidonic acid; ACLS4, acyl-CoA synthetase long chain family member 4; Ada, adrenic acid; AIFM2, apoptosis inducing factor mitochondria associated 2; ALOXs, lipoxygenases; ANGPTL4, angiopoietin like 4; CoA, coenzyme A; CoQ10, coenzyme Q10; CoQ10H2, ubiquinol; DPP4, dipeptidyl peptidase 4; EMP1, epithelial membrane protein 1; ESCRT-III, endosomal sorting complex required for transport-III; FA, fatty acid; G6PD, glucose-6-phosphate dehydrogenase; GCL, glutamate-cysteine ligase; GPX4, glutathione peroxidase 4; GSH, glutathione; GSR, glutathione-disulfide reductase; GSS, glutathione synthetase; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; HDDC3, HD domain containing 3; LPCAT3, lysophosphatidylcholine acyltransferase 3; NAC, N-acetyl cysteine; NADK, NAD kinase; NCOA4, nuclear receptor coactivator 4; NOXs, NADPH oxidases; PGD, phosphogluconate dehydrogenase; PL, phospholipid; PLOOH, phospholipid hydroperoxides; POR, cytochrome p450 oxidoreductase; PPP, pentose phosphate pathway; RAB7A, RAB7A, member RAS oncogene family; RTAs, radical-trapping antioxidants; Se, selenium; t-BuOOH, tert-butyl hydroperoxide

Figure 2. Iron metabolism and ferroptosis. Extracellular iron enters cells, mainly through endosome-mediated internalization of the TF-TFRC complex and receptor-mediated NTBI or heme uptake. Free iron in the cells is stored in ferritin, and iron is released again by ferritinophagy-mediated ferritin degradation. The iron chaperones PCBP1 and PCBP2 may play an important role in cellular iron transmission. SLC40A1 is an iron exporter, cooperating with iron oxidases (e.g., CP, HEPH, and HEPHL1) to transport iron to the extracellular space. Iron, heme, or Fe-S are all incorporated into ROS-generating enzymes (e.g., ALOXs, NOXs, XDH, CYP/CYP450, and ETC complexes) or antioxidant enzymes (e.g., CAT). ACO1 and IREB2 regulate iron homeostasis by controlling the translation of mRNA related to iron metabolism. Abbreviations: ABCB7, ATP binding cassette subfamily B member 7; ACO1, aconitase 1; ALOXs, lipoxygenases; CAT, catalase; CISD1, CDGSH iron sulfur domain 1; CP, ceruloplasmin; CYBRD1, cytochrome B reductase 1; CYP450, cytochrome P450; ETC, electron transport chain; Fe-S, iron-sulfur cluster; FLVCR1, FLVCR heme transporter 1; FLVCR2, FLVCR heme transporter 2; HAMP, hepcidin antimicrobial peptide; HB, hemoglobin; HEPH, hephaestin; HEPHL1, hephaestin like 1; HMOX1, heme oxygenase 1; HP, haptoglobin; HPX, hemopexin; IREB2, iron responsive element binding protein 2; LIP, labile iron pool; LRP1, LDL receptor related protein 1; LTF, lactotransferrin; NCOA4, nuclear receptor coactivator 4; NFS1, NFS1 cysteine desulfurase; NOXs, NADPH oxidases; NTBI, nontransferrin-bound iron; PCBP1, poly(RC) binding protein 1; PCBP2, poly(rC) binding protein 2; POR, cytochrome p450 oxidoreductase; SLC11A2, solute carrier family 11 member 2; SLC25A28, solute carrier family 25 member 28; SLC25A37, solute carrier family 25 member 37; SLC39A8, solute carrier family 39 member 8; SLC39A14, solute carrier family 39 member 14; SLC40A1, solute carrier family 40 member 1; SLC46A1, solute carrier family 46 member 1; STEAP3, STEAP3 metalloreductase; TF, transferrin; TFRC, transferrin receptor; XDH, xanthine dehydrogenase

