Table 4.

Summary of small molecules that target ferroptosis in vivo and in clinical trials

Targeted pathway	Agent	Effect on ferroptosis	Proposed mechanism	Disease model	Refs	Indication	NCT #	Phase	Status
Iron metabolism	Compound 9a	Inhibitor	Perturbation of NCOA4-Fth1 interaction	Ischemic stroke MCAO rats	136	N/A	N/A	N/A	N/A
	CPX	Inhibitor	Iron chelator	MDAY-D2 murine leukemia cells metastasis in NOD/SCID mice; OCI-AML2 and K562 cells xenografts in NOD/SCID mice; polycystic kidney disease model with Pkd1RC/RC Pkd2+/–	121,372	Relapsed or refractory hematologic malignancy	NCT00990587	I	Completed
						Vulvar Cancer	NCT00382330	N/A	Withdrawn
	DFO	Inhibitor	Iron chelator	MCD-induced NASH in mice; hepatic I/R injury in mice; aged (15–18 months) C57 mice exposed to LPS	82,109,373	Hypotension, acute renal failure	NCT00870883	II	Completed
						Ischemic stroke	NCT00777140	II	Completed
						AKI	NCT04633889	II	Recruiting
						Aneurysmal subarachnoid hemorrhage	NCT04566991	II	Recruiting
	DFP	Inhibitor	Iron chelator	DSS-induced ulcerative colitis in mice	374	Acute myocardial infarction Type 1	NCT05604131	I	Recruiting
						Neurodegeneration with brain iron accumulation (NBIA)	NCT00907283	II	Active, not recruiting
						Stroke	NCT05111821	II	Recruiting
	DFX	Inhibitor	Iron chelator	ICH mice; mid-thoracic spinal contusion rat	116,118	Myelodysplasia	NCT03387475	II	Recruiting
						Sickle cell disease	NCT05392101	II	Recruiting
	DXZ	Inhibitor	Iron chelator	DOX- and I/R-induced cardiomyopathy in mice	3	During congenital heart surgery	NCT04997291	I	Recruiting
						Preventing heart-related side effects of chemotherapy in participants with blood cancers	NCT03589729	II	Recruiting
	JQ1	Inducer	BRD4 inhibitor	A549 cell xenografts	133	N/A	N/A	N/A	N/A
Reductive -oxidative	APAP	Inducer	Blocking the system Xc–	A549 cells xenografts	185	Delirium in old age; delirium; coronary artery disease	NCT04093219	III	Recruiting
						Nephrectomy	NCT03365622	IV	Recruiting
						Acute respiratory distress syndrome	NCT04291508	II	Recruiting
						Ductus arteriosus in preterm infants	NCT04459117	II, III	Recruiting
						Fear	NCT05396677	N/A	Recruiting
	AOA	Inhibitor	Pan-transaminases inhibitor	Colitis induced in mice with DSS; chronic alcoholism in rats	375,376	N/A	N/A	N/A	N/A
	AUF	Inducer	TXNRD inhibitor; inhibiting GSH biosynthesis	Hemochromatosis model (Hfe−/− mice)	22	Glioblastoma	NCT02770378	I, II	Completed
						Recurrent non-small cell lung cancer or small cell lung cancer	NCT01737502	I, II	Recruiting
						Chronic lymphocytic leukemia (CLL)	NCT01419691	II	Completed
						Recurrent epithelial ovarian; primary peritoneal, or fallopian tube cancer	NCT01747798	Early phase 1	Completed
	Brequinar	Inducer	DHODH inhibitor	HT-1080 xenografts; NCI-H226 xenografts and lung cancer PDXs	20	SARS-CoV-2 infection	NCT04575038	II	Completed
						Acute myeloid leukemia	NCT03760666	I, II	Terminated
	BSO	Inducer	Inhibition of GCL; GSH-depleting	MDA-MB-231 xenografts	167	Neuroblastoma	NCT00005835, NCT00002730	I	Completed
	CH004	Inducer	CBS inhibitor	H22 xenografts	227	N/A	N/A	N/A	N/A
	CUR	Inhibitor	GPX4 agonist	DSS-induced UC mice	220	N/A	N/A	N/A	N/A
	DHA	Inhibitor	Inactivating the PRIM2/SLC7A11 axis; suppressing GPX4, ferritinophagy	NCI-H23 xenografts	285	Polycystic ovary syndrome	NCT05465135	IV	Active, not recruiting
	Edaravone	Inhibitor	RTA	CSDS depression model in mouse; particulate Matter-induced lung inflammation model in mouse	377,378	Optic neuritis	NCT05540262	N/A	Recruiting
