General Information of the Ferroptosis Regulator (ID: REG10081)
Regulator Name High mobility group protein B1 (HMGB1)
Synonyms
HMG1; High mobility group protein 1
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Gene Name HMGB1
Gene ID 3146
Regulator Type Protein coding
Uniprot ID P09429
Sequence
MGKGDPKKPRGKMSSYAFFVQTCREEHKKKHPDASVNFSEFSKKCSERWKTMSAKEKGKF
EDMAKADKARYEREMKTYIPPKGETKKKFKDPNAPKRPPSAFFLFCSEYRPKIKGEHPGL
SIGDVAKKLGEMWNNTAADDKQPYEKKAAKLKEKYEKDIAAYRAKGKPDAAKKGVVKAEK
SKKKKEEEEDEEDEEDEEEEEDEEDEDEEEDDDDE

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Family HMGB family
Function
Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability. Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors. In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance. Has proangiogdenic activity. May be involved in platelet activation. Binds to phosphatidylserine and phosphatidylethanolamide. Bound to RAGE mediates signaling for neuronal outgrowth. May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP.

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HGNC ID
HGNC:4983
KEGG ID hsa:3146
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
HMGB1 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
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Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Hypoxic ischemic brain injury ICD-11: 8B24
Responsed Drug Glycyrrhizin Phase 3
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
rPCNs (Rat primary cortical neurons)
In Vivo Model
Male and female neonatal SpragueDawley rats on postpartum day 7 (P7) were provided by SPF Biotechnology (Beijing, China). Each animal was anesthetized with isoflurane (4% for induction, 2% for maintenance), the skin was incised, and the left common carotid artery was exposed. This artery was ligated with a 5-0 suture and cut, and the skin was sutured closed. Next, the pups recovered for 1 h with their mother. Subsequently, the pups were placed in a hypoxia chamber (8% O2 + 92% N2 mixture) for 2 h. After 2 h of hypoxia, the animals were placed back with their dam.

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Response regulation Glycyrrhizin (GL) not only inhibited ferroptosis induced by RSL3 and oxygen-glucose deprivation in vitro but also inhibited ferroptosis induced by hypoxic-ischemic brain damage (HIBD) in vivo. GL could suppress the occurrence of neuronal ferroptosis and reduce neuronal loss in HIBD via the HMGB1/GPX4 pathway.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [2]
Target for Ferroptosis Suppressor
Responsed Disease Acute kidney failure ICD-11: GB60
Responsed Drug Isoliquiritigenin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Male C57BL/6 mice (aged 6-8 weeks and weighing 22-25g) were obtained from the Experimental Animal Center, Sichuan Provincial Peoples Hospital, and were fed a standard laboratory diet. LPS and ISL were dissolved in normal saline and 0.5% Tween-20/saline, respectively. AKI mice were developed by intraperitoneal (i.p.) LPS injection. A total of 30 mice were randomly divided into six groups (n = 5): control, ISL, Fer, LPS, LPS plus ISL, and LPS plus Fer. An intraperitoneal injection of LPS (10 mg/kg) was made to induce septic AKI. ISL was administered via gavage at 50 mg/kg 30 min before LPS injection. Mice were dosed intraperitoneally with Fer (Ferrostatin-1, SML0583, Sigma-Aldrich, St. Louis, MO) at 5 mg/kg. Mice were sacrificed by cervical dislocation 8 h after LPS injection. Kidney tissue and serum samples were collected concurrently.