Figure 3. Lipid metabolism and ferroptosis. Both lipid catabolism and anabolic changes affect lipid peroxidation during ferroptosis. De novo lipogenesis is the synthesis of fatty acids from acetyl-CoA produced by the mitochondrial tricarboxylic acid (TCA) cycle. FA is transported into mitochondria for β-oxidation to release acetyl-CoA. Lipid droplets are intracellular sites for neutral lipid storage, and lipophagy induces autophagic degradation of lipid droplets and promotes the release of free FA. Lipolysis is defined as the catabolism of TAG stored in cell lipid droplets, which is regulated by PNPLA2/ATGL, LIPE/HSL, and MGLL. Oxygenases, such as ALOX and POR, catalyze the oxidation of PUFA to activate lipid peroxidation. ACSL4 and LPCAT act as positive regulators of lipid peroxidation by shaping cellular phospholipids. The NOX protein family reduces oxygen to produce free radicals, thereby attacking PUFA-containing lipids. Abbreviations: AA, arachidonic acid; AdA, adrenic acid; ACACs, acetyl-CoA carboxylases; ACLY, ATP citrate lyase; ACSL4, acyl-CoA synthetase long chain family member 4; ACSLs, acyl-CoA synthetase long chain family member proteins; ACSMs, acyl-CoA synthetase medium chain family member proteins; ALOXs, lipoxygenases; CAT, catalase; CoA, coenzyme A; CPT1, carnitine palmitoyltransferase 1; CPT2, carnitine palmitoyltransferase 2; DAG, diacylglycerol; DAGL, diacylglycerol lipase; ETC, electron transport chain; FA, fatty acid; FABPs, fatty acid binding proteins; FASN, fatty acid synthase; GPX4, glutathione peroxidase 4; GPXs, glutathione peroxidases; GSH, glutathione; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; LIPE, lipase E, hormone sensitive type; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAG, monoacylglycerol; MGLL, monoglyceride lipase; NOXs, NADPH oxidases; PE, phosphatidylethanolamine; PL, phospholipid; PNPLA2, patatin like phospholipase domain containing 2; POR, cytochrome p450 oxidoreductase; PRDXs, peroxiredoxins; PUFAs, polyunsaturated fatty acids; RAB7A, RAB7A, member RAS oncogene family; SLC25A20, solute carrier family 25 member 20; SOD1, superoxide dismutase 1; SOD2, superoxide dismutase 2; SOD3, superoxide dismutase 3; TAG, triacylglycerol; TCA cycle, tricarboxylic acid cycle

Figure 4. The membrane repair function of ESCRT-III in RCD. ESCRT-III plays a key role in plasma membrane repair in three forms of regulated cell death (RCD), including pyroptosis, necroptosis, and ferroptosis. In pyroptosis and necroptosis, GSDMD and MLKL are transported from the cytoplasm to the cell membrane and form oligomers and large permeability pores, resulting in cell death. In the case of ferroptosis, the accumulation of lethal lipid peroxidation production or the translocation of unknown pore-forming protein in the cell membrane leads to cell death. ESCRT-III machines, including the CHMP family and VPS4, can promote membrane sprouting and shedding of injured plasma membranes. Abbreviations: CASPs, caspases; CHMP2A, charged multivesicular body protein 2A; CHMP3, charged multivesicular body protein 3; CHMP4B, charged multivesicular body protein 4; CHMP5, charged multivesicular body protein 5; CHMP6, charged multivesicular body protein 6; ESCRT-III, endosomal sorting complex required for transport-III; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; MLKL, mixed lineage kinase domain like pseudokinase; RIPK3, receptor interacting serine/threonine kinase 3; VPS4, vacuolar protein sorting 4

