Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0034)
Name
Apigenin
Synonyms
apigenin; 520-36-5; 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one; Versulin; Apigenol; 4',5,7-Trihydroxyflavone; Chamomile; Spigenin; Apigenine; C.I. Natural Yellow 1; Pelargidenon 1449; 5,7,4'-Trihydroxyflavone; 5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one; 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; NSC 83244; 2-(p-Hydroxyphenyl)-5,7-dihydroxychromone; 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-benzopyrone; 4H-1-Benzopyran-4-one, 5,7-dihydroxy-2-(4-hydroxyphenyl)-; UCCF 031; CCRIS 3789; FLAVONE, 4',5,7-TRIHYDROXY-; CHEBI:18388; EINECS 208-292-3; MFCD00006831; NSC-83244; UNII-7V515PI7F6; APEGENIN; BRN 0262620; 8002-66-2; Chamomile oil, german; DTXSID6022391; HSDB 7573; 7V515PI7F6; CHEMBL28; PELARGIDENON-1449; CI NATURAL YELLOW 1; DTXCID902391; UCCF-031; 5-18-04-00574 (Beilstein Handbook Reference); NSC83244; CAS-520-36-5; LY-080400; 4',5,7-Trihydroxyflavone;Apigenol;C.I. Natural Yellow 1; SMR000326850; 4?5,7-Trihydroxyflavone; SR-01000075663; Pelargidenone; 4der; 4dgm; 4hkk; Naringenin, 18; 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; 4',5,7-Trihydroxyflavone; Pelargidenon 1449;; Prestwick_719; Apigenin, 13; Tocris-1227; 3cf9; ST056301; APIGENIN [HSDB]; APIGENIN [INCI]; 4',7-Trihydroxyflavone; APIGENIN [MI]; BiomolKI_000078; Prestwick0_000414; Prestwick1_000414; Prestwick2_000414; Prestwick3_000414; Spectrum2_000428; Spectrum3_001882; Spectrum4_001999; Lopac-A-3145; APIGENIN [USP-RS]; APIGENIN [WHO-DD]; BiomolKI2_000082; 4,5, 7-Trihydroxyflavone; Lopac0_000065; Oprea1_622293; SCHEMBL19428; 4',5,7-trihydroxy-Flavone; Apigenin, analytical standard; BSPBio_000368; BSPBio_003384; KBioGR_002565; SPECTRUM200846; MLS000697626; MLS000859991; MLS001074874; MLS006011839; BIDD:ER0135; DivK1c_000798; SCHEMBL222227; SPBio_000416; SPBio_002307; ghl.PD_Mitscher_leg0.1194; BDBM7458; BPBio1_000406; GTPL4136; MEGxp0_000176; ACon1_002450; cid_5280443; HMS502H20; KBio1_000798; KBio3_002887; NINDS_000798; Bio1_000376; Bio1_000865; Bio1_001354; HMS1569C10; HMS1922P22; HMS2096C10; HMS2230D17; HMS3260M11; HMS3267D21; HMS3373B18; HMS3412A08; HMS3561P09; HMS3655D18; HMS3676A08; HMS3866D03; Apigenin, >=95.0% (HPLC); BCP28288; HY-N1201; Tox21_201542; Tox21_302884; Tox21_500065; Apigenin; 4',5,7-Trihydroxyflavone; BBL010499; CCG-40061; HB0117; HSCI1_000221; LMPK12110005; NSC815095; s2262; STK801630; ZB1873; AKOS002140699; AC-8011; CS-5432; DB07352; LP00065; ND-9076; NSC-815095; SDCCGMLS-0066379.P001; SDCCGSBI-0050053.P003; IDI1_000798; SMP2_000338; Apigenin, >=97% (TLC), from citrus; NCGC00015049-01; NCGC00015049-02; NCGC00015049-03; NCGC00015049-04; NCGC00015049-05; NCGC00015049-06; NCGC00015049-07; NCGC00015049-08; NCGC00015049-09; NCGC00015049-10; NCGC00015049-11; NCGC00015049-12; NCGC00015049-13; NCGC00015049-14; NCGC00015049-15; NCGC00015049-16; NCGC00015049-18; NCGC00015049-28; NCGC00025057-01; NCGC00025057-02; NCGC00025057-03; NCGC00025057-04; NCGC00025057-05; NCGC00025057-06; NCGC00025057-07; NCGC00025057-08; NCGC00025057-09; NCGC00169835-01; NCGC00169835-02; NCGC00169835-03; NCGC00256419-01; NCGC00259092-01; NCGC00260750-01; LY080400; NCI60_041830; SY005957; TS-00897; APIGENIN (CONSTITUENT OF CHAMOMILE); LY 080400; EU-0100065; FT-0622445; FT-0623582; FT-0662251; SW196866-2; A 3145; C01477; K00045; M01289; O11338; Apigenin 100 microg/mL in Acetonitrile:Methanol; Apigenin, >=97% (TLC), from parsley, powder; Biochem Biophys Res Comm 212: 767 (1997); EN300-7382221; 5,7-dihydroxy-2-(4-hydroxyphenyl)-chromen-4-one; A828903; APIGENIN (CONSTITUENT OF CHAMOMILE) [DSC]; Apigenin, primary pharmaceutical reference standard; Q424567; 2-(P-HYDROXYPHENYL)-5,7-DIHYDROXY-CHROMONE; 4 inverted exclamation mark ,5,7-trihydroxyflavone; Q-100586; Q-200822; SR-01000075663-1; SR-01000075663-3; SR-01000075663-7; SR-01000075663-8; BRD-K01493881-001-10-4; BRD-K01493881-001-17-9; 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one #; Z1741982550; 4H-1-Benzopyran-4-one,7-dihydroxy-2-(4-hydroxyphenyl)-; D50A2D8A-6D8B-4708-B21E-2DE9580D033F; Apigenin, United States Pharmacopeia (USP) Reference Standard; 4H-1BENZOPYRAN-4-ONE,5,7-DIHYDROXY-2-(4-HYDROXY-PHENYL)-

