Table 4 Summary of small molecules that target ferroptosis in vivo and in clinical trials

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 Pkd1^RC/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Withdrawn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

^{73,380,381,382}

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