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Oxeiptosis: A Cell Death Pathway That Reduces Free Radical Damage

Cell Programmed Death Cell Death & Disease Oxidative Stress Cellular Stress

Oxeiptosis is a ROS-sensitive, caspase-independent, non-inflammatory cell-death pathway that mitigates damage caused by radicals. It was defined after studies showed that ROS-induced cell death was not blocked by canonical ROS-sensing pathways or known cell-death pathways, but required interactions among KEAP1, PGAM5, and AIFM1. This positioned oxeiptosis as a regulated oxidative-stress response linking free radical damage, pathogen exposure, tissue inflammation, and cell-death biology[1][2][3].

Mechanistically, oxeiptosis uses KEAP1 as a ROS sensor, PGAM5 as a mitochondrial phosphatase, and AIFM1 as the downstream death effector. Under high ROS, KEAP1 releases PGAM5, PGAM5 dephosphorylates AIFM1 at Ser116, and cells undergo apoptosis-like death without caspase dependence. In ozone exposure and influenza A virus infection models, loss of PGAM5 increased lung inflammation, cytokine expression, viral infiltration, lymphocytic bronchiolitis, and mortality, supporting oxeiptosis as a protective non-inflammatory way to terminate ROS-damaged cells[1][2][3].

Disease applications now include infection-associated oxidative injury, inflammatory lung disease, vitiligo, neurodegeneration, and cancer therapy. In vitiligo models, oxidative stress induced melanocyte death through KEAP1-PGAM5-AIFM1 signaling and AIFM1 Ser116 dephosphorylation. In colorectal cancer, sanguinarine induced ROS-dependent oxeiptosis through KEAP1-PGAM5-AIFM1 signaling, and knockdown of KEAP1, PGAM5, or AIFM1 reduced this cytotoxic effect. In Alzheimer’s disease research, the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway has been linked to neuronal cell death under oxidative stress[4][5][6].

Key gaps include limited disease validation, incomplete downstream mapping after AIFM1 dephosphorylation, few selective pharmacological tools, and uncertain boundaries between oxeiptosis, apoptosis-like death, ferroptosis, necroptosis, and general oxidative toxicity. Future studies should define cell-type-specific thresholds for ROS-induced oxeiptosis, develop biomarkers for AIFM1 Ser116 dephosphorylation, test KEAP1-PGAM5-AIFM1 modulation in inflammatory and degenerative disease, and evaluate whether pro-oxeiptotic therapy can kill cancer cells without increasing tissue injury[1][3][4][5][6].

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Cat. No. Product Name Information Application Publication
HY-16658B Z-VAD-FMK
Z-VAD-FMK is a pan-caspase inhibitor and also an ICE-like protease inhibitor, which inhibits apoptosis by preventing the processing of CPP32 to its active form. Z-VAD-FMK sensitivity varies primarily due to differential expression of receptor-interacting protein 1 (RIP1). Z-VAD-FMK limits the cryopreservation-induced apoptosis by reducing caspase-3 activity of in vitro produced bovine embryos. Z-VAD-FMK is immunosuppressive in vitro and inhibits T cell proliferation without blocking the processing of caspase-8 and caspase-3. Z-VAD-FMK leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. Z-VAD-FMK is due to oxidative stress via the depletion of GSH. Z-VAD-FMK can be used for the study of acute pancreatitis.
Caspase   Apoptosis   RIP kinase   Glutathione Peroxidase   Reactive Oxygen Species (ROS)  
Cancer   Digestive System Disease   Pancreatitis  
850
HY-100523 ML385
ML385 is a potent and selective Nrf2 inhibitor with an IC50 of 1.9 μM. ML385 directly binds to the Neh1 domain of NRF2, interferes with the binding of the MAFG-NRF2 protein complex to the antioxidant response element (ARE) DNA sequence, thereby blocking the expression of downstream target genes of NRF2. ML385 can be used in studies related to adult T-cell leukemia, breast cancer, myocardial ischemia/reperfusion injury, non-small cell lung cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma.