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Response regulation Isoliquiritigenin (ISL) attenuates septic acute kidney injury by regulating ferritinophagy-mediated ferroptosis. ISL inhibited Fe2+ and lipid peroxidation accumulation in LPS-stimulated HK2 cells. It also increased the expression of GPX4 and xCT, reduced the expression of HMGB1 and NCOA4 then attenuated mitochondria injury in renal tubular following LPS stimulation.
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [3]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Chronic kidney disease ICD-11: GB61
Responsed Drug D-Glucose Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
SV40 MES 13 cells Normal Mus musculus CVCL_5368
Response regulation Erastin and high glucose both induced ferroptosis in mesangial cells. Suppression of HMGB1 restored cellular proliferation, prevented ROS and LDH generation, decreased ACSL4, PTGS2, and NOX1, and increased GPX4 levels in mesangial cells. Furthermore, nuclear factor E2-related factor 2 (Nrf2) was decreased in diabetic nephropathy (DN) patients and high glucose-mediated translocation of HMGB1 in mesangial cells.
Unspecific Target [Unspecific Target]
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [4]
Responsed Disease Sepsis ICD-11: 1G40
Responsed Drug Resveratrol Phase 3
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
hCMs (Human cardiomyocytes)
In Vivo Model
Clean male C57BL/6 mice (8-10 wk old, weighing 25-29 g) were purchased from Beijing HFK Bioscience Co. Ltd. The 90 mice were randomly assigned into nine groups after 1 wk of adaptive feeding with 10 mice in each group: normal group (intraperitoneally injected with the same amount of PBS), LPS group [intraperitoneally injected with 15 mg/kg LPS (Sigma-Aldrich, St. Louis, Cat. No. L2880)], LPS + Rsv group (intraperitoneally injected with 15 mg/kg LPS and pretreated with 50 mg/kg resveratrol; 30), LPS + antagomiR-NC group [intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 0.4 pmol/uL antagomiR-NC group (Merck, Darmstadt, Germany)], LPS + miR-149 antagomiR group (intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 0.4 pmol/uL miR-149 antagomiR), LPS + Rsv + miR-149 antagomiR group (intraperitoneally injected with 15 mg/kg LPS, pretreated with 50 mg/kg resveratrol, and simultaneously injected with 0.4 pmol/uL miR-149 antagomiR), LPS + Fer-1 group (intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 2.5 umol/kg ferroptosis inhibitor ferrostatin-1), and LPS + Rsv + Fer-1 group (intraperitoneally injected with 15 mg/kg LPS, pretreated with 50 mg/kg resveratrol, and simultaneously injected with 2.5 umol/kg ferroptosis inhibitor ferrostatin-1.

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Response regulation Resveratrol inhibited ferroptosis by upregulating miR-149 and downregulating HMGB1, thus improving endotoxemia-induced myocardial injury in mice.
Experiment 2 Reporting the Ferroptosis Target of This Regulator [5]
Responsed Disease Cardiomyopathy ICD-11: BC43
Responsed Drug Dexrazoxane Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Male Wistar rats (250-300 g,n = 230) were purchased from Vitalriver. Ten rats were recruited in each group in the experiment. The rats in the control, DOX, FER-1 + DOX, NEC-1 + DOX, 3-MA + DOX, and Emricasan + DOX groups were used for the overall survival analysis, and those from control and DOX groups were used for detection of the expression of PTGS2 in the indicated organs of rats.

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Response regulation Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). HMGB1 was induced by DOX but was inhibited by DXZ or FER-1. Overexpression of HMGB1 promoted the ferroptosis and cardiotoxicity induced by DOX in the rats although silencing of HMGB1 showed opposite effects.
Experiment 3 Reporting the Ferroptosis Target of This Regulator [6]
Responsed Disease Hepatoblastoma ICD-11: DB91
Responsed Drug Glycyrrhizin Phase 3
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
In total, 40 male specific- pathogen-free C57BL/6 mice (Hubei Animal Experimental Center) 6-8 weeks old. The mice were randomly divided into 5 groups: The normal group, model group, 15 mg/kg GLY group, 30 mg/kg GLY group and 60 mg/kg GLY group. Except for the normal group, the other four groups of mice were injected intraperitoneally with D-GalN (400 mg/kg) and LPS (100 ug/kg) to induce the ALF model. According to a previous study on GLY gavage doses, three doses of GLY (15, 30 and 60 mg/kg/day) intervention groups were used. A total of 24 mice were divided into three groups. Mice received gavage with different doses of GLY for 3 days before induction of the ALF model.

