Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0116)
Name
Artesunate
Synonyms
Artesunate; Artesunic acid; Arsumax; 88495-63-0; Plasmotrin; Qinghaozhi; Saphnate; Dihydroqinghasu hemsuccinate; Artesunatum; Zysunate; Arinate; Artesunato; Asumax; Gsunate Forte; Plasmotrim; CHEBI:63918; .alpha.-artesunic acid; Dihydroqinghaosu hemisuccinate; Succinyl dihydroartemisinin; LJPC-0118; 60W3249T9M; NSC-712571; Butanedioic acid, 1-[(3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl] ester; Arsuamoon; WR-256283; cosunate; Artesunata; Cosinate; Artesunate [USAN]; (3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin-10-ol, hydrogen succinate; 4-oxo-4-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)butanoic acid; 4-oxo-4-{[(3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j][1,2]benzodioxepin-10-yl]oxy}butanoic acid; Artesunate [INN]; Butanedioic acid, mono((3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin-10-yl) ester; Armax 200; Artesunatum [INN-Latin]; Artesunato [INN-Spanish]; DTXSID3042681; Artsuna; Nuartez; Artesunate [USAN:INN:BAN]; UNII-60W3249T9M; HSDB 7458; Quinghaosu reduced succinate ester; D95; Dihydroartemisinine-12alpha-succinate; ARTESUNATE [MI]; WR 256283; ARTESUNATE [HSDB]; ARTESUNATE [VANDF]; ARTESUNATE [MART.]; ARTESUNATE [USP-RS]; ARTESUNATE [WHO-DD]; ARTESUNATE [WHO-IP]; MLS006011590; CHEMBL361497; GTPL9956; ARTESUNATE [ORANGE BOOK]; SCHEMBL14552891; FIHJKUPKCHIPAT-AHIGJZGOSA-N; ARTESUNATUM [WHO-IP LATIN]; HY-N0193; STR09744; BDBM50248021; AKOS037515734; CS-8151; DB09274; NCGC00164600-10; NCGC00164600-15; SMR002499399; DIHYDROARTEMISININE-12.ALPHA.-SUCCINATE; EN300-6482026; Q707939; BRD-K54634444-001-05-9; WR-256283;ART;Armax 200;SM-804;HSDB-7458; 3R,5AS,6R,8AS,9R,10S,12R,12AR)-3,6,9-TRIMETHYLDECAHYDRO-3,12-EPOXY-12H-PYRANO(4,3-J)-1,2-BENZODIOXEPIN-10-YL HYDROGEN BUTANEDIOATE; 4-Oxo-4-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3,12-epoxypyrano(4,3-j)-1,2-benzodioxepin-10-yl hydrogen butanedioate; 4-OXO-4-(3R,5AS,6R,8AS,9R,10S,12R,12AR)-3,6,9-TRIMETHYLDECAHYDRO-3,12-EPOXYPYRANO(4,3-J)-1,2-BENZODIOXEPIN-10-YL HYDROGEN BUTANEDIOATE; 4-oxo-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxy]butanoic acid; 4-oxo-4-{[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0?,(1)(3).0?,(1)(3)]hexadecan-10-yl]oxy}butanoic acid; 4-oxo-4-{[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0^{4,13}.0^{8,13}]hexadecan-10-yl]oxy}butanoic acid; BUTANEDIOIC ACID, MONO(DECAHYDRO-3,6,9-TRIMETHYL-3,12-EPOXY-12H-PYRANO(4,3-J)-1,2-BENZODIOXEPIN-10-YL) ESTER, (3R-(3.ALPHA.,5A.BETA.,6.BETA.,8A.BETA.,9.ALPHA.,10.BETA.,12.BETA.,12AR*))-