Table 1. Ferroptosis inducers

Compound	Mechanism of action	Effects	Ref
2-imino-6-methoxy-2 H-chromene-3-carbothioamide	Downregulation of SLC7A11	Induces ferroptosis in DLD-1 and HCT116 colorectal cancer cells	[192]
Acetaminophen	Depletion of GSH	Induces ferroptosis in primary mouse hepatocytes	[193]
Altretamine	GPX4 inhibitor	Inhibits GPX4 activity	[194]
Arsenite (NaAsO2)	Toxicant	Induces iron accumulation and mitochondrial dysfunction	[195]
Artemisinin	Organic peroxides	Induces peroxidation of cellular lipids, and increases cellular free iron	[196]
Artesunate	Organic peroxides	Induces peroxidation of cellular lipids, and increases cellular free iron	[197]
BAY 11–7085	NFKBIA/IkBa inhibitor	Upregulates HMOX1 by NFE2L2 activation	[198]
BAY 87–2243	Inhibition of mitochondrial complex I	Induces ferroptosis G361 and SK-MEL-28 cells by decreasing the mitochondrial membrane potential, and increasing ROS levels	[199]
Brefeldin A	Golgi-dispersing agents	Induces Golgi stress and ferroptosis in HeLa, A549, DU145, HT-29, PANC-1, and primary lung fibroblast cells	[200]
Buthionine sulfoximine (BSO)	GCL inhibitor	Induces GSH depletion	[2,50]
CH004	CBS inhibitor	Induces ferroptosis in HepG2 cells	[95]
Concanavalin A	Lectin	Induces ferroptosis in mouse hepatocytes through increasing RNS	[201,202]
Cyst(e)inase	Cyst(e)ine degrading enzyme	Induces ferroptosis in AsPC-1, PANC-1, BxPC-3, and S2-013 cells	[20]
Dihydroartemisinin	Organic peroxides	Induces peroxidation of cellular lipids, and increases cellular free iron	[203,204]
Doxorubicin	Induction of HMOX1	Induces ferroptosis in cardiomyopathy model	[205]
Erastin	System xc^− inhibitor	Inhibits cystine import, induces GSH depletion	[2]
Erianin	Natural product	Induces ferroptosis in H460 and H1299 cells through increasing calmodulin	[206]
FeCl2	Iron overload	Induces ferroptosis in vitro and intracerebral hemorrhage in an in vivo model	[126]
Ferric citrate	Iron overload	Induces ferroptosis in mouse cardiomyocytes, hepatocytes, BMDMs, and HT1080 cells	[19,127,207]
Ferroptocide	TXN inhibitor	Induces ferroptosis in ES-2 cells	[32]
FIN56	Induction of GPX4 degradation	Causes GPX4 degradation and depletes CoQ10 via the mevalonate pathway	[33]
FINO2	Organic peroxides	Oxidizes iron and indirectly inhibits GPX4 activity	[125]
General anesthesia	Dysregulation of iron homeostasis	Induces ferroptosis in vitro in hippocampal neurons and in vivo in hippocampus	[208]
Glutamate	System xc^− inhibitor	Inhibits cystine import, induces depletion of GSH in neuron and PC12 cells	[2,98]
Hemin	Iron overload	Induces ferroptosis in vitro and intracerebral hemorrhage in an in vivo model	[48,49,180]
HB (hemoglobin)	Iron overload	Induces ferroptosis in vitro and intracerebral hemorrhage in an in vivo model	[126]