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Response regulation The HMGB1 inhibitor glycyrrhizin (GLY) significantly reduced the degree of ferroptosis during acute liver failure (ALF) by inhibiting oxidative stress. Treatment with GLY reduced the degree of liver damage, the expression of HMGB1 was decreased, and the levels of Nrf2, HO1 and GPX4 were increased.
Transferrin receptor protein 1 (TFRC) [Driver; Suppressor; Marker]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [7]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Myeloid leukaemia ICD-11: 2B33
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
In Vitro Model
HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
NB4 cells Acute promyelocytic leukemia Homo sapiens CVCL_0005
KG-1 cells Adult acute myeloid leukemia Homo sapiens CVCL_0374
U-937 cells Adult acute monocytic leukemia Homo sapiens CVCL_0007
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
In Vivo Model
Seven- to eight-week male NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice that weighed about 20 g were purchased from Xiangya Medical College Animal Laboratory (Changsha, China). Indicated HL-60/NRASQ61L cells were subcutaneously injected into the dorsal flanks right of the midline in NOD/SCID mice (weight, approximately 20 g). At day seven, mice were intraperitoneal injected with erastin (20 mg/kg i.v., three times a week) for two weeks. Erastin was dissolved in the vehicle (2% DMSO and 98% PBS) and prepared by Ultrasonic Cleaner (Fisher Scientific, Hampton, NH). A final volume of 300 uL of erastin was applied via intraperitoneal injection.

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Response regulation HMGB1 could be a potential drug target for therapeutic interventions in leukemia.Importantly, these data were further supported by our in vivo experiment, in which xenografts formed by HMGB1 knockdown HL-60/NRASQ61L cells had lower PTGS2 and TfR1 expression than that in control mice.
Prostaglandin G/H synthase 2 (PTGS2) [Driver; Marker]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [7]
Target for Ferroptosis Marker
Responsed Disease Myeloid leukaemia ICD-11: 2B33
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
In Vitro Model
HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
NB4 cells Acute promyelocytic leukemia Homo sapiens CVCL_0005
KG-1 cells Adult acute myeloid leukemia Homo sapiens CVCL_0374
U-937 cells Adult acute monocytic leukemia Homo sapiens CVCL_0007
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
In Vivo Model
Seven- to eight-week male NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice that weighed about 20 g were purchased from Xiangya Medical College Animal Laboratory (Changsha, China). Indicated HL-60/NRASQ61L cells were subcutaneously injected into the dorsal flanks right of the midline in NOD/SCID mice (weight, approximately 20 g). At day seven, mice were intraperitoneal injected with erastin (20 mg/kg i.v., three times a week) for two weeks. Erastin was dissolved in the vehicle (2% DMSO and 98% PBS) and prepared by Ultrasonic Cleaner (Fisher Scientific, Hampton, NH). A final volume of 300 uL of erastin was applied via intraperitoneal injection.

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Response regulation HMGB1 could be a potential drug target for therapeutic interventions in leukemia.Importantly, these data were further supported by our in vivo experiment, in which xenografts formed by HMGB1 knockdown HL-60/NRASQ61L cells had lower PTGS2 and TfR1 expression than that in control mice.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4) [Driver]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [8]
Target for Ferroptosis Driver
Responsed Disease Pancreatic cancer ICD-11: 2C10
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 PANC1 cells in 100 ul PBS were injected subcutaneously to the right of the dorsal midline in 6- to 8-week-oldathymic nude mice(n = 5 mice/group). After the tumor reached 60-80 mm3 on day 7, the mice were randomly grouped and treated with IKE (imidazole ketone erastin; 40 mg/kg; i.p., once every other day) for 3 weeks, and then samples were collected and assayed.