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Structure
Formula
C19H28O8
IUPAC Name
4-oxo-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxy]butanoic acid
Canonical SMILES
CC1CCC2C(C(OC3C24C1CCC(O3)(OO4)C)OC(=O)CCC(=O)O)C
InChI
InChI=1S/C19H28O8/c1-10-4-5-13-11(2)16(23-15(22)7-6-14(20)21)24-17-19(13)12(10)8-9-18(3,25-17)26-27-19/h10-13,16-17H,4-9H2,1-3H3,(H,20,21)/t10-,11-,12+,13+,16-,17-,18-,19-/m1/s1
InChIKey
FIHJKUPKCHIPAT-AHIGJZGOSA-N
PubChem CID
6917864
Full List of Ferroptosis Target Related to This Drug
Solute carrier family 40 member 1 (SLC40A1)
 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 Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 ( MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 (MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 3 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 ( MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 (MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Intracerebral hemorrhage ICD-11: 8B00
 Disease Info 
Responsed Regulator 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) Driver
 Regulator Info 
Pathway Response mTOR signaling pathway hsa04150
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model BV-2 cells Normal Mus musculus CVCL_0182
In Vivo Model
Rats were anaesthetised through intraperitoneal injection of pentobarbital (40 mg/kg) and placed onto a stereotaxic instrument (RWD Life Science Co., Ltd.). A 1-cm midline incision was performed in the rat scalp to expose the intersection point. Then, a hole 3.2 mm lateral and 1.4 mm anterior to the right bregma was produced. Next, 1.0 ul collagenase type IV (0.25 IU/ul; C5138; Sigma-Aldrich, USA) was injected into the basal ganglia via a microinjection pump (4.2 mm depth below the endocranium) at a rate of 0.2 ul/min. The needle was maintained for 5 min after injection to prevent backflow. Thereafter, the skin incision was closed using sutures. Rats in the sham group received 1.0 ul saline instead of collagenase type IV.

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Response regulation Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1-polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway
Nuclear receptor coactivator 4 (NCOA4)
 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 Driver
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 ( MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Driver
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 (MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Natural resistance-associated macrophage protein 2 (SLC11A2)
 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 Driver
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 ( MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Driver
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Mitogen-activated protein kinase 14 (MAPK14) Driver
 Regulator Info 
Pathway Response MAPK signaling pathway hsa04010
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
The xenografts were established via the subcutaneous inoculation of U251 cells (1 x 107 cells/per mouse) into the armpit of one mouse. After two weeks of growth, the cancer tissues were cut into pieces with the dimensions of 1.5 x 1.5 x 1.5 mm3 and inoculated subcutaneously into the right armpit of the mice with a puncture needle. When tumor volume reached approximately 80 mm3, mice were randomly divided into four groups (n = 5): Vehicle control, ART (20 mg/kg), ART (40 mg/kg), and TMZ (40 mg/kg). TMZ was used as the positive control. Drugs and vehicle were given by intraperitoneal injection daily for 21 days. Tumor volume and body weight were measured every three days.

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Response regulation Artesunate triggers ferroptosis in glioblastoma in vitro and in vivo through regulation of iron metabolism and p38 (MAPK14) and ERK signaling pathways. Meanwhile, ART reduced the protein level of GPX4 and FPN1, increased the protein level of DMT1, TfR, ferritin and NCOA4.
Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Marker/Driver
Responsed Disease Burkitt lymphoma ICD-11: 2A85
 Disease Info 
Responsed Regulator Cyclic AMP-dependent transcription factor ATF-4 (ATF4) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model Daudi cells Burkitt lymphoma Homo sapiens CVCL_0008
CA46 cells Burkitt lymphoma Homo sapiens CVCL_1101
In Vivo Model
Four -week-old NOD/SCID mice were purchased from Chu Shang Technology (Kunming, China). CA-46 cells were collected and re-suspended in PBS at a concentration of 1-5 x 107 cells/mL. Totally, 0.2 mL cells were inoculated subcutaneously in the middle and posterior armpits of mice. When the transplanted tumor was established, the mice were injected the artesunate solution intraperitoneally in accordance with the body weight (200 mg/kg) daily.