Hydrogen peroxide (H2O2)	Organic peroxides	Induces ferroptosis in GPX4^cys/cys and C6 glioma cells	[29,209]
IFNG/IFNγ	Downregulation of SLC7A11	Inhibits cystine import, induces depletion of GSH in HT1080 cells	[210]
iFSP1	AIFM2 inhibitor	Induces ferroptosis in GPX4-knockout Pfa1 and HT1080 cells that overexpress AIFM2	[34]
Imidazole ketone erastin	System xc^− inhibitor	Inhibits cystine import, induces GSH depletion	[121]
Ionizing radiation	Downregulation of SLC7A11	Inhibits cystine import, induces GSH depletion	[211–213]
JKE-1674	GPX4 inhibitor	Inhibits GPX4 activity	[123]
JKE-1716	GPX4 inhibitor	Inhibits GPX4 activity	[123]
JQ1	Induction of ferritinophagy	Induces ferroptosis in MDA-MB-231, Hs 578 T, A549, and H1299 cells	[130]
ML162	GPX4 inhibitor	Inhibits GPX4 activity	[14]
ML210	GPX4 inhibitor	Inhibits GPX4 activity	[122]
Nanomaterials	Induction of lipid peroxidation	Induces ferroptosis in vitro and in vivo	[214,215]
(NH4)2Fe(SO4)2	Iron overload	Induces ferroptosis in vitro and intracerebral hemorrhage in an in vivo model	[49]
Piperazine erastin	System xc^− inhibitor	Inhibits cystine import, induces GSH depletion	[2,14]
Piperlongumine	Induction of lipid peroxidation	Induces ferroptosis in PANC-1 cells	[216]
PM2.5	Iron overload	Induces ferroptosis in human endothelial cells through regulation of TFRC, FTL, and FTH1	[217]
Pseudolaric acid B	Induction of lipid peroxidation	Induces ferroptosis in C6, SHG-44, U251 and U87 glioma cells through upregulating TFRC, activating NOX4, and downregulating SLC7A11	[218]
RSL3	GPX4 inhibitor	Inhibits GPX4 activity	[14]
Salinomycin	Induction of ferritinophagy	Induces ferroptosis in iCSCL-10A2 cells	[129]
Siramesine and lapatinib	Induction of lipid peroxidation	Induces ferroptosis in MDA-MB-231, MCF7, ZR-75, and SKBR3 breast cancer cells through regulation of iron transport	[40]
Sorafenib	System xc^− inhibitor	Inhibits cystine import, induces GSH depletion	[115]
Sulfasalazine	System xc^− inhibitor	Inhibits cystine import, induces GSH depletion	[2,115]
Tertiary-butyl hydroperoxide (t-BuOOH)	Organic peroxides	Induces peroxidation of cellular lipids, loss of mitochondrial membrane potential, and formation of DNA double-strand breaks	[124,161,219]
Withaferin A	GPX4 inhibitor	Inhibits GPX4 activity, increases cellular free iron	[49]
Zalcitabine	Activation of STING1-mediated autophagy	Induces ferroptosis in PANC-1, Capan2, and pHsPDAC cells	[131]
ZnCl2	Inhibition of system xc^− activity	Increases phosphorylation of system xc^−, and decreases system xc^− activity in A549 cells	[220]

Table 2. Ferroptosis inhibitors

Compound	Mechanism of action	Effects	Work concentration	Ref
1-methyl tryptophan	IDO inhibitor	Suppresses concanavalin A-induced ferroptosis in mouse hepatocytes	50 mg/kg	[202]
2-acetylphenothiazine	NOXs inhibitor	Inhibits NOXs-mediated lipid peroxidation	NA	[108]
2-amino-5-chloro-N,3-dimethylbenzamide (CDDO)	HSP90 inhibitor	Inhibits erastin-induced GPX4 degradation in HT-22 cells	10 μM	[140]
2,2-bipyridyl	Iron chelator	Inhibits iron-mediated lipid peroxidation	100 μM	[2]
2,2,6,6-tetramethylpiperidin-N-oxyl	RTA	Inhibits lipid peroxidation	2 μM	[136]
