Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10230)
Regulator Name [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial (PDK4)
Synonyms
PDHK4; Pyruvate dehydrogenase kinase isoform 4
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Gene Name PDK4
Gene ID 5166
Regulator Type Protein coding
Uniprot ID Q16654
Sequence
MKAARFVLRSAGSLNGAGLVPREVEHFSRYSPSPLSMKQLLDFGSENACERTSFAFLRQE
LPVRLANILKEIDILPTQLVNTSSVQLVKSWYIQSLMDLVEFHEKSPDDQKALSDFVDTL
IKVRNRHHNVVPTMAQGIIEYKDACTVDPVTNQNLQYFLDRFYMNRISTRMLMNQHILIF
SDSQTGNPSHIGSIDPNCDVVAVVQDAFECSRMLCDQYYLSSPELKLTQVNGKFPDQPIH
IVYVPSHLHHMLFELFKNAMRATVEHQENQPSLTPIEVIVVLGKEDLTIKISDRGGGVPL
RIIDRLFSYTYSTAPTPVMDNSRNAPLAGFGYGLPISRLYAKYFQGDLNLYSLSGYGTDA
IIYLKALSSESIEKLPVFNKSAFKHYQMSSEADDWCIPSREPKNLAKEVAM

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Family PDK/BCKDK protein kinase family
Function
Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.

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HGNC ID
HGNC:8812
KEGG ID hsa:5166
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
PDK4 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
Unspecific Target [Unspecific Target]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Citrate cycle hsa00020
Cell Process Cell ferroptosis
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
PHsPDAC (Primary human pancreatic ductal adenocarcinoma cells)
In Vivo Model
At 6 weeks of age, male C57BL/6J mice received standard diet (SCD) or high-fat diet (HFD; 5.24 kcal/g with 20% energy derived from protein, 60% from fat, and 20% from carbohydrate; Research Diets; D12492) for 12 weeks. Then the mouse PDAC cell lineKPC (male) was implanted subcutaneously into the right abdomen of SCD and HFD mice. Once the tumors reached 60-80 mm3 at day 7, tumor-bearing mice were treated with IKE (40 mg/kg, i.p.,once every other day) or the ferroptosis inhibitor liproxstatin-1 (10 mg/kg, i.p., once every other day) or the PDK inhibitor dichloroacetate (DCA, 50 mg/kg, i.p., once every other day) under the corresponding diet.

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Response regulation PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xcinhibitors in vitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). Individuals with pancreatic ductal adenocarcinoma (PDAC) and diabetes might be particularly suitable for this kind of therapeutic approach.
Pancreatic cancer [ICD-11: 2C10]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial (PDK4) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Citrate cycle hsa00020
Cell Process Cell ferroptosis
In Vitro Model
 PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
MIA PaCa-2 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
PHsPDAC (Primary human pancreatic ductal adenocarcinoma cells)
In Vivo Model
At 6 weeks of age, male C57BL/6J mice received standard diet (SCD) or high-fat diet (HFD; 5.24 kcal/g with 20% energy derived from protein, 60% from fat, and 20% from carbohydrate; Research Diets; D12492) for 12 weeks. Then the mouse PDAC cell lineKPC (male) was implanted subcutaneously into the right abdomen of SCD and HFD mice. Once the tumors reached 60-80 mm3 at day 7, tumor-bearing mice were treated with IKE (40 mg/kg, i.p.,once every other day) or the ferroptosis inhibitor liproxstatin-1 (10 mg/kg, i.p., once every other day) or the PDK inhibitor dichloroacetate (DCA, 50 mg/kg, i.p., once every other day) under the corresponding diet.

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Response regulation PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xcinhibitors in vitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). Individuals with pancreatic ductal adenocarcinoma (PDAC) and diabetes might be particularly suitable for this kind of therapeutic approach.
References
Ref 1 PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis. Cell Rep. 2021 Feb 23;34(8):108767. doi: 10.1016/j.celrep.2021.108767.