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Response regulation Artesunate induced ferroptosis in different types of Burkitt's lymphoma cells, and caused a significant ERS response in tumor cells. The activation of the ATF4-CHOP-CHAC1 pathway up-regulated the expression of CHAC1 and degraded intracellular GSH, thus weakening the ability of lymphoma cells to resist ferroptosis.
Unspecific Target
In total 7 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Responsed Disease Diffuse large B-cell lymphoma ICD-11: 2A81
 Disease Info 
Responsed Regulator Signal transducer and activator of transcription 3 (STAT3) Suppressor
 Regulator Info 
Pathway Response JAK-STAT signaling pathway hsa04630
Ferroptosis hsa04216
Autophagy hsa04140
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
In Vitro Model U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
SU-DHL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_9550
SU-DHL-4 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_0539
SU-DHL-6 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2206
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female NOD/SCID mice (age, 6 weeks; body weight, 20 ± 2 g) were purchased from Beijing Huafukang Biotechnology Co., Ltd., maintained under pathogen-free conditions and allowed free access to sterilized food and water. After a week of adaptation to their surroundings, 1 x 107 U2932 cells were subcutaneously injected into the right flank near the hind leg of each mouse. Following the growth of palpable tumors (tumor volume of 50-100 mm3), the mice were randomly divided into two groups (n = 5 mice/group) and treated with 100 ul normal saline (NS) or ART (120 mg/kg/day) via intraperitoneal injection.

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Response regulation Artesunate (ART) was found to exert its effects via inhibition of STAT3 activation. ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in diffuse large B cell lymphoma (DLBCL) cells.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [5]
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Responsed Regulator Endoplasmic reticulum chaperone BiP (HSPA5) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model PaTu 8988t cells Pancreatic adenocarcinoma Homo sapiens CVCL_1847
AsPC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0152
In Vivo Model
AsPC-1 cells (1 x 106) with a control or GRP78 shRNA transfection were injected into right subcutaneous flank of nude mice (five mice per group). The nude mice were randomized into two groups and treated with DMSO or artesunate (30 mg/kg/i.p.), respectively. Artesunate was administered every two days. The tumor growth speed and volume were monitored every two days until the end point at day 35. All the tumor size and weight in the artesunate-treated groups were measured by using a caliper and an electronic balance.

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Response regulation Artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 (HSPA5) enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo. Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [6]
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Cathepsin B (CTSB) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
SNU-182 cells Adult hepatocellular carcinoma Homo sapiens CVCL_0090
SNU-449 cells Adult hepatocellular carcinoma Homo sapiens CVCL_0454
In Vivo Model
A total of 20 male Balb/c nude mice aged 6-8 weeks were purchased from Hunan SJA Laboratory Animal Co., Ltd. (Changsha, China). Five million Huh7 cells were inoculated into the right flanks of the mice. When the tumor size reached 80-100 mm3, the mice were randomly divided into four groups and administered artesunate (30 mg/kg mouse weight) alone, sorafenib (20 mg/kg mouse weight) alone, a combination of artesunate and sorafenib, or the same volume of PBS by gavage every other day.

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Response regulation Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in hepatocellular carcinoma treatment.
Experiment 4 Reporting the Ferroptosis-centered Drug Act on This Target [7]
Responsed Disease Hereditary Leiomyomatosis ICD-11: 2C90
 Disease Info 
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model Caki-1 cells Clear cell renal cell carcinoma Homo sapiens CVCL_0234
786-O cells Renal cell carcinoma Homo sapiens CVCL_1051
KTCTL-26 cells Clear cell renal cell carcinoma Homo sapiens CVCL_5872
A-498 cells Renal cell carcinoma Homo sapiens CVCL_1056
Response regulation Artesunate (ART) significantly increased cytotoxicity and inhibited proliferation and clonogenic growth in both parental and sunitinib-resistant renal cell carcinoma (RCC) cells. P53 exclusively appeared in the KTCTL-26 cells, indicating that p53 might be predictive for ART-dependent ferroptosis. Thus, ART may hold promise for treating selected patients with advanced and even therapy-resistant RCC.
Experiment 5 Reporting the Ferroptosis-centered Drug Act on This Target [8]
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
Responsed Regulator Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hHSCs (Human hepatic stellate cells)
hHSCs (Human hepatic stellate cells)
In Vivo Model
6-8-week-old, 20 ± 2 g, male ICR mice, obtained from Nanjing Medical University (Nanjing, China), were randomly divided into five groups (n = 8 per group). Mouse model of chronic liver fibrosis was established by 10% carbon tetrachloride (CCl4, 0.5 ml/100 g body weight) injection. Groups are follows: (1) Control group was intraperitoneally (i.p.) injected with olive oil; (2) Model group was i.p. injected with 10% CCl4 every other day a week for 8 weeks; (3) Low-dose artesunate treatment groups were i.p. injected by CCl4 every other day a week for 8 weeks and daily i.p. injected by 50 mg/kg artesunate for last 4 weeks; (4) Middle-dose artesunate treatment groups were i.p. injected by CCl4 every other day a week for 8 weeks and daily i.p. injected by 100 mg/kg artesunate for last 4 weeks; (5) High-dose artesunate treatment groups were i.p. injected by CCl4 every other day a week for 8 weeks and daily i.p. injected by 200 mg/kg artesunate for last 4 weeks.