3-methylaldehyde (3-MA)	Autophagy inhibitor	Suppresses ferroptosis following a short-term incubation of erastin	10 μM	[175]
5-(tetradecyloxy)-2-furoic acid (TOFA)	ACACs inhibitor	Inhibits fatty acid synthesis and FIN56-induced GPX4 degradation	10 μM	[33,78]
6-aminonicotinamide	Inhibitor of pentose phosphate pathway	Inhibits NOX-mediated lipid peroxidation	200 μM	[2]
1400 W	NOS2 inhibitor	Suppresses concanavalin A-induced ferroptosis in mouse hepatocytes	5 mg/kg	[201]
AA-861	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	2 μM	[90]
Alogliptin	DPP4 inhibitor	Inhibits NOX1-mediated lipid peroxidation	10 μM	[108]
Aminooxyacetic acid	Transaminase inhibitor	Suppresses erastin- or cystine deprivation-induced ferroptosis through inhibiting a-KG synthesis	2 mM	[2,41,100]
Ammonium chloride	Autophagy or lysosome inhibitor	Suppresses ferroptosis following a short-term incubation of erastin or RSL3	10 mM	[221]
β-carotene	Antioxidant	Inhibits lipid peroxidation	0.2 μM	[184]
β-mercaptoethanol (2ME)	Reductant	Suppresses erastin-induced ferroptosis through bypassing system xc^−	50 μM	[2]
Bafilomycin A1	Autophagy or lysosome inhibitor	Suppresses ferroptosis following a short-term incubation of erastin, cystine starvation, or RSL3	0.4 μM	[68,221,222]
Baicalein	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	20 μM	[90,223]
BI-6c9	BID inhibitor	Suppresses glutamate-, erastin-, or RSL3-induced ferroptosis in HT-22 cells	10 μM	[224,225]
Butylated hydroxyanisole	RTA	Inhibits lipid peroxidation	140 μM	[33]
Butylated hydroxytoluene	RTA	Inhibits lipid peroxidation	400 μM	[14]
C15-THN	RTA	Inhibits lipid peroxidation	2 μM	[133]
CA-074Me	CTSB inhibitor	Suppresses erastin-induced ferroptosis	100 μM	[222]
Carvedilol	RTA	Inhibits lipid peroxidation	1 μM	[226]
Chloroquine	Autophagy or lysosome inhibitor	Suppresses ferroptosis following a short-term incubation of erastin	50 μM	[68]
Ciclopirox	Iron chelator	Inhibits iron-mediated lipid peroxidation	5 μM	[2]
Cinnamyl-3,4-dihydroxya-cyanocinnamate (CDC)	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	20 μM	[90]
CoA	Metabolite	Suppresses glutamate-, erastin-, and cystine starvation-induced ferroptosis	500 μM	[20,152]
Compound 968	Transaminase inhibitor	Suppresses erastin- or cystine deprivation-induced ferroptosis through inhibiting α-KG synthesis	20 μM	[41,100]
CoQ10/idebenone	Metabolite, antioxidant	Inhibits lipid peroxidation	10 μM	[33]
Cycloheximide	Protein synthesis inhibitor	Suppresses erastin-induced ferroptosis	5 μM	[2]
Deferiprone	Iron chelator	Inhibits iron-mediated lipid peroxidation	100 μM	[227]
Deferoxamine	Iron chelator	Inhibits iron-mediated lipid peroxidation	100 μM	[2]
Deuterated polyunsaturated fatty acids	Fatty acids	Inhibits lipid peroxidation through decreasing oxidizable PUFAs	80 μM	[90]
Dexrazoxane	Iron chelator	Inhibits iron-mediated lipid peroxidation	200 μM	[205]
Diphenylene iodonium	NOXs inhibitor	Inhibits NOX-mediated lipid peroxidation	0.5 μM	[2]
Dopamine	Neurotransmitter	Suppresses erastin-induced GPX4 degradation	25 μM	[143]
Ebselen	GPXs mimic	Inhibits lipid peroxidation	5 μM	[2]
Estradiol	RTA	Inhibits lipid peroxidation	10 μM	[226]