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Structure
Formula
C15H10O5
IUPAC Name
5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one
Canonical SMILES
C1=CC(=CC=C1C2=CC(=O)C3=C(C=C(C=C3O2)O)O)O
InChI
InChI=1S/C15H10O5/c16-9-3-1-8(2-4-9)13-7-12(19)15-11(18)5-10(17)6-14(15)20-13/h1-7,16-18H
InChIKey
KZNIFHPLKGYRTM-UHFFFAOYSA-N
PubChem CID
5280443
Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Status epilepticus ICD-11: 8A66
 Disease Info 
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model SH-SY5Y cells Neuroblastoma Homo sapiens CVCL_0019
In Vivo Model
5-weeks-old kainate (KA)-induced BALB/c nude mice, a widely used epilepsy mouse model, were performed with intraperitoneal (i.p.) injection of KA (6 mg/kg). Pre-treatment 21 with antioxidant apigenin (60 mg/Kg, 2 days) or post-treatment with apigenin (60 mg/Kg, 1 day), mice were injected with KA (6 mg/kg) via intraperitoneal (i.p.) injection, and then HCP (0.5 mg/Kg) were injected by intravenous (i.v.) injection. In vivo and Ex vivo fluorescence images of relative ClO levels in mice brains 5, 15, 30, 45, and 60 min post injection of HCP were further performed by using the IVIS Spectrum imaging system (Nanjing University) with an excitation filter of 430 nm and the collection wavelength range is from 500-600 nm.

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Response regulation Apigenin can efficiently reduce the expression of intracellular MPO and increase the levels of GPX4 and SIRT1, thereby conferring neuroprotection through regulation of kainic acid (KA)-induced ferroptosis. And the level of Ac-p53 inside the brains treated with apigenin was down-regulated, suggesting that the p53-mediated ferroptosis pathway might be blocked. Overall, apigenin was screened and confirmed as an efficient lead compound for epilepsy prevention and treatment.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Injury of intra-abdominal organs ICD-11: NB91
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model AML12 cells Normal Mus musculus CVCL_0140
Response regulation DEHP caused oxidative stress and increased the Fe2+ content, finally resulting in ferroptosis in AML12 cells. Apigenin restrained the toxicity of DEHP and antagonized DEHP-induced ferroptosis in AML12 cells. The protective effects of APG on DEHP-induced liver injury were achieved by activating GPX4 and suppressing intracellular iron accumulation.
Unspecific Target
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Responsed Disease Status epilepticus ICD-11: 8A66
 Disease Info 
Responsed Regulator NAD-dependent protein deacetylase sirtuin-1 (SIRT1) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model SH-SY5Y cells Neuroblastoma Homo sapiens CVCL_0019
In Vivo Model
5-weeks-old kainate (KA)-induced BALB/c nude mice, a widely used epilepsy mouse model, were performed with intraperitoneal (i.p.) injection of KA (6 mg/kg). Pre-treatment 21 with antioxidant apigenin (60 mg/Kg, 2 days) or post-treatment with apigenin (60 mg/Kg, 1 day), mice were injected with KA (6 mg/kg) via intraperitoneal (i.p.) injection, and then HCP (0.5 mg/Kg) were injected by intravenous (i.v.) injection. In vivo and Ex vivo fluorescence images of relative ClO levels in mice brains 5, 15, 30, 45, and 60 min post injection of HCP were further performed by using the IVIS Spectrum imaging system (Nanjing University) with an excitation filter of 430 nm and the collection wavelength range is from 500-600 nm.