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Response regulation Artesunate evidently triggered ferritinophagy accompanied by up-regulation of LC3 (microtubule-associated protein light chain 3), Atg3, Atg5, Atg6/beclin1, Atg12 (autophagy related genes) and down-regulation of p62, FTH1 (ferritin heavy chain), NCOA4 (nuclear receptor co-activator 4) in activated HSCs. These results suggested that ferritinophagy-mediated HSC ferroptosis was responsible for artesunate-induced anti-fibrosis efficacy in liver fibrosis.
Experiment 6 Reporting the Ferroptosis-centered Drug Act on This Target [10]
Responsed Disease Merkel cell carcinoma ICD-11: 2C34
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MKL-1 cells Merkel cell carcinoma Homo sapiens CVCL_2600
MKL-2 cells Merkel cell carcinoma Homo sapiens CVCL_D027
MS-1 cells Lung small cell carcinoma Homo sapiens CVCL_1429
WaGa cells Merkel cell carcinoma Homo sapiens CVCL_E998
PeTa cells Merkel cell carcinoma Homo sapiens CVCL_LC73
In Vivo Model
Five-week-old female NOD.CB17/Prkdcscid mice (Charles River) were used for the xenotransplantation experiments. They were housed under specific pathogen-free conditions. Each mouse was injected subcutaneously with a suspension of 5 x 106 MKL-1 or WaGa tumor cells mixed with an equal volume of Matrigel (Corning) in a total volume of 100 uL. The tumor size was measured daily using a vernier calipers.

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Response regulation Artesunate predominantly induces ferroptosis in MCPyV-positive merkel cell carcinoma (MCC) cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and -mercaptoethanol reduced artesunate-induced death. Rosiglitazone (Rosi), an inhibitor of the Acyl-CoA synthetase long-chain family member 4 (ACSL4). Indeed, Rosi exerted a protective effect on all three tested artesunate-treated MCC cell lines.
Experiment 7 Reporting the Ferroptosis-centered Drug Act on This Target [11]
Responsed Disease Osteoporosis ICD-11: FB83
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model RAW 264.7 cells Leukemia Mus musculus CVCL_0493
In Vivo Model
The mice were fed a standard pellet diet (mice maintenance diet; Tengxin Biotechnology Co., Ltd) and distilled water ad libitum and kept at a 12-h lightdark cycle, a temperature of 23 to 25 and a relative humidity of 50% ± 5%. Mice were divided into four groups: control (Ctrl), ferric ammonium citrate (FAC), ART and combined treatment (FAC + ART). FAC (Sigma-Aldrich; 40 mg/kg) were injected intraperitoneally every 3 days for 8 weeks. ART group mice were administered 50 mg/kg by oral gavage every other day for 8 weeks.