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Response regulation Pirin (PIR), an iron-binding nuclear protein, plays a previously unrecognized role in mediating ferroptosis resistance in human pancreatic cancer cells. The depletion of PIR initiates HMGB1-dependent autophagy by binding to BECN1, and subsequently promotes ferroptosis by activating ACSL4.
Hypoxic ischemic brain injury [ICD-11: 8B24]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Responsed Drug Glycyrrhizin Phase 3
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
rPCNs (Rat primary cortical neurons)
In Vivo Model
Male and female neonatal SpragueDawley rats on postpartum day 7 (P7) were provided by SPF Biotechnology (Beijing, China). Each animal was anesthetized with isoflurane (4% for induction, 2% for maintenance), the skin was incised, and the left common carotid artery was exposed. This artery was ligated with a 5-0 suture and cut, and the skin was sutured closed. Next, the pups recovered for 1 h with their mother. Subsequently, the pups were placed in a hypoxia chamber (8% O2 + 92% N2 mixture) for 2 h. After 2 h of hypoxia, the animals were placed back with their dam.

    Click to Show/Hide
Response regulation Glycyrrhizin (GL) not only inhibited ferroptosis induced by RSL3 and oxygen-glucose deprivation in vitro but also inhibited ferroptosis induced by hypoxic-ischemic brain damage (HIBD) in vivo. GL could suppress the occurrence of neuronal ferroptosis and reduce neuronal loss in HIBD via the HMGB1/GPX4 pathway.
Acute kidney failure [ICD-11: GB60]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [2]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Responsed Drug Isoliquiritigenin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Male C57BL/6 mice (aged 6-8 weeks and weighing 22-25g) were obtained from the Experimental Animal Center, Sichuan Provincial Peoples Hospital, and were fed a standard laboratory diet. LPS and ISL were dissolved in normal saline and 0.5% Tween-20/saline, respectively. AKI mice were developed by intraperitoneal (i.p.) LPS injection. A total of 30 mice were randomly divided into six groups (n = 5): control, ISL, Fer, LPS, LPS plus ISL, and LPS plus Fer. An intraperitoneal injection of LPS (10 mg/kg) was made to induce septic AKI. ISL was administered via gavage at 50 mg/kg 30 min before LPS injection. Mice were dosed intraperitoneally with Fer (Ferrostatin-1, SML0583, Sigma-Aldrich, St. Louis, MO) at 5 mg/kg. Mice were sacrificed by cervical dislocation 8 h after LPS injection. Kidney tissue and serum samples were collected concurrently.

    Click to Show/Hide
Response regulation Isoliquiritigenin (ISL) attenuates septic acute kidney injury by regulating ferritinophagy-mediated ferroptosis. ISL inhibited Fe2+ and lipid peroxidation accumulation in LPS-stimulated HK2 cells. It also increased the expression of GPX4 and xCT, reduced the expression of HMGB1 and NCOA4 then attenuated mitochondria injury in renal tubular following LPS stimulation.
Chronic kidney disease [ICD-11: GB61]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [3]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Responsed Drug D-Glucose Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
SV40 MES 13 cells Normal Mus musculus CVCL_5368
Response regulation Erastin and high glucose both induced ferroptosis in mesangial cells. Suppression of HMGB1 restored cellular proliferation, prevented ROS and LDH generation, decreased ACSL4, PTGS2, and NOX1, and increased GPX4 levels in mesangial cells. Furthermore, nuclear factor E2-related factor 2 (Nrf2) was decreased in diabetic nephropathy (DN) patients and high glucose-mediated translocation of HMGB1 in mesangial cells.
Sepsis [ICD-11: 1G40]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [4]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Responsed Drug Resveratrol Phase 3
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
hCMs (Human cardiomyocytes)
In Vivo Model
Clean male C57BL/6 mice (8-10 wk old, weighing 25-29 g) were purchased from Beijing HFK Bioscience Co. Ltd. The 90 mice were randomly assigned into nine groups after 1 wk of adaptive feeding with 10 mice in each group: normal group (intraperitoneally injected with the same amount of PBS), LPS group [intraperitoneally injected with 15 mg/kg LPS (Sigma-Aldrich, St. Louis, Cat. No. L2880)], LPS + Rsv group (intraperitoneally injected with 15 mg/kg LPS and pretreated with 50 mg/kg resveratrol; 30), LPS + antagomiR-NC group [intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 0.4 pmol/uL antagomiR-NC group (Merck, Darmstadt, Germany)], LPS + miR-149 antagomiR group (intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 0.4 pmol/uL miR-149 antagomiR), LPS + Rsv + miR-149 antagomiR group (intraperitoneally injected with 15 mg/kg LPS, pretreated with 50 mg/kg resveratrol, and simultaneously injected with 0.4 pmol/uL miR-149 antagomiR), LPS + Fer-1 group (intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 2.5 umol/kg ferroptosis inhibitor ferrostatin-1), and LPS + Rsv + Fer-1 group (intraperitoneally injected with 15 mg/kg LPS, pretreated with 50 mg/kg resveratrol, and simultaneously injected with 2.5 umol/kg ferroptosis inhibitor ferrostatin-1.