						Acute ischemic stroke	NCT02430350	III	Completed
						Nasopharyngeal carcinoma, brain necrosis	NCT01865201	II	Completed
						Myocardial infarction	NCT00265239	IV	Completed
						Cerebral infarction	NCT00200356	IV	Completed
						ALS	NCT00415519	III	Completed
	Erastin	Inducer	SLC7A11 inhibitor	A375 melanoma xenografts; Hepa1–6 cells xenografts	34,379	N/A	N/A	N/A	N/A
	Erastin-APAP	Inducer	Nrf2/HO-1 inhibitor	A549 xenografts	185	N/A	N/A	N/A	N/A
	Ferrostatin-1	Inhibitor	RTA	Auranofin-treated Hfe-/- mice; DOX- and I/R-induced cardiomyopathy in mice; hepatic I/R mice; cisplatin-induced AKI mice	3,22,82,268	N/A	N/A	N/A	N/A
	IKE	Inducer	SLC7A11 inhibitor	SUDHL6 xenografts	153	N/A	N/A	N/A	N/A
	Liproxsatain-1	Inhibitor	RTA	MCD-induced NASH in mice; hepatic I/R-induced mice; acute renal failure mice	5,109	N/A	N/A	N/A	N/A
	NAC	Inhibitor	GSH synthesis regulator	Polycystic ovary syndrome model in rats; hemorrhagic stroke in mice; diabetic nephropathy model in beagle; intermittent hypoxia-induced myocardial injury in mic	73,380–382	Drug-resistant epilepsy	NCT05485558	II	Recruiting
						Autism spectrum disorder	NCT04278898	II	Recruiting
						Alcohol use disorder	NCT03707951	II	Recruiting
						Cannabis use disorder	NCT03055377	II, III	Recruiting
						Progressive MS	NCT05122559	II	Recruiting
						Neurofibromatosis 1	NCT04481048	II	Recruiting
						Cocaine addiction	NCT03423667	II	Recruiting
						Cannabis use disorder; tobacco use disorder; drug use disorder	NCT04627922	IV	Recruiting
						Skin disorder	NCT05287724	Early phase 1	Recruiting
						Chronic thromboembolic pulmonary hypertension	NCT04081012	N/A	Recruiting
						Mitochondrial disease	NCT05241262	I	Recruiting
						Diabetic neuropathies	NCT04766450	IV	Recruiting
						Bipolar disorder	NCT05340504	II	Recruiting
						Vascular cognitive impairment no dementia	NCT03306979	II	Recruiting
						Systemic lupus erythematosus (SLE)	NCT00775476	II	Recruiting
						Infertile women with endometrioma	NCT05460858	III	Recruiting
						Gaucher disease type 1	NCT02583672	II	Recruiting
						Alcohol use disorder; bipolar disorder	NCT03220776	II	Recruiting
						Mild cognitive impairment	NCT03493178	Early phase 1	Recruiting
	PE	Inducer	SLC7A11 inhibitor	HT-1080 cell xenografts	13	N/A	N/A	N/A	N/A
	RSL3	Inducer	GPX4 inhibitor	HT-1080 cell xenografts; MCD-induced NASH in mice; HepG2 cell xenografts	13,109,205	N/A	N/A	N/A	N/A
	SAS	Inducer	SLC7A11 inhibitor	Prostate cancer cell DU-145 and PC-3 xenografts; B16F10 melanoma xenografts; glioblastomas xenografts	161,166,168	Glioma; glioblastoma; recurrent glioblastoma	NCT04205357	I	Recruiting
						Breast cancer; chronic pain due to malignancy	NCT03847311	II	Recruiting
	TRG	Inducer	NRF2 inhibitor	HN3R xenografts; Hepa1–6 xenografts	34,204	N/A	N/A	N/A	N/A
	TRG+erastin +sorafenib	Inducer	Inhibiting NRF2 and system Xc-	Hepa1–6 xenografts	34	N/A	N/A	N/A	N/A
	UAMC-3203	Inhibitor	RTA	Ferroptosis model using acute iron poisoning	264	N/A	N/A	N/A	N/A
	WA	Inducer	Alkylation of GPX4	IMR-32 xenografts	202	Recurrent ovarian cancer	NCT05610735	I and II	Not yet recruiting
Lipid metabolism	Baicalein	Inhibitor	ALOX12 inhibitor; ALOX12/ALOX15 inhibitor; ACSL4 inhibitor	Heart I/R injury in rat; transient MCAO mice; myocardial I/R rat	295,296,383	Influenza	NCT03830684	II	Unknown
	IMA-1	Inhibitor	Perturbation of ALOX12-ACC1 interaction	HFHC-treated NASH in mice; spontaneous NASH in Cynomolgus macaques;	258	N/A	N/A	N/A	N/A