Keap1-Nrf2   Ferroptosis   Apoptosis   mTOR  
Breast Cancer   Colorectal Cancer   Cardiovascular Disease   Non-Small Cell Lung Cancer   Lung Squamous Cell Carcinoma   Squamous Cell Carcinoma   Esophageal Cancer  
644
HY-100218A RSL3
RSL3 ((1S,3R)-RSL3) is an inhibitor of glutathione peroxidase 4 (GPX4) (ferroptosis activator), reduces the expression of GPX4 protein, and induces ferroptotic death of head and neck cancer cell. RSL3 increases the expression of p62 and Nrf2 and inactivates Keap1 in HN3-rslR cells.
p62   Glutathione Peroxidase   Ferroptosis   Reactive Oxygen Species (ROS)  
Ovarian Cancer  
573
HY-16658 Z-VAD(OMe)-FMK
Z-VAD(OMe)-FMK (Z-Val-Ala-Asp(OMe)-FMK) is a cell-permeable and irreversible pan-caspase inhibitor. Z-VAD(OMe)-FMK is an ubiquitin carboxy-terminal hydrolase L1 (UCHL1) inhibitor. Z-VAD(OMe)-FMK irreversibly modifies UCHL1 by targeting the active site of UCHL1.
Caspase  
Cancer  
211
HY-13205 Belnacasan
Belnacasan (VX-765) is an orally bioactive proagent of VRT-043198, which is a potent and selective inhibitor of IL-converting enzyme (ICE)/caspase-1 with Kis of 0.8 nM and less than 0.6 nM for caspase-1 and caspase-4, respectively. Belnacasan (VX-765) inhibits the release of LPS-induced IL-1β and IL-18 by human PBMCs with an IC50 of ~0.7 μM.
Caspase  
Inflammation or Immune System Disease   Depression   Pain  
180
HY-16561 Resveratrol
Resveratrol (trans-Resveratrol; SRT501) is a CNS-penetrant natural polyphenolic phytoalexin that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. Resveratrol (SRT 501) has a wide spectrum of targets including mTOR, JAK, β-amyloid, Adenylyl cyclase, IKKβ, DNA polymerase. Resveratrol also is a specific SIRT1 activator. Resveratrol is a potent pregnane X receptor (PXR) inhibitor. Resveratrol is an Nrf2 activator, ameliorates aging-related progressive renal injury in mice model. Resveratrol increases production of NO in endothelial cells.
DNA/RNA Synthesis   IKK   Autophagy   Mitophagy   Sirtuin   Apoptosis   Bacterial   Fungal   Antibiotic   Keap1-Nrf2  
Neurological, Eye or Ear Disease   Prostate Cancer   Liver Cancer   Bacterial Infection   Fungal Infection   Digestive System Inflammation   Glucose Metabolism   SARS-CoV-2 Infection   Obesity   Lung Fibrosis  
174
HY-100573 Necrosulfonamide
Necrosulfonamide is a MLKL and Gasdermin D (GSDMD) inhibitor, capable of separately inhibiting necroptosis and pyroptosis of cells. Necrosulfonamide does not affect the activation of upstream signals, but specifically inhibits the downstream executor oligomerization step. Necrosulfonamide reduces the expression of the key kinases NLRP3 and caspase-1 involved in necroptosis and pyroptosis, activate the Nrf2 pathway and the downstream antioxidant enzymes, and also downregulates a variety of inflammatory factors. Necrosulfonamide plays significant roles in various diseases such as neurodegenerative diseases (such as Parkinson’s disease), tissue damage and ischemia-reperfusion injury, inflammatory bowel disease, osteoarthritis and fracture repair, and hair loss by regulating two important programmed necrosis pathways.
Mixed Lineage Kinase   Necroptosis   Pyroptosis   Caspase   NOD-like Receptor (NLR)   Keap1-Nrf2   TNF Receptor   Interleukin Related   NO Synthase   Heme Oxygenase (HO)  
Digestive System Disease   Prostate Cancer   Leukemia/Lymphoma/Myeloma   Depression   Digestive System Inflammation   Cardiovascular Disease   Parkinson's Disease   Obesity   Lung Fibrosis   Rheumatoid Arthritis  
147
HY-12466 Z-DEVD-FMK
Z-DEVD-FMK is a specific and irreversible caspase-3 inhibitor with an IC50 of 18 μM.
Caspase  
Cancer   Neurodegenerative Disease  
139
HY-N0005 Curcumin
Curcumin (Diferuloylmethane), a natural phenolic compound, is a p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. Curcumin is a photosensitizer against microorganisms. Curcumin shows inhibitory effects on NF-κB and MAPKs, and has diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification.