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Response regulation Resveratrol inhibited ferroptosis by upregulating miR-149 and downregulating HMGB1, thus improving endotoxemia-induced myocardial injury in mice.
Myeloid leukaemia [ICD-11: 2B33]
In total 2 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [7]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
In Vitro Model
HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
NB4 cells Acute promyelocytic leukemia Homo sapiens CVCL_0005
KG-1 cells Adult acute myeloid leukemia Homo sapiens CVCL_0374
U-937 cells Adult acute monocytic leukemia Homo sapiens CVCL_0007
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
In Vivo Model
Seven- to eight-week male NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice that weighed about 20 g were purchased from Xiangya Medical College Animal Laboratory (Changsha, China). Indicated HL-60/NRASQ61L cells were subcutaneously injected into the dorsal flanks right of the midline in NOD/SCID mice (weight, approximately 20 g). At day seven, mice were intraperitoneal injected with erastin (20 mg/kg i.v., three times a week) for two weeks. Erastin was dissolved in the vehicle (2% DMSO and 98% PBS) and prepared by Ultrasonic Cleaner (Fisher Scientific, Hampton, NH). A final volume of 300 uL of erastin was applied via intraperitoneal injection.

    Click to Show/Hide
Response regulation HMGB1 could be a potential drug target for therapeutic interventions in leukemia.Importantly, these data were further supported by our in vivo experiment, in which xenografts formed by HMGB1 knockdown HL-60/NRASQ61L cells had lower PTGS2 and TfR1 expression than that in control mice.
Experiment 2 Reporting the Ferroptosis-centered Disease Response [7]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Pathway Response Ferroptosis hsa04216
Apoptosis hsa04210
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
In Vitro Model
HL-60 cells Adult acute myeloid leukemia Homo sapiens CVCL_0002
NB4 cells Acute promyelocytic leukemia Homo sapiens CVCL_0005
KG-1 cells Adult acute myeloid leukemia Homo sapiens CVCL_0374
U-937 cells Adult acute monocytic leukemia Homo sapiens CVCL_0007
THP-1 cells Childhood acute monocytic leukemia Homo sapiens CVCL_0006
In Vivo Model
Seven- to eight-week male NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice that weighed about 20 g were purchased from Xiangya Medical College Animal Laboratory (Changsha, China). Indicated HL-60/NRASQ61L cells were subcutaneously injected into the dorsal flanks right of the midline in NOD/SCID mice (weight, approximately 20 g). At day seven, mice were intraperitoneal injected with erastin (20 mg/kg i.v., three times a week) for two weeks. Erastin was dissolved in the vehicle (2% DMSO and 98% PBS) and prepared by Ultrasonic Cleaner (Fisher Scientific, Hampton, NH). A final volume of 300 uL of erastin was applied via intraperitoneal injection.

    Click to Show/Hide
Response regulation HMGB1 could be a potential drug target for therapeutic interventions in leukemia.Importantly, these data were further supported by our in vivo experiment, in which xenografts formed by HMGB1 knockdown HL-60/NRASQ61L cells had lower PTGS2 and TfR1 expression than that in control mice.
Pancreatic cancer [ICD-11: 2C10]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [8]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model
PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 PANC1 cells in 100 ul PBS were injected subcutaneously to the right of the dorsal midline in 6- to 8-week-oldathymic nude mice(n = 5 mice/group). After the tumor reached 60-80 mm3 on day 7, the mice were randomly grouped and treated with IKE (imidazole ketone erastin; 40 mg/kg; i.p., once every other day) for 3 weeks, and then samples were collected and assayed.