Farnesyl pyrophosphate	Metabolite	Suppresses FIN56-induced ferroptosis	10 μM	[33]
Fe-TMPyP	ONOO- scavenger	Suppresses concanavalin A-induced ferroptosis in mouse hepatocytes	10 mg/kg	[201]
Ferrostatin-1	RTA	Inhibits lipid peroxidation	0.5 μM	[2]
FG-4592	EGLNs inhibitor	Suppresses folic acid-induced ferroptosis of renal injury through activating HIF1A and NFE2L2 pathway	10 mg/kg	[228]
GKT137831	NOXs inhibitor	Inhibits NOX-mediated lipid peroxidation	20 μM	[2]
Indole-3-carbinol	RTA	Inhibits lipid peroxidation	100 μM	[226]
JP4-039	RTA	Inhibits lipid peroxidation	1–10 μM	[137]
L-g-glutamyl-p-nitroanilide	SLC1A5 inhibitor	Suppresses cystine deprivation-induced ferroptosis through inhibiting α-KG synthesis	5 mM	[41,100]
Linagliptin	DPP4 inhibitor	Inhibits NOX1-mediated lipid peroxidation	10 μM	[108]
Liproxstatin-1	RTA	Inhibits lipid peroxidation	0.1 μM	[92]
Mitoquinone mesylate (MitoQ)	Antioxidant	Inhibits lipid peroxidation	1 μM	[92,225]
Ml351	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	10 μM	[81]
Monounsaturated fatty acids (MUFAs)	Fatty acids	Inhibits lipid peroxidation through decreasing oxidizable PUFAs	500 μM	[75,77]
N-acetyl cysteine (NAC)	Antioxidant, a precursor of GSH	Suppresses erastin-induced ferroptosis through supplementing GSH	1 mM	[2,14]
NCTT-956	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	20 μM	[81]
Omeprazole	RTA	Inhibits lipid peroxidation	100 μM	[226]
PD146176	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	5 μM	[81,90]
PepA-Me	Autophagy or lysosome inhibitor	Suppresses ferroptosis following a short-term incubation of erastin or RSL3	25 μM	[221]
Phenoxazines and phenothiazines	RTA	Inhibits lipid peroxidation	2 μM	[135]
Pioglitazone	ACSL4 inhibitor	Inhibits ACSL4-mediated lipid peroxidation	50 μM	[84]
Promethazine	RTA	Inhibits lipid peroxidation	1 μM	[226]
Propranolol	RTA	Inhibits lipid peroxidation	20 μM	[226]
Puerarin	Antioxidant	Suppresses erastin- or ISO-induced ferroptosis in H9c2 cells	20 μM	[229]
Rifampicin	RTA	Inhibits lipid peroxidation	20 μM	[226]
Rosiglitazone	ACSL4 inhibitor	Inhibits ACSL4-mediated lipid peroxidation	50 μM	[81,84]
Sodium selenite	GPXs inducer	Suppresses FIN56-induced ferroptosis	100 nM	[33]
Triacsin C	ACSL4 inhibitor	Inhibits ACSL4-mediated lipid peroxidation	2.5 μM	[81]
Triiodothyronine	RTA	Inhibits lipid peroxidation	10 μM	[226]
Troglitazone	ACSL4 inhibitor	Inhibits ACSL4-mediated lipid peroxidation	50 μM	[84]
Trolox	Antioxidant	Inhibits lipid peroxidation	100 μM	[2]
U0126	MEK inhibitor, antioxidant	Inhibits lipid peroxidation	10 μM	[41]
Vildagliptin	DPP4 inhibitor	Inhibits NOX1-mediated lipid peroxidation	10 μM	[108,200]
Vitamin E/α-tocopherol	RTA	Inhibits lipid peroxidation, may inhibit ALOXs	100 μM	[14,33]
Wortmannin	Autophagy inhibitor	Suppresses ferroptosis following a short-term incubation of erastin	10 μM	[68]
XJB-5-131	RTA	Inhibits lipid peroxidation	0.1–1 μM	[137]
YM-53,601	FDFT1/SQS inhibitor	Suppresses FIN56-induced ferroptosis	5 μM	[33]
Zaragozic acid A	FDFT1/SQS inhibitor	Suppresses FIN56-induced ferroptosis	NA	[33]
Zileuton	ALOXs inhibitor	Inhibits ALOX-mediated lipid peroxidation	50 μM	[81,90]