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Response regulation Apigenin can efficiently reduce the expression of intracellular MPO and increase the levels of GPX4 and SIRT1, thereby conferring neuroprotection through regulation of kainic acid (KA)-induced ferroptosis. And the level of Ac-p53 inside the brains treated with apigenin was down-regulated, suggesting that the p53-mediated ferroptosis pathway might be blocked. Overall, apigenin was screened and confirmed as an efficient lead compound for epilepsy prevention and treatment.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Responsed Disease Ischemia/reperfusion injury ICD-11: DB98
 Disease Info 
Responsed Regulator Amine oxidase [flavin-containing] B (MAOB) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HUVECs (Human umbilical vein endothelial cells)
In Vivo Model
Mice were exposed to 12/12 h of light/darkness and given free access to food and water. All C57BL/6J mice were fasted for 12 h and anesthetized by intraperitoneal injection of 1% sodium pentobarbital before modeling. Later, the superior mesenteric artery (SMA) was subjected to 45 min of global no-flow ischemia, followed by 90 min of reperfusion to induce IIRI. The successful model could be revealed by the microcirculation detector. In order to investigate the effects of APG, mice were randomly divided into different groups: Sham group, IIRI group, APG groups (2 mg/kg, 4 mg/kg and 8 mg/kg), ZnPPIX group (Protoporphyrin Zinc(), Dalian Meilun Biotech Co., Ltd., China, 10mg/kg), Selegiline group (10 mg/kg, Shandong Topscience Biotech Co., Ltd., China) and the ZnPPIX + Selegiline group (10 mg/kg ZnPPIX and 10 mg/kg Selegiline). As mentioned above, drug was intraperitoneal injected after a 10-min-ischemia.

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Response regulation MST analysis suggested that Apigenin could specifically bind to heme oxygenase 1 (HO-1) and monoamine oxidase b (MAO-B). Simultaneously, APG could attenuate ROS generation and Fe2+ accumulation, maintain mitochondria function thus inhibit ferroptosis and alleviate intestinal ischemia-reperfusion injury.
Heme oxygenase 1 (HMOX1)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Ischemia/reperfusion injury ICD-11: DB98
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HUVECs (Human umbilical vein endothelial cells)
In Vivo Model
Mice were exposed to 12/12 h of light/darkness and given free access to food and water. All C57BL/6J mice were fasted for 12 h and anesthetized by intraperitoneal injection of 1% sodium pentobarbital before modeling. Later, the superior mesenteric artery (SMA) was subjected to 45 min of global no-flow ischemia, followed by 90 min of reperfusion to induce IIRI. The successful model could be revealed by the microcirculation detector. In order to investigate the effects of APG, mice were randomly divided into different groups: Sham group, IIRI group, APG groups (2 mg/kg, 4 mg/kg and 8 mg/kg), ZnPPIX group (Protoporphyrin Zinc(), Dalian Meilun Biotech Co., Ltd., China, 10mg/kg), Selegiline group (10 mg/kg, Shandong Topscience Biotech Co., Ltd., China) and the ZnPPIX + Selegiline group (10 mg/kg ZnPPIX and 10 mg/kg Selegiline). As mentioned above, drug was intraperitoneal injected after a 10-min-ischemia.

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Response regulation MST analysis suggested that Apigenin could specifically bind to heme oxygenase 1 (HO-1) and monoamine oxidase b (MAO-B). Simultaneously, APG could attenuate ROS generation and Fe2+ accumulation, maintain mitochondria function thus inhibit ferroptosis and alleviate intestinal ischemia-reperfusion injury.
References
Ref 1 Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis. Proc Natl Acad Sci U S A. 2020 May 12;117(19):10155-10164. doi: 10.1073/pnas.1917946117. Epub 2020 Apr 23.
Ref 2 Old targets, new strategy: Apigenin-7-O--d-(-6-p-coumaroyl)-glucopyranoside prevents endothelial ferroptosis and alleviates intestinal ischemia-reperfusion injury through HO-1 and MAO-B inhibition. Free Radic Biol Med. 2022 May 1;184:74-88. doi: 10.1016/j.freeradbiomed.2022.03.033. Epub 2022 Apr 7.
Ref 3 Apigenin ameliorates di(2-ethylhexyl) phthalate-induced ferroptosis: The activation of glutathione peroxidase 4 and suppression of iron intake. Food Chem Toxicol. 2022 Jun;164:113089. doi: 10.1016/j.fct.2022.113089. Epub 2022 Apr 30.