	ML355	Inhibitor	ALOX12 inhibitor	HFHC-treated NASH in mice; spontaneous NASH in Cynomolgus macaques	258	N/A	N/A	N/A	N/A
	NDGA	Inhibitor	Pan-LOX inhibitor	HFD-induced fatty liver in obese mice	384	Prostate cancer	NCT00678015	II	Terminated
	Pioglitazone	Inducer	ACSL4 inhibitor	BxPC-3 xenografts; HT-29 and SW480 xenografts	385,386	Breast cancer; muscle fatigue	NCT05013255	II	Recruiting
						Gastroparesis	NCT04300127	Early phase 1	Recruiting
						Chronic kidney diseases	NCT03471117	IV	Recruiting
						Uric acid nephrolithiasis	NCT04370093	IV	Recruiting
						NASH	NCT05254626	IV	Recruiting
						Cocaine use disorder	NCT04843046	II	Recruiting
						Alcohol use disorder	NCT05107765	I, II	Recruiting
	Rosiglitazone	Inducer	ACSL4 inhibitor	I/R-induced intestinal injury mice; renal Gpx4-/- mice	4,15	Solid tumor malignancies	NCT04114136	II	Recruiting
						Prostate cancer	NCT00182052	III	completed
						Ulcerative colitis; inflammatory bowel disease	NCT00065065	II	completed
						HIV infection	NCT00367744	II	completed
						Sarcoma	NCT00004180	II	completed
						Alzheimer’s disease	NCT00688207	I	completed
						NASH	NCT00492700	II	completed
						Kidney transplant	NCT00309309	II	Completed
	PRGL493	Inhibitor	ACSL4 inhibitor	HCG treated mice; MDA-MB-231 and PC-3 xenografts	387	N/A	N/A	N/A	N/A
	Troglitazone	Inducer	ACSL4 inhibitor	MIA Paca2 cells	388	Sarcoma	NCT00003058	II	Completed
	Zileuton	Inhibitor	ALOX5 selective inhibitor	NaIO3-induced acute retinal degeneration in mice	389	Chronic myelogenous leukemia	NCT02047149	I	Terminated
						Chronic myelogenous leukemia	NCT01130688	I	Terminated
						Sickle cell disease	NCT01136941	I	Completed
						Head and neck cancer; lung cancer	NCT00056004; NCT00070486	II	Completed
						Tobacco use disorder	NCT02348203	II	Completed
						Tobacco use disorder	NCT01021215	I, II	Completed
						Acne vulgaris	NCT00098358	II	Unknown

Abbreviations: ACC1 acetyl-CoA carboxylase 1, ACSL4 acyl-CoA synthetase long-chain family member 4, AKI acute kidney injury, ALOX arachidonate lipoxygenase, ALS amyotrophic lateral sclerosis, AOA aminooxyacetic acid, APAP acetaminophen, AUF auranofin, BRD4 bromodomain-containing protein 4, BSO buthionine sulphoximine, CBS cystathionine beta-synthase, CPX ciclopirox, CSDS chronic social defeat stress, CUR curculigoside, DFO deferoxamine, DFP deferiprone, DFX deferasirox, DHA dihydroartemisinin, DHODH dihydroorotate dehydrogenase, DOX doxorubicin, DSS dextran sulfate sodium, DXZ dexrazoxane, Fth1 ferritin heavy chain 1, GCL glutamate-cysteine ligase, GPNA L-g-glutamyl-p-nitroanilide, GSH glutathione, HFD high-fat diet, HFHC high-fat/high-cholesterol, Ho-1 heme oxygenase 1, ICH intracranial hemorrhage, IKE imidazole ketone erastin, I/R ischemia/reperfusion, LPS lipopolysaccharide, MCAO middle cerebral artery occlusion, MCD methionine/choline-deficient diet, MS multiple sclerosis, N/A not applicable, NAC N-acetylcysteine, NASH non-alcoholic steatohepatitis, NCOA4 nuclear receptor coactivator 4, NCT national clinical trial, NDGA nordihydroguaiaretic acid, NOD nonobese diabetic, Nrf2 nuclear factor erythroid 2-related factor 2, PDTC pyrrolidine dithiocarbamate, PDXs patient-derived xenografts, PE piperazine erastin, RSL3 RAS-selective lethal small molecule 3, RTA radical trap antioxidant, SAS sulfasalazine, SCID severe combined immunodeficiency, SLC solute carrier family, UC ulcerative colitis, TRG trigonelline, TXNRD thioredoxin reductase, WA withaferin A