Table 3. Transcriptional regulators in ferroptosis

Transcription factor	Effects	Targets	Mechanism of action	Ref
ATF3	Downregulation	SLC7A11	Enhances ferroptosis induced by erastin through inhibiting cystine import in HT1080 and RPE cells	[230]
ATF4	Upregulation	HSPA5	Suppresses ferroptosis induced by erastin and sulfasalazine in PANC-1 and CFPAC-1 cells, as well as induced by dihydroartemisinin in U251 and U373 cells, through inhibiting GPX4 degradation	[142,231]
	Upregulation	SLC7A11	Suppresses ferroptosis induced by sorafenib or erastin in U87 cells	[232]
	Upregulation	CHAC1	Enhances ferroptosis induced by artesunate in CA-46 cells, as well as induced by cystine starvation in MDA-MB-231, Hs 578 T, and HCC 1937 cells, through promoting GSH degradation	[233,234]
ARNTL	Downregulation	EGLN2	Suppresses ferroptosis through activation of HIF1A in HT1080 and Calu-1 cells	[177]
	Upregulation	SLC7A11, GPX4, SOD1, TXN, NFE2L2, CHMP5	Suppresses ferroptosis through promoting antioxidant or membrane repair systems in mouse pancreas cells	[179]
BACH1	Downregulation	SLC7A11, GCLM, FTH1, FTL, SLC40A1	Enhances ferroptosis induced by erastin through repressing the transcription of GSH/iron metabolism in MEFs	[235]
ΔNp63α (TP63)	Upregulation	GCLC, GSS, IDH2, GPX2	Suppresses ferroptosis through promoting GSH synthesis in MEFs	[236]
HIC1	Upregulation	HBA1, NNMT, PLIN4	Enhances ferroptosis induced by erastin through inhibiting GSH synthesis in HepG2 and Bel-7402 cells	[237]
HIF1A	Upregulation	FABP3, FABP7	Suppresses ferroptosis induced by RSL3 or FIN56 through promoting lipid storage in HT1080 and Calu-1 cells	[177]
HIF1A	Downregulation	HELLS	Enhances ferroptosis induced by erastin through promoting the expression of GLUT1, SCD1 and FADS2 in A549 and H358 cells	[76]
EPAS1	Upregulation	HILPDA	Enhances ferroptosis induced by ML210 or RSL3 through enriching polyunsaturated lipids in RCC4 and 786-O cells	[82,238]
HNF4A	Upregulation	STMN1, RRM2, CAPG	Suppresses ferroptosis induced by erastin through promoting GSH synthesis in HepG2 and Bel-7402 cells	[237]
HSF1	Upregulation	HSPB1	Suppresses ferroptosis induced by erastin through reducing iron levels in HeLa, U2OS, and LNCaP cells	[239]
JUN (OGlcNAcylated)	Upregulation	PSAT1, CBS	Suppresses ferroptosis induced by erastin through promoting GSH synthesis in Bel-7402 and SMMC-7721 cells	[240]
MTF1	Upregulation	FTH1, FTL, SLC40A1	Suppresses ferroptosis induced by erastin through inhibiting iron accumulation in MDA-MB-231 cells	[241]
NFE2L2	Upregulation	FTH1, SLC40A1, HMOX1, MT1G	Suppresses ferroptosis through regulating iron metabolism	[50,153–155,198,205]
NFE2L2	Upregulation	SLC7A11, CBS, GCLM, CHAC1, ABCC1	Suppresses ferroptosis through regulating GSH metabolism	[156–158,198,242,243]
NFE2L2	Upregulation	NQO1, TXNRD1, AKR1Cs, SESN2, GSTP1	Suppresses ferroptosis through induction of detoxification or antioxidation enzymes	[50,154,155,243,244]
SP1	Upregulation	GPX4	Suppresses ferroptosis induced by hemin through inhibiting lipid peroxidation in primary cortical neurons and a hemorrhagic stroke model	[30]
	Upregulation	ACSL4	Enhances ferroptosis in ischemia/reperfusion injury	[245]