Histone Acetyltransferase   Epigenetic Reader Domain   Keap1-Nrf2   Autophagy   Mitophagy   Influenza Virus   Ferroptosis   Apoptosis  
Prostate Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Viral Infection   Pain   Digestive System Inflammation   Glucose Metabolism   Metastatic Breast Cancer   SARS-CoV-2 Infection   Obesity   Lung Fibrosis  
138
HY-100489 TBHQ
TBHQ (tert-Butylhydroquinone) is a widely used Nrf2 activator, protects against Doxorubicin (DOX)-induced cardiotoxicity through activation of Nrf2. TBHQ (tert-Butylhydroquinone) is also an ERK activator; rescues Dehydrocorydaline (DHC)-induced cell proliferation inhibitionin melanoma.
Environmental Pollutants   Autophagy   ERK   Ferroptosis   Keap1-Nrf2   Apoptosis  
Cancer   Digestive System Disease   Depression   Pain   Digestive System Inflammation   Obesity   Lung Fibrosis  
131
HY-12305 Q-VD-OPh
Q-VD-OPh is an irreversible pan-caspase inhibitor with potent antiapoptotic properties; inhibits caspase 7 with an IC50 of 48 nM and 25-400 nM for other caspases including caspase 1, 3, 8, 9, 10, and 12. Q-VD-OPh can inhibits HIV infection. Q-VD-OPh is able to cross the blood-brain barrier.
Caspase   HIV  
Leukemia/Lymphoma/Myeloma   Viral Infection   Alzheimer's Disease  
117
HY-19696 Tauroursodeoxycholate
Tauroursodeoxycholate (Tauroursodeoxycholic acid) is an orally active endoplasmic reticulum (ER) stress inhibitor. Tauroursodeoxycholate significantly reduces expression of apoptosis molecules, such as caspase-3 and caspase-12. Tauroursodeoxycholate also inhibits ERK.
ERK   Caspase   Endogenous Metabolite   Apoptosis  
Colorectal Cancer   Prostate Cancer   Liver Cancer   Viral Infection   Neurodegenerative Disease   Pain   Digestive System Inflammation   Glucose Metabolism   Obesity  
111
HY-112675 4-Octyl itaconate
4-Octyl Itaconate is a cell-permeable Itaconate derivative. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.
Keap1-Nrf2  
Inflammation or Immune System Disease   Obesity   Lung Fibrosis  
98
HY-N0162 Luteolin
Luteolin (Luteoline), a flavanoid compound, is a potent Nrf2 inhibitor. Luteolin has anti-inflammatory, anti-cancer properties, including the induction of apoptosis and cell cycle arrest, and the inhibition of metastasis and angiogenesis, in several cancer cell lines, including human non-small lung cancer cells.
Keap1-Nrf2   Apoptosis   Autophagy   Endogenous Metabolite  
Lung Cancer   Colorectal Cancer   Ovarian Cancer   Digestive System Inflammation   Glucose Metabolism   Obesity  
96
HY-13755 Sulforaphane
Sulforaphane is an orally active inducer of the Keap1/Nrf2/ARE pathway. Sulforaphane promotes the transcription of tumor-suppressing proteins and effectively inhibits the activity of HDACs. Through the activation of the Keap1/Nrf2/ARE pathway and further induction of HO-1 expression, Sulforaphane protects the heart. Sulforaphane suppresses high glucose-induced pancreatic cancer through AMPK-dependent signal transmission. Sulforaphane exhibits both anticancer and anti-inflammatory properties.
HDAC   Keap1-Nrf2   Apoptosis   Bcl-2 Family   Caspase   Reactive Oxygen Species (ROS)  
Inflammation or Immune System Disease  
79
HY-112654 GCN2iB
GCN2iB is an ATP-competitive, selective GCN2 inhibitor with an IC50 of 2.4 nM. GCN2iB inhibits the activation of the GCN2 pathway and upregulates GPX4. GCN2iB enhances the anticancer effect of ASNase against acute lymphoblastic leukemia. GCN2iB increases left ventricular ejection fraction, while reducing fasting blood glucose and myocardial fibrosis. GCN2iB can be used in research related to acute lymphoblastic leukemia, acute myeloid leukemia and diabetic cardiomyopathy.