    Click to Show/Hide
Response regulation Pirin (PIR), an iron-binding nuclear protein, plays a previously unrecognized role in mediating ferroptosis resistance in human pancreatic cancer cells. The depletion of PIR initiates HMGB1-dependent autophagy by binding to BECN1, and subsequently promotes ferroptosis by activating ACSL4.
Cardiomyopathy [ICD-11: BC43]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [5]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Responsed Drug Dexrazoxane Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Male Wistar rats (250-300 g,n = 230) were purchased from Vitalriver. Ten rats were recruited in each group in the experiment. The rats in the control, DOX, FER-1 + DOX, NEC-1 + DOX, 3-MA + DOX, and Emricasan + DOX groups were used for the overall survival analysis, and those from control and DOX groups were used for detection of the expression of PTGS2 in the indicated organs of rats.

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Response regulation Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). HMGB1 was induced by DOX but was inhibited by DXZ or FER-1. Overexpression of HMGB1 promoted the ferroptosis and cardiotoxicity induced by DOX in the rats although silencing of HMGB1 showed opposite effects.
Hepatoblastoma [ICD-11: DB91]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [6]
Target Regulator High mobility group protein B1 (HMGB1) Protein coding
Responsed Drug Glycyrrhizin Phase 3
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
In total, 40 male specific- pathogen-free C57BL/6 mice (Hubei Animal Experimental Center) 6-8 weeks old. The mice were randomly divided into 5 groups: The normal group, model group, 15 mg/kg GLY group, 30 mg/kg GLY group and 60 mg/kg GLY group. Except for the normal group, the other four groups of mice were injected intraperitoneally with D-GalN (400 mg/kg) and LPS (100 ug/kg) to induce the ALF model. According to a previous study on GLY gavage doses, three doses of GLY (15, 30 and 60 mg/kg/day) intervention groups were used. A total of 24 mice were divided into three groups. Mice received gavage with different doses of GLY for 3 days before induction of the ALF model.

    Click to Show/Hide
Response regulation The HMGB1 inhibitor glycyrrhizin (GLY) significantly reduced the degree of ferroptosis during acute liver failure (ALF) by inhibiting oxidative stress. Treatment with GLY reduced the degree of liver damage, the expression of HMGB1 was decreased, and the levels of Nrf2, HO1 and GPX4 were increased.
Glycyrrhizin [Phase 3]
In total 2 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Suppressor
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
Responsed Disease Hypoxic ischemic brain injury ICD-11: 8B24
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model
rPCNs (Rat primary cortical neurons)
In Vivo Model
Male and female neonatal SpragueDawley rats on postpartum day 7 (P7) were provided by SPF Biotechnology (Beijing, China). Each animal was anesthetized with isoflurane (4% for induction, 2% for maintenance), the skin was incised, and the left common carotid artery was exposed. This artery was ligated with a 5-0 suture and cut, and the skin was sutured closed. Next, the pups recovered for 1 h with their mother. Subsequently, the pups were placed in a hypoxia chamber (8% O2 + 92% N2 mixture) for 2 h. After 2 h of hypoxia, the animals were placed back with their dam.

