TABLE 3.
Natural products induced ferroptosis.
| Classification | Compounds | Functional targets | Diseases | Test models | Mechanisms/Effects | Refs |
|---|---|---|---|---|---|---|
| Terpenoids | Artemisinin | Iron | Osteosarcoma | D-17 cells | Decreasing iron levels | Isani et al. (2019) |
| Artesunate | NRF2; p62; FTH1; Activating transcript-tion factor 4 (ATF4) | Head and neck cancer (HNC); Pancreatic cancer; Ovarian cancer; Burkitt’s lymphoma; Liver fibrosis | Several HNC/PDAC/ovarian cancer cells and xenograft mice; DAUDI and CA-46 cells and xenograft mice; Mouse HSCs; LX2 cells | Decreasing GSH level; Increasing iron and lipid ROS levels; Increasing GRP78 levels; Inducing ATF4-CHOP-CHAC1 pathway | Eling et al. (2015), Greenshields et al. (2017), Roh et al. (2017), Wang N. et al. (2019), Wang K. et al. (2019), Kong et al. (2019) | |
| Dihydroartemisinin (DHA) | FTH1; GPX4 | Several types of cancers, including glioma, head and neck carcinoma; Acute myeloid leukemia | Dozens of multiple cancer cells; Human umbilical vein endothelial cells (HUVECs), MEFs; U251, U373, HL60, H292 xenograft mice; Patient-derived glioma cells | Inducing lysosomal degradation of ferritin; Inducing iron and ROS accumulation; Inhibiting GPX4 expression; Activating the feedback path of ferroptosis | Chan et al. (2013), Lin et al. (2016), Chen et al. (2019), Du et al. (2019), Chen G. -Q. et al. (2020) | |
| Artemether | Iron | Liver fibrosis | HSC-T6 cells; CCl4-induced hepatic fibrosis model mice | Promoting accumulation of iron and lipid peroxides; Inducing p53-dependent ferroptosis of HSC; Ameliorating CCl4-induced hepatic fibrosis | Wang L. et al. (2019) | |
| Dihydro-isotanshinone I (DT) | GPX4 | Breast cancer | MDA-MB-231 cells; MCF-7 cells and xenograft mice; Patients | Reducing GSH/GSSG ratio and GPX4 activity; Inducing apoptosis and ferroptosis | Lin et al. (2019) | |
| Magnesium isoglycyrrhizinate (MgIG) | HO-1 | Liver fibrosis | CCl4-induced liver fibrosis model rats; HSC-T6 cells | Increasing HO-1, TF, TFRC expression and nuclear abundance; Reducing GSH level and FPN expression; Increasing levels of ROS, iron and lipid peroxides | Sui et al. (2018) | |
| Ferroptocide, a compound from pleuromutilin | Thioredoxin | Many cancer types | A dozen of cancer cell lines and primary cancer cells | Inhibiting thioredoxin; Inducing lipid ROS accumulation | Llabani et al. (2019) | |
| β-elemene | Unknown | Colorectal cancer | HCT116, LOVO, Caco-2 cells; Orthotopic HCT116 mice | Inducing iron-mediated ROS accumulation, GSH depletion, lipid peroxidation; Upregulating HO-1 and TF and downregulating GPX4, FTH1, GLS, SLC7A11, SLC40A1 | Chen et al. (2020e) | |
| Pseudolaric acid B (PAB) | p53; TFRC; NOX4; xCT | Glioblastoma | SHG-44, U87, U251 cells; C6 cells and xenograft mice | Upregulating TFRC and NOX4; Increasing ferrous and lipid peroxidation; Inducing GSH exhaustion by xCT inhibition | Wang Z. et al. (2018) | |
| Flavonoids | Amentoflavone | FTH1; AMPK/mTOR signaling | Glioblastoma | Normal human astrocytes; U373 cells; U251 cells and xenograft mice | Increasing intracellular levels of iron, MDA and lipid ROS; Reducing levels of GSH, FTH1 and the mitochondrial membrane potential | Chen et al. (2020c) |
| Typhaneoside (TYP) | AMPK/mTOR signaling | Acute myeloid leukemia | Kas-1, NB4, K562, 293T cells HL60 cells and xenograft mice | Triggering autophagy by activating AMPK signaling; Inducing ferritin degradation, ROS accumulation and ferroptosis | Zhu et al. (2019) | |
| Polyphenols | Epigallocatechin gallate (EGCG) | HSPA5 | Pancreatic cancer | PANC1, CFPAC1 cells | Inhibiting GPX4 activity; Enhancing erastin-induced MDA production and ferroptosis | Zhu et al. (2017) |
| Gallic acid | GPX4 | Cervical cancer; Lung cancer Neuroblastoma; Breast cancer; Melanoma | HeLa, H446, SH-SY5Y, MDA-MB-231, MCF10A, A375 cells; Human dermal fibroblasts (HDF) | Decreasing GPX4 activity; Promoting ROS generation and lipid peroxidation | Tang and Cheung, (2019), Khorsandi et al. (2020) | |