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Response regulation ART inhibits iron-uptake stimulated osteoclast differentiation by inducing ferroptosis. Artemisinin compounds are potential drugs for treating iron overload-induced osteoporosis.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [9]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Extraocular muscles disorder ICD-11: 9C82
 Disease Info 
Pathway Response Ferroptosis hsa04216
PI3K-Akt signaling pathway hsa04151
Cell Process Cell ferroptosis
In Vitro Model hOFs (Human ocular fibroblasts)
Response regulation Expression of mitochondrial GPX4 but no other forms of GPX4 was decreased after artesunate treatment and that mitochondrial GPX4 overexpression rescued artesunate-induced lipid peroxidation and ferroptosis. Other cellular ferroptosis defense mechanisms, including cellular FSP1 and Nrf2, were also inhibited by artesunate. In conclusion, our study demonstrated that artesunate protects against fibrosis through abrogation of fibroblast activation and induction of mitochondria-dependent ferroptosis in ocular fibrosis, which may offer a potential treatment for ocular fibrosis.
Ferroptosis suppressor protein 1 (AIFM2)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [9]
Target for Ferroptosis Suppressor
Responsed Disease Extraocular muscles disorder ICD-11: 9C82
 Disease Info 
Pathway Response Ferroptosis hsa04216
PI3K-Akt signaling pathway hsa04151
Cell Process Cell ferroptosis
In Vitro Model hOFs (Human ocular fibroblasts)
Response regulation Expression of mitochondrial GPX4 but no other forms of GPX4 was decreased after artesunate treatment and that mitochondrial GPX4 overexpression rescued artesunate-induced lipid peroxidation and ferroptosis. Other cellular ferroptosis defense mechanisms, including cellular FSP1 and Nrf2, were also inhibited by artesunate. In conclusion, our study demonstrated that artesunate protects against fibrosis through abrogation of fibroblast activation and induction of mitochondria-dependent ferroptosis in ocular fibrosis, which may offer a potential treatment for ocular fibrosis.
References
Ref 1 Artesunate induces ferroptosis via modulation of p38 and ERK signaling pathway in glioblastoma cells. J Pharmacol Sci. 2022 Mar;148(3):300-306. doi: 10.1016/j.jphs.2022.01.007. Epub 2022 Jan 13.
Ref 2 Artesunate alleviates intracerebral haemorrhage secondary injury by inducing ferroptosis in M1-polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway. Basic Clin Pharmacol Toxicol. 2023 May;132(5):369-383. doi: 10.1111/bcpt.13848. Epub 2023 Mar 7.
Ref 3 Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma. Biochem Biophys Res Commun. 2019 Nov 12;519(3):533-539. doi: 10.1016/j.bbrc.2019.09.023. Epub 2019 Sep 16.
Ref 4 Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling. Cell Signal. 2021 Dec;88:110167. doi: 10.1016/j.cellsig.2021.110167. Epub 2021 Oct 7.
Ref 5 Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Drug Des Devel Ther. 2019 Jul 2;13:2135-2144. doi: 10.2147/DDDT.S199459. eCollection 2019.
Ref 6 Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. 2021 Feb;42(2):301-310. doi: 10.1038/s41401-020-0478-3. Epub 2020 Jul 22.
Ref 7 Artesunate Inhibits Growth of Sunitinib-Resistant Renal Cell Carcinoma Cells through Cell Cycle Arrest and Induction of Ferroptosis. Cancers (Basel). 2020 Oct 27;12(11):3150. doi: 10.3390/cancers12113150.
Ref 8 Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 2019 Jan;109:2043-2053. doi: 10.1016/j.biopha.2018.11.030. Epub 2018 Nov 26.
Ref 9 Artesunate protects against ocular fibrosis by suppressing fibroblast activation and inducing mitochondria-dependent ferroptosis. FASEB J. 2023 Jun;37(6):e22954. doi: 10.1096/fj.202201867R.
Ref 10 Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma. Cancers (Basel). 2020 Apr 9;12(4):919. doi: 10.3390/cancers12040919.
Ref 11 Artesunate inhibits osteoclast differentiation by inducing ferroptosis and prevents iron overload-induced bone loss. Basic Clin Pharmacol Toxicol. 2023 Feb;132(2):144-153. doi: 10.1111/bcpt.13817. Epub 2022 Dec 2.