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Response regulation Glycyrrhizin (GL) not only inhibited ferroptosis induced by RSL3 and oxygen-glucose deprivation in vitro but also inhibited ferroptosis induced by hypoxic-ischemic brain damage (HIBD) in vivo. GL could suppress the occurrence of neuronal ferroptosis and reduce neuronal loss in HIBD via the HMGB1/GPX4 pathway.
Experiment 2 Reporting the Ferroptosis-centered Drug Response [6]
Drug for Ferroptosis Suppressor
Response Target Unspecific Target
Responsed Disease Hepatoblastoma ICD-11: DB91
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
In total, 40 male specific- pathogen-free C57BL/6 mice (Hubei Animal Experimental Center) 6-8 weeks old. The mice were randomly divided into 5 groups: The normal group, model group, 15 mg/kg GLY group, 30 mg/kg GLY group and 60 mg/kg GLY group. Except for the normal group, the other four groups of mice were injected intraperitoneally with D-GalN (400 mg/kg) and LPS (100 ug/kg) to induce the ALF model. According to a previous study on GLY gavage doses, three doses of GLY (15, 30 and 60 mg/kg/day) intervention groups were used. A total of 24 mice were divided into three groups. Mice received gavage with different doses of GLY for 3 days before induction of the ALF model.

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Response regulation The HMGB1 inhibitor glycyrrhizin (GLY) significantly reduced the degree of ferroptosis during acute liver failure (ALF) by inhibiting oxidative stress. Treatment with GLY reduced the degree of liver damage, the expression of HMGB1 was decreased, and the levels of Nrf2, HO1 and GPX4 were increased.
Isoliquiritigenin [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [2]
Drug for Ferroptosis Suppressor
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
Responsed Disease Acute kidney failure ICD-11: GB60
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Male C57BL/6 mice (aged 6-8 weeks and weighing 22-25g) were obtained from the Experimental Animal Center, Sichuan Provincial Peoples Hospital, and were fed a standard laboratory diet. LPS and ISL were dissolved in normal saline and 0.5% Tween-20/saline, respectively. AKI mice were developed by intraperitoneal (i.p.) LPS injection. A total of 30 mice were randomly divided into six groups (n = 5): control, ISL, Fer, LPS, LPS plus ISL, and LPS plus Fer. An intraperitoneal injection of LPS (10 mg/kg) was made to induce septic AKI. ISL was administered via gavage at 50 mg/kg 30 min before LPS injection. Mice were dosed intraperitoneally with Fer (Ferrostatin-1, SML0583, Sigma-Aldrich, St. Louis, MO) at 5 mg/kg. Mice were sacrificed by cervical dislocation 8 h after LPS injection. Kidney tissue and serum samples were collected concurrently.

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Response regulation Isoliquiritigenin (ISL) attenuates septic acute kidney injury by regulating ferritinophagy-mediated ferroptosis. ISL inhibited Fe2+ and lipid peroxidation accumulation in LPS-stimulated HK2 cells. It also increased the expression of GPX4 and xCT, reduced the expression of HMGB1 and NCOA4 then attenuated mitochondria injury in renal tubular following LPS stimulation.
D-Glucose [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [3]
Drug for Ferroptosis Inducer
Response Target Nuclear factor erythroid 2-related factor 2 (NFE2L2) Suppressor; Marker
Responsed Disease Chronic kidney disease ICD-11: GB61
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
SV40 MES 13 cells Normal Mus musculus CVCL_5368
Response regulation Erastin and high glucose both induced ferroptosis in mesangial cells. Suppression of HMGB1 restored cellular proliferation, prevented ROS and LDH generation, decreased ACSL4, PTGS2, and NOX1, and increased GPX4 levels in mesangial cells. Furthermore, nuclear factor E2-related factor 2 (Nrf2) was decreased in diabetic nephropathy (DN) patients and high glucose-mediated translocation of HMGB1 in mesangial cells.
Resveratrol [Phase 3]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [4]
Drug for Ferroptosis Suppressor
Response Target Unspecific Target
Responsed Disease Sepsis ICD-11: 1G40
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model
hCMs (Human cardiomyocytes)
In Vivo Model
Clean male C57BL/6 mice (8-10 wk old, weighing 25-29 g) were purchased from Beijing HFK Bioscience Co. Ltd. The 90 mice were randomly assigned into nine groups after 1 wk of adaptive feeding with 10 mice in each group: normal group (intraperitoneally injected with the same amount of PBS), LPS group [intraperitoneally injected with 15 mg/kg LPS (Sigma-Aldrich, St. Louis, Cat. No. L2880)], LPS + Rsv group (intraperitoneally injected with 15 mg/kg LPS and pretreated with 50 mg/kg resveratrol; 30), LPS + antagomiR-NC group [intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 0.4 pmol/uL antagomiR-NC group (Merck, Darmstadt, Germany)], LPS + miR-149 antagomiR group (intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 0.4 pmol/uL miR-149 antagomiR), LPS + Rsv + miR-149 antagomiR group (intraperitoneally injected with 15 mg/kg LPS, pretreated with 50 mg/kg resveratrol, and simultaneously injected with 0.4 pmol/uL miR-149 antagomiR), LPS + Fer-1 group (intraperitoneally injected with 15 mg/kg LPS, and simultaneously injected with 2.5 umol/kg ferroptosis inhibitor ferrostatin-1), and LPS + Rsv + Fer-1 group (intraperitoneally injected with 15 mg/kg LPS, pretreated with 50 mg/kg resveratrol, and simultaneously injected with 2.5 umol/kg ferroptosis inhibitor ferrostatin-1.