Eukaryotic Initiation Factor (eIF)   Glutathione Peroxidase  
Glucose Metabolism   Acute Myeloid Leukemia   Acute Lymphoblastic Leukemia   Cardiomyopathy  
65
HY-17363 Dimethyl fumarate
Dimethyl fumarate (DMF) is an orally active and brain-penetrant Nrf2 activator and induces upregulation of antioxidant gene expression. Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway, and also induces cell autophagy. Dimethyl fumarate can be used for multiple sclerosis research.
Keap1-Nrf2   Reactive Oxygen Species (ROS)   HIV   Autophagy   Endogenous Metabolite  
Neurological, Eye or Ear Disease   Inflammation or Immune System Disease   Colorectal Cancer   Viral Infection   Obesity   Lung Fibrosis  
65
HY-B1081A Oxidopamine hydrobromide
Oxidopamine (6-OHDA) hydrobromide is an antagonist of the neurotransmitter dopamine. Oxidopamine hydrobromide is a widely used neurotoxin and selectively destroys dopaminergic neurons. Oxidopamine hydrobromide promotes COX-2 activation, leading to PGE2 synthesis and pro-inflammatory cytokine IL-1β secretion. Oxidopamine hydrobromide can be used for the research of Parkinson’s disease (PD), attention-deficit hyperactivity disorder (ADHD), and Lesch-Nyhan syndrome.
Dopamine Receptor   Autophagy   Mitophagy   COX   PGE synthase   Interleukin Related   p38 MAPK   Apoptosis   Caspase  
Breast Cancer   Parkinson's Disease  
50
HY-14654 Aspirin
Aspirin (Acetylsalicylic acid) is an orally active, potent and irreversible inhibitor of cyclooxygenase COX-1 and COX-2, with IC50 values of 5 and 210 μg/mL, respectively. Aspirin induces apoptosis. Aspirin inhibits the activation of NF-κB. Aspirin also inhibits platelet prostaglandin synthetase, and can prevent coronary artery and cerebrovascular thrombosis.
Environmental Pollutants   Apoptosis   Virus Protease   NF-κB   Mitophagy   p38 MAPK   Autophagy   COX   Caspase  
Breast Cancer   Colorectal Cancer   Prostate Cancer   Liver Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Ovarian Cancer   Viral Infection   Neurodegenerative Disease   Depression   Pain   Digestive System Inflammation   Cardiovascular Disease   Non-Small Cell Lung Cancer   SARS-CoV-2 Infection   Obesity   Rheumatoid Arthritis  
38
HY-100003 ML-210
ML-210 is a selective and covalent glutathione peroxidase 4 (GPX4) inhibitor with an EC50 of 30 nM. ML-210 binds the GPX4 selenocysteine residue. ML-210 has anti-cancer activity.
Glutathione Peroxidase   Ferroptosis  
Ovarian Cancer  
33
HY-12212 Omaveloxolone
Omaveloxolone (RTA 408) is an antioxidant inflammation modulator (AIM), which activates Nrf2 and suppresses nitric oxide (NO). Omaveloxolone attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling.
Keap1-Nrf2   STING   Apoptosis  
Cancer   Digestive System Disease   Digestive System Inflammation   Obesity   Lung Fibrosis  
26
HY-14909 Bardoxolone
Bardoxolone (CDDO; RTA 401) is a Nrf2 activator. Bardoxolone shows anti-SARS-CoV-2 3CLpro with IC50 of 27.99 μM. Bardoxolone activates the Nrf2 pathway and inhibits the NF-κB pathway. Bardoxolone can induce cells differentiation, apoptosis and shows antiproliferative activity against cancer cells. Bardoxolone can increase ROS and decrease intracellular GSH levels. Bardoxolone inhibits Z-VAD-FMK (HY-16658B)-induced necroptosis. Bardoxolone can be used for the research of cancer, inflammation and infection, such as SARS-CoV infection and glioblastoma.