| Iso-thiocyanates | β-Phenethyl isothiocyanate (PEITC) | MAPK signaling pathway | Osteosarcoma | K7M2, U-2 OS, MG-63, 143B cells; MNNG/HOS cells and xenograft mice; Orthotopic osteosarcoma mice | Triggering ROS accumulation; Inducing GSH depletion | Lv H. -H. et al. (2020), Lv H. et al. (2020) |
| Alkaloids | Trigonelline | NRF2 | Hepatocellular carcinoma; (HCC); HNC | HepG2, SNU-182, Hep3B cells; Hepa1-6 cells and xenograft mice; Several HNC cells; Cisplatin-resistant HNC xenograft mice | Blocking NRF2; Inducing GSH depletion and ROS production; Increasing iron level | Sun et al. (2016a), Shin et al. (2018) |
| Piperlongumine (PL) | GSH; GSTP1; Thioredoxin reductase (TrxR) | Pancreatic cancer | MIAPaCa-2, PANC-1, CFPAC-1, BxPC-3 cells | Increasing ROS level; Decreasing GSH level | Yamaguchi et al. (2018) | |
| Ungeremine | Unknown | Breast cancer; Leukemia; Glioblastoma; Colon cancer; Liver cancer | Several cell models including sensitive and resistant counterparts | Increasing ROS production; Inducing apoptosis, necrosis and ferroptosis | Mbaveng et al. (2019) | |
| Solasonine | GPX4 | HCC | HepRG cells; HepG2 cells and xenograft mice | Inhibiting GPX4 and GSS expressions; Increasing lipid ROS | Jin et al. (2020) | |
| Saponins | Ruscogenin | TF; FPN | Pancreatic cancer | SW 1990, PANC-1, AsPC-1, HPDE6-C7 cells; BxPC-3 cells and xenograft mice | Increasing ferrous irons and ROS production | Song et al. (2020) |
| Ardisiacrispin B | Iron | Leukemia; Breast cancer; Colon cancer; Glioblastoma | Several cell models including sensitive and their resistant counterparts | Increasing ROS production; Inducing ferroptosis and apoptosis | Mbaveng et al. (2018a) | |
| Albiziabioside A derivative, Compounds D13 | p53 | Colon cancer | HCT116 cells and xenograft mice | Activating p53; Reducing mitochondrial membrane potential and GPX4 expression; Inducing ROS production and lipid peroxidation | Wei et al. (2018) | |
| N-acetylglycoside of oleanolic acid (aridanin) | Unknown | Many kinds of cancer | 18 cancer cell lines with sensitive and drug-resistant phenotypes; Metastasizing B16/F10, HepG2, AML12 cells | Increasing ROS levels and mitochondrial membrane potential (MMP) breakdown | Mbaveng et al. (2020) | |
| Steroidal lactone | Withaferin A | GPX4; NRF2 | Neuroblastoma | A dozen of neuroblastoma cells; IMR-32 cells and xenograft mice | Inducing lipid peroxidation; Reducing GPX4 activity; Activating HO-1 | Hassannia et al. (2018) |
| Anthra-quinones | Physcion 8-O-β-glucopyranoside | GLS2 | Gastric cancer | MKN-45 cells; MGC-803 cells and xenograft mice | Increasing levels of ROS, Fe2+ and MDA; Inducing ferroptosis via miR-103a-3p/GLS2 axis | Niu et al. (2019) |
| Bibenzyls | Erianin | Ca2+/CaM signaling | Lung caner | H1299 cells; H460 cells and orthotopic mice | Inducing ROS generation, lipid peroxidation and GSH exhaustion | Chen et al. (2020d) |
| Benzo- phenones | Epunctanone | Unknown | Many kinds of cancer | 9 cancer cell lines including sensitive and drug-resistant cell lines | Increasing ROS levels and MMP breakdown | Mbaveng et al. (2018b) |
| Multiple | Cotylenin A+ PEITC | Unknown | Pancreatic cancer | (resistant)PANC-1, MIAPaCa-2 cells | Inducing ROS production | Kasukabe et al. (2016) |
| Methanolic extract of Betula etnensis Raf. bark | HO-1 | Colon cancer | Caco-2 cells | Increasing ROS and lipid peroxidation; Reducing HO-1 activity | Malfa et al. (2019) | |
| Actinidia chinensis Planch (ACP) | EMT; GPX4; xCT | Gastric cancer | HGC-27 cells and zebrafish xenografts | Inhibiting GPX4 and xCT proteins; Inducing ROS accumulation | Gao et al. (2020) | |
| Bromelain | ACSL4 | Colorectal cancer | Caco-2, NCI-H508, HCT116, DLD1, G13D, G12D cells; DSS-treated KRAS mutant mice | Increasing ACSL4 level, lipid biosynthesis and fatty acid degradation | Park et al. (2018) |