TABLE 1.
The relevance of ferroptosis in diseases.
| Diseases | Disease subtype | Test models | Impact of ferroptosis | Related effects and important findings in diseases | Refs |
|---|---|---|---|---|---|
| Cancer | Head and neck cancer (HNC) | A dozen of HNC cells; HN3R, HN9, HN9R HN10 xenograft mice Normal oral keratinocytes or fibroblasts obtained from patients | Ferroptosis of cancer cells inhibiting diseases | GPX4 inhibitors, (1S, 3R)-RSL 3 and ML-162 induce ferroptosis; Accumulated mitochondrial iron and lipid ROS promote ferroptosis | Roh et al. (2017), Kim et al. (2018), Shin et al. (2018) |
| Breast Cancer | MDA-MB-231, T47D, HCC-1806, BT549, MCF-7(X) cells; TUBO, 4T1 xenograft mice; Patients’ samples | TRFC is a candidate marker of a subgroup of ER+/luminal-like breast cancer with poor outcome and tamoxifen resistance; GPX4-ACSL4 DKO cells show marked resistance to ferroptosis; Siramesine and lapatinib combination increase intracellular iron and ROS levels, and initially induce ferroptosis | Tonik et al. (1986), Habashy et al. (2010), Lanzardo et al. (2016), Ma et al. (2017), Yu et al. (2019) | ||
| Hepatocellular carcinoma (HCC) | A dozen of HCC cells; THLE-3, HL-7702 primary human hepatocytes (PHH); Hepa1-6, Bel-7402 xenograft mice; DEN/CCl4-liver cancer model mice; Patients’ samples | The p62-Keap1-NRF2 pathway prevents ferroptosis and reduced GSH promote ferroptosis in liver cancer cells; Metallothionein-1 (MT-1), which inhibits lipid peroxidation, are associated with drug resistance and reduced overall survival; Ferroptosis inhibits liver tumorgenesis and is suppressed in liver cancer; XCT expression is higher, inversely related to the patient’s overall survival rate and disease-free survival rate | Kinoshita et al. (2013), Sun et al. (2016a), Sun et al. (2016b), Houessinon et al. (2016), Zhang X. et al. (2019), Bai et al. (2019) | ||
| Lung cancer | A dozen of lung cancer cells; Mouse metastatic lung tumors | Lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from ferroptosis; Erastin upregulates p53 and inhibits SLC7A11, which induce ROS accumulation and ferroptosis | Wang S. J.et al. (2016), Alvarez et al. (2017) | ||
| Gastric cancer (GC) | AGS, SGC7901, MGC803, MKN45 cells; BGC823 cells and xenograft mice; Patients’ samples | Cysteine dioxygenase 1 (CDO1) uptakes cysteine competitively, thereby restricting GSH synthesis and promoting ferroptosis; Suppression of CDO1 restores GSH level, prevents ROS production, upregulates GPX4 expression, and ultimately blocks lipid peroxidation and ferroptosis | Hao et al. (2017) | ||
| Colorectal cancer (CRC) | TP53+/+ and TP53−/− HCT116 cells and mice | Loss of p53 restricts the nuclear accumulation of DPP4 and thus facilitates plasma membrane-associated DPP4-dependent lipid peroxidation, which eventually leads to ferroptosis | Xie et al. (2017) | ||
| Pancreatic cancer | MIAPaCa-2, CFPAC-1, BxPC-3, (resistant) PANC-1 cells | Ferroptosis inducer increases ROS production and activates ferroptosis; STAT3 is a positive regulator of ferroptosis and STAT3 silencing blocks erastin-induced ferroptosis | Kasukabe et al. (2016), Gao et al. (2018), Yamaguchi et al. (2018) | ||
| Ovarian cancer | A dozen of ovarian cancer cells; HEY1 and HEY2 spheroids; ID8 cells and xenograft mice; Ovarian cancer cells isolated from patients | IFNγ cooperated with cyst(e)inase to increase lipid peroxidation and induce ferroptosis | Greenshields et al. (2017), Wang W. et al. (2019) | ||
| Melanoma | SK-MEL-28 cells; A375, G-361, B16 cells and xenograft mice; Human melanoma cell lines established from patient biopsies | Inhibition of mitochondrial complex I triggers ROS production, lipid peroxidation and ferroptosis; Melanoma dedifferentiation increases sensitivity to ferroptosis; Depletion of cyst(e)ine and inhibition of system xc − promote lipid peroxidation and ferroptosis; Expression of system xc− is negatively associated with CD8+ T cell signature, IFNγ expression and patient outcome | Basit et al. (2017), Luo et al. (2018), Tsoi et al. (2018), Wang W. et al. (2019) | ||
| Glioblastoma | F98, U87 cells; Glioblastoma patients | NRF2 level is inversely related to clinical outcome and overall survival; Fostered NRF2 expression and conversely Keap1 inhibition promote resistance to ferroptosis | Fan et al. (2017) | ||
| Leukemia | Dozens of leukemia cells; Patient-derived xenografts (PDXs) of leukemia cells | High level of ACSL4 mRNA is expressed and is sensitive to ferroptosis; Low expression of FPN results in the susceptibility via increased iron levels; ROS produced by free ferrous iron leads to increased oxidative stress and ferroptosis | Yuan et al. (2016), Probst et al. (2017), Trujillo-Alonso et al. (2019) | ||