Keap1-Nrf2   NF-κB   SARS-CoV   Apoptosis   Reactive Oxygen Species (ROS)   Glutathione Peroxidase   Necroptosis  
Inflammation or Immune System Disease   Glioblastoma   SARS-CoV-2 Infection  
25
HY-N0171A Beta-Sitosterol (purity>98%)
Beta-Sitosterol (purity>98%) is orally active. Beta-Sitosterol exhibits multiple activities, including anti-inflammatory, anticancer, antioxidant, antimicrobial, antidiabetic, antioxidant enzyme, and analgesic. Beta-Sitosterol inhibits inflammation and impaired adipogenesis in bovine mammary epithelial cells by reducing levels of ROS, TNF-α, IL-1β, and NF-κB p65 and restoring the activity of the HIF-1α/mTOR signaling pathway. Beta-Sitosterol induces apoptosis in cancer cells through ROS-mediated mitochondrial dysregulation and p53 activation. Beta-Sitosterol exerts its anticancer effects in cancer cells by activating caspase-3, caspase-8, and caspase-9, mediating PARP inactivation, MMP loss, altered Bcl-2-Bax ratio, and cytochrome c release. Beta-Sitosterol modulates macrophage polarization and reduces rheumatoid inflammation in mice. Beta-Sitosterol inhibits tumor growth in multiple mouse cancer models. Beta-Sitosterol can be used in the research of arthritis, lung cancer, breast cancer and other cancers, diabetes, etc.
Bacterial   Apoptosis   Reactive Oxygen Species (ROS)   MDM-2/p53   Caspase   PARP   MMP   Bcl-2 Family   HIF/HIF Prolyl-Hydroxylase   TNF Receptor   Interleukin Related   NF-κB   mTOR   Lactate Dehydrogenase   CDK   Glutathione Peroxidase   SOD  
Lung Cancer   Breast Cancer   Prostate Cancer   Liver Cancer   Leukemia/Lymphoma/Myeloma   Pancreatic Cancer   Ovarian Cancer   Bacterial Infection   Depression   Pain   Digestive System Inflammation   Cardiovascular Disease   Glucose Metabolism   Obesity   Lung Fibrosis   Rheumatoid Arthritis  
24
HY-100002 ML162
ML162 is a covalent glutathione peroxidase 4 (GPX4) inhibitor. ML162 has a selective lethal effect on mutant RAS oncogene-expressing cell lines
Glutathione Peroxidase   Ferroptosis  
Ovarian Cancer  
18
HY-112005 DOPE
DOPE (Dioleoylphosphatidylethanolamine; 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine) is an orally active inhibitor of ferroptosis with anti-inflammatory and intestinal barrier maintenance activities. DOPE regulates the expression of ACSL4, SLC7A11 and GPX4 to restore the redox system balance, thereby reducing the levels of lipid peroxides, iron ions and intestinal inflammatory factors (IL-1β and IL-6). DOPE promotes the migration and proliferation of intestinal epithelial cells and increases the level of tight junction proteins; it also destabilizes endosomal membranes, mediates the conjugation of RVG peptides with mesenchymal stem cell-derived exosomes to enhance brain targeting. DOPE can be applied to research related to neonatal necrotizing enterocolitis and Alzheimer's disease.
Liposome   Endogenous Metabolite   ACSL Family   Amino acid Transporter   Ferroptosis   Glutathione Peroxidase  
Cancer   Inflammation or Immune System Disease  
14
HY-B0388 Probucol
Probucol (DH-581) is an anti-hyperlipidemic agent. Probucol activates glutathione peroxidase. Probucol promotes low density lipoprotein (LDL) catabolism, inhibits ABCA1-dependent cholesterol efflux, and decreases HDL-C levels. Probucol also has anti-inflammatory, antioxidant and neuroprotective properties. Probucol can be used for researches on bone, cardiovascular, cancer, neurological, and metabolism-related diseases.
Virus Protease   Apoptosis   Reactive Oxygen Species (ROS)   Glutathione Peroxidase   Caspase  
Cancer   Neurological, Eye or Ear Disease   Digestive System Disease   Viral Infection   Digestive System Inflammation   Glucose Metabolism  
5
HY-Y0669 Pipecolic acid
Pipecolic acid is an orally bioavailable, blood-brain barrier-permeable metabolite of lysine with antioxidant, inhibitor, and inducer activity. Pipecolic acid modulates the YAP-GPX4 signaling pathway, reduces retinal vascular tube formation, and mitigates ferroptosis. Pipecolic acid potentiates voltage-sensitive Ca2+ channel currents and induces neuronal apoptosis. Pipecolic acid can be used for the research of diabetic retinopathy.
Endogenous Metabolite   YAP   Glutathione Peroxidase   Ferroptosis  
Neurological, Eye or Ear Disease   Inflammation or Immune System Disease   Metabolic or Endocrine Disease  
2

Keywords

oxeiptosis, ROS-induced cell death, free radical damage, KEAP1, PGAM5, AIFM1, oxidative stress, non-inflammatory cell death