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Response regulation Resveratrol inhibited ferroptosis by upregulating miR-149 and downregulating HMGB1, thus improving endotoxemia-induced myocardial injury in mice.
Dexrazoxane [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [5]
Drug for Ferroptosis Suppressor
Response Target Unspecific Target
Responsed Disease Cardiomyopathy ICD-11: BC43
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Male Wistar rats (250-300 g,n = 230) were purchased from Vitalriver. Ten rats were recruited in each group in the experiment. The rats in the control, DOX, FER-1 + DOX, NEC-1 + DOX, 3-MA + DOX, and Emricasan + DOX groups were used for the overall survival analysis, and those from control and DOX groups were used for detection of the expression of PTGS2 in the indicated organs of rats.

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Response regulation Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). HMGB1 was induced by DOX but was inhibited by DXZ or FER-1. Overexpression of HMGB1 promoted the ferroptosis and cardiotoxicity induced by DOX in the rats although silencing of HMGB1 showed opposite effects.
References
Ref 1 Glycyrrhizin Attenuates Hypoxic-Ischemic Brain Damage by Inhibiting Ferroptosis and Neuroinflammation in Neonatal Rats via the HMGB1/GPX4 Pathway. Oxid Med Cell Longev. 2022 Apr 7;2022:8438528. doi: 10.1155/2022/8438528. eCollection 2022.
Ref 2 Isoliquiritigenin attenuates septic acute kidney injury by regulating ferritinophagy-mediated ferroptosis. Ren Fail. 2021 Dec;43(1):1551-1560. doi: 10.1080/0886022X.2021.2003208.
Ref 3 HMGB1 regulates ferroptosis through Nrf2 pathway in mesangial cells in response to high glucose. Biosci Rep. 2021 Feb 26;41(2):BSR20202924. doi: 10.1042/BSR20202924.
Ref 4 Resveratrol mediates the miR-149/HMGB1 axis and regulates the ferroptosis pathway to protect myocardium in endotoxemia mice. Am J Physiol Endocrinol Metab. 2022 Jul 1;323(1):E21-E32. doi: 10.1152/ajpendo.00227.2021. Epub 2022 May 9.
Ref 5 Protective Effects of Dexazoxane on Rat Ferroptosis in Doxorubicin-Induced Cardiomyopathy Through Regulating HMGB1. Front Cardiovasc Med. 2021 Jul 14;8:685434. doi: 10.3389/fcvm.2021.685434. eCollection 2021.
Ref 6 Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress. Mol Med Rep. 2019 Nov;20(5):4081-4090. doi: 10.3892/mmr.2019.10660. Epub 2019 Sep 10.
Ref 7 HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRAS(Q61L) cells. Am J Cancer Res. 2019 Apr 1;9(4):730-739. eCollection 2019.
Ref 8 Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis. Biochem Biophys Res Commun. 2021 Jan 15;536:100-106. doi: 10.1016/j.bbrc.2020.12.066. Epub 2020 Dec 26.