STAT1	Downregulation	SLC7A11	Enhances ferroptosis induced by IFNG through inhibiting cystine import in HT1080 cells	[210]
STAT3	Downregulation	ACSL4	Suppresses ferroptosis through inhibiting lipid peroxidation in MCF10-A cells	[246]
STAT3	Upregulation	CSTB	Enhances ferroptosis induced by erastin or sorafenib through promoting lysosomal cell death in PANC-1 and CFPAC-1 cells	[222]
TFAP2C	Upregulation	GPX4	Suppresses ferroptosis induced by hemin through inhibiting lipid peroxidation in primary cortical neurons and a hemorrhagic stroke model	[30]
TFEB	Upregulation	SOD1	Suppresses ferroptosis induced by erastin through inhibiting lipid peroxidation in RAW264.7 cells	[247]
TP53	Downregulation	SLC7A11	Enhances ferroptosis induced by erastin through inhibiting cystine import in MEFs and H1299 cells	[147]
TP53	Upregulation	SAT1	Enhances ferroptosis induced by t-BuOOH through promoting SAT1-ALOX12 axis in MEFs and H1299 cells	[151]
TP53	Upregulation	GLS2	Enhances ferroptosis through promoting the glutaminolysis pathway	[101]
TP53	Inhibition of activity	DPP4	Suppresses ferroptosis induced by erastin through inhibiting DPP4-NOX1 axis in HCT116 and SW48 cells	[108]
TP53	Upregulation	CDKN1A	Suppresses ferroptosis in MEFs and HT1080 cells	[150]
WWTR1	Upregulation	EMP1	Enhances ferroptosis induced by erastin through promoting NOX4-dependent lipid peroxidation in RCC4 and 786-O cells	[109]
WWTR1	Upregulation	ANGPTL4	Enhances ferroptosis induced by cysteine deprivation through promoting CYBB-dependent lipid peroxidation in CAOV2 and TOV-21 G cells	[110]
YAP1	Upregulation	TFRC, ACSL4	Enhances ferroptosis induced by cysteine deprivation through promoting iron-dependent lipid peroxidation in HCT116 cells	[160]

Figure 5. Dual role of TP53 in ferroptosis. 1) Pro-ferroptosis role of TP53. TP53 inhibits the expression of SLC7A11 or promotes the expression of SAT1, thus regulating ALOX12- or ALOX15-dependent lipid peroxidation reactions, respectively. 2) Anti-ferroptosis role of TP53. TP53 binds with DDP4 in the nucleus, which limits DPP4 binding to NOX1 to mediate ROS production in the cell membrane. TP53 also promotes the expression of CDKN1A, thereby inducing the production of GSH to inhibit lipid peroxidation. Abbreviations: ALOX12, arachidonate 12-lipoxygenase; ALOX15, arachidonate 15-lipoxygenase; CDKN1A, cyclin dependent kinase inhibitor 1A; DPP4, dipeptidyl peptidase 4; GSH, glutathione; NOX1, NADPH oxidase 1; SAT1, spermidine/spermine N1-acetyltransferase 1; SLC7A11, solute carrier family 7 member 11; TP53, tumor protein P53

Figure 6. Mechanisms of autophagy-dependent ferroptosis. Several types of selective autophagy, including ferritinophagy, lipophagy, clockophagy, and CMA, promote ferroptotic cell death by inducing the degradation of ferritin, lipid droplets, ARNTL, and GPX4, respectively. Abbreviations: ARNTL, aryl hydrocarbon receptor nuclear translocator like; CMA, chaperone-mediated autophagy; GPX4, glutathione peroxidase 4; HSP90, heat shock protein 90; NCOA4, nuclear receptor coactivator 4; RAB7A, RAB7A, member RAS oncogene family; SQSTM1, sequestosome 1

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