| DLBCL; Renal cell carcinoma (RCC) | Dozens of DLBCL and RCC cells | DLBCL and RCC are particularly susceptible to GPX4-regulated ferroptosis; GPX4 is an essential mediator of ferroptotic cell death | Yang et al. (2014) | ||
| Adrenocortical carcinoma (ACC) | NCI-H295R, HEK cells | Elevated expression of GPX4 and higher sensitivity to ferroptosis are found in ACCs | Belavgeni et al. (2019) | ||
| Neuro-degenerative diseases | Alzheimer’s disease (AD) | AD Patients; Brain tissues from GPX4BIKO mice; Tauopathy model mice | Ferroptosis of useful or functional cells inducing diseases | Iron-induced lipid peroxidation is abnormally elevated in the brain; Cerebrospinal fluid ferritin level is negatively correlated with cognitive ability; Ferroptosis inhibitors prevent neuronal damage | Ayton et al. (2015), Hambright et al. (2017), Zhang Y.-H. et al. (2018) |
| Parkinson’s disease (PD) | PD Patients; LUHMES cells; Human brain tissues; MPTP-induced PD model mice | Iron concentration in the SN is related to the degree of disease progression and DFP improves related symptoms; Levels of MDA and lipid hydroperoxide are increased in the SN. | Devos et al. (2014), Pyatigorskaya et al. (2015), Do Van et al. (2016) | ||
| Huntington’s disease (HD) | R6/2 HD mice; HD Patients | Plasma MDA, 4-hydroxynonenal (4-HNE) and lipid peroxidation are increased; IRPs 1/2, TFRC and GPX are decreased and FPN is increased | Klepac et al. (2007), Lee et al. (2011), Chen et al. (2013) | ||
| Periventricular leukomalacia (PVL) | Oligodendrocytes | Fer-1 increases the number of healthy spinous neurons and inhibits oxidized lipid damage and ferroptosis | Skouta et al. (2014) | ||
| Brain diseases | Neonatal brain injury | Organotypic hippocampal slice cultures (OHSCs); Neonatal hypoxia-ischemia rats | Free iron is accumulated, TFRC expression is increased and ferritin expression is reduced | Lu et al. (2015) | |
| Traumatic Brain Injury (TBI) | TBI model HT22 cells; TBI model mice | AA/AdA-PE are increased; ALOX15, ACSL4 and GSH are exhausted; Ferroptosis inducers and mechanical stretch injury cause cell death | Kenny et al. (2019) | ||
| Secondary brain injury (SBI) | Mouse brain astrocytes; ICH rats | GPX4 is downregulated in brain after ICH; GPX4 contributes to SBI following ICH by mediating ferroptosis; Induction of NRF2 expression serves as an adaptive self-defense mechanism | Cui et al. (2016), Zhang Z. et al. (2018) | ||
| Intracerebral hemorrhage (ICH) | ICH mice; OHSCs; Human induced pluripotent stem cell (iPSC)-derived neurons | Fer-1 reduces iron accumulation, prostaglandin-endoperoxide synthase 2 (PTGS2) expression, lipid ROS and protects hemorrhagic brain from neuronal death | Li et al. (2017) | ||
| Cerebral ischemia | MCAO mice and rats; Transient forebrain ischemia (TRI) rats | Ferritin, TFRC and iron accumulation are increased, and infarct focus is strengthened; The leaking blood-brain barrier (BBB) increases the iron level; Targeting iron-mediated oxidative stress holds extended therapeutic time window against an ischemic event | Park et al. (2011), Tuo et al. (2017) | ||
| Heart diseases | Ischemia-reperfusion (I/R) | Isolated hearts of mice; Cardiomyocytes | GSH level is significantly reduced and ROS level is increased; Inhibition of glutamate breakdown reduces I/R-induced heart damage; DFO improves function and reduces in myocardial infarcts size | Gao et al. (2015), Baba et al. (2018), Fang et al. (2019) | |
| Heart failure | Isolated adult cardiomyocytes; FPN knockout mice; Mice with cardiomyocyte-specific deletion of FTH1, hepcidin, or knock-in of hepcidin-resistant FPN | DXZ relieves myocardial toxicity; FTH1 deficiency leads to a decrease in cardiac iron level and an increase in oxidative stress; FPN knockout causes iron deposits in the myocardium and impairs cardiac function | Lakhal-Littleton et al. (2015), Lakhal-Littleton et al. (2016), Fang et al. (2020) | ||
| Inflammation | Several immune deficient mice; Heart transplantation mice | Ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through TLR4/TRIF signaling pathway, which inhibited by Fer-1 | Li W. et al. (2019) | ||
| Atherosclerosis | Overexpressing GPX4 and control Apolipoprotein E (ApoE)−/− mice | Iron accumulation causes ROS accumulation and death in macrophages; Increased antioxidant capacity can reduce the ferroptosis of macrophages; GPX4 overexpression inhibits plaque formation by inhibiting oxidized lipid modification and reduces mid-advanced aortic sinus lesions | Guo et al. (2008) | ||
| Blood diseases | Hemolysis | J774 cells; RBC transfusion and clearance model mice | Increased red blood cells (RBCs)through phagocytosis lead to iron degeneration, ROS accumulation and lipid peroxidation in splenic red plasma macrophage (RPMs), which can be ameliorated by Fer-1; Ferroptosis may be clinically relevant to transfusion-related immunomodulation and impaired host immunity | Youssef et al. (2018) | |
| Hereditary hemo-chromatosis (HH) | Primary hepatocytes; Bone marrow-derived macrophage (BMDMs); SLC7A11−/− mice; HH model mice | Iron overload is sufficient to trigger ferroptosis both in vitro and in vivo; SLC7A11 confers protection against ferroptosis during iron overload; SLC7A11 depletion facilitates ferroptosis onset specifically under high-iron conditions | Wang et al. (2017a) | ||
| Lung diseases | Chronic obstructive pulmonary (COPD) | Human bronchial epithelial cells (HBECs); BEAS-2B, A549 cells; GPX4 deficient or transgenic mice | Cigarette triggers NCOA4-mediated ferritinophagy; Iron accumulation and lipid peroxidation are increased, which can be reversed by GPX4 knockout, DFO and Fer-1 | Yoshida et al. (2019) | |
| Pulmonary I/R | Pulmonary I/R model mice; Hypoxia-reoxygenation model A549 cells | ACSL4 expression is enhanced and GPX4 expression is reduced; Ferroptotic features emerge after lung I/R injury, which is prevented by liproxstatin-1 (Lip-1) | Xu et al. (2020) | ||
| Liver diseases | Acute liver failure | ACSL4 KO mice; acetaminophen (APAP)-induced acute liver failure mice | APAP administration induces hepato-toxicity, lipid peroxidation, PTGS2 upregulation and GSH depletion, which are markedly suppressed by Fer-1and DFO. | Yamada et al. (2020b), Yamada et al. (2020c) | |
| Non-alcoholic steatohepatitis (NASH) | Several NASH model mice; CCl4 induced liver injury mice | Enhanced AA metabolism, iron-mediated lipid ROS accumulation, mitochondrial morphological changes are alleviated by ferroptosis inhibitors | Tsurusaki et al. (2019), Li X. et al. (2020) | ||
| Alcoholic liver disease (ALD) | ALD patients | Serum hepcidin is decreased; Iron, ferritin and FPN are upregulated | Dostalikova-Cimburova et al. (2014) | ||
| Hepatic I/R; Living donor liver transplantation (LDLT) | Hepatic I/R model mice; Hepatic I/R injury in pediatric LDLT | A high serum ferritin level, a marker of iron overload, is an independent risk factor for liver damage after LT; Liver damage, lipid peroxidation, and upregulation of PTGS2 are induced by I/R | Yamada et al. (2020a) | ||
| Pancreas diseases | Diabetes mellitus and its complications | NRK-52E cells; Type 2 diabetes (T2DM) mice; Diabetic nephropathy mice | Depleted GSH and downregulated GPX4 induce oxidative stress in pancreatic tissue of T2DM molding; ACSL4 is increased and GPX4 is decreased in DN mice | Li D. et al. (2020), Wang et al. (2020) | |
| Gastrointestinal diseases | Intestinal I/R | Caco-2 cells; Intestinal I/R model mice | ACSL4 and cyclooxygenase 2 (COX2) are increased while GPX4 and FTH1 are reduced in I/R-induced intestinal injury | Li Y. et al. (2019) | |
| Crohn’s disease (CD) | GPX4 deficient intestinal epithelial cells (IECs); GPX4+/−IEC mice; CD patients | IECs in CD exhibit impaired GPX4 activity and signs of lipid peroxidation | Mayr et al. (2020) | ||
| Kidney diseases | Acute kidney injury; Acute renal failure (ARF) | Human renal proximal tubule epithelial cells (HRPTEpiCs); GPX4−/− Pfa1 cells; GPX4−/− mice | Mitochondrial lipid phosphatidylcholine (PC), PE and cardiolipin are heavily oxidized; Ferroptosis inhibitor, SRS16-86 strongly protects kidneys | Friedmann Angeli et al. (2014), Skouta et al. (2014) | |
| Immune diseases | Immune disorders | GPX4-deficient T cells; T cell-specific GPX4 deficient mice; Peripheral blood mononuclear cell (PBMCs) | GPX4 deficiency causes T cells to fail to protect against viruses and infections, which can be rescued by vitamin E; Rapid accumulation of membrane lipid peroxides induces ferroptosis; Erastin-induced lipid peroxidation promotes PBMCs proliferation and differentiation into B cells and natural killer cells | Matsushita et al. (2015), Wang D. et al. (2018) | |
| Other diseases | Age-related macular degeneration (AMD) | ARPE-19 cells | Oxidative stress-mediated senescence upon GSH depletion and subsequent death of photoreceptors are observed in AMD. | Sun et al. (2018) |