Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10280)
Regulator Name Proprotein convertase subtilisin/kexin type 9 (PCSK9)
Synonyms
NARC1; Neural apoptosis-regulated convertase 1; Proprotein convertase 9; Subtilisin/kexin-like protease PC9
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Gene Name PCSK9
Gene ID 255738
Regulator Type Protein coding
Uniprot ID Q8NBP7
Sequence
MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGT
TATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLP
GFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLV
EVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAG
VAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAA
CQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVD
LFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSA
KDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPD
EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAP
PAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASC
CHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRD
VSTTGSTSEGAVTAVAICCRSRHLAQASQELQ

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Family Peptidase S8 family
Function
Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non- proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.

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HGNC ID
HGNC:20001
KEGG ID hsa:255738
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
PCSK9 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
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
HuH-6 cells Hepatoblastoma Homo sapiens CVCL_4381
In Vivo Model
Zebrafish were maintained at 28 and in light cycle conditions (12 h). The Casper mutant fish line was purchased from the Zebrafish International Resource Center (ZIRC). For zebrafish xenotransplantation, 48 hours post-fertilization (hpf) zebrafish embryos were dechorionated and anesthetized in egg water solution containing 0.04 mg/mL tricaine (Sigma-Aldrich, St. Louis, MO, USA) before human cell injection. Approximately 200 to 500 fluorescent cells were injected (Eppendorf Femtojet microinjector) into the ducts of Cuvier of each embryo, and the zebrafish were maintained in 0.3X Danieaus solution for 1 h at 28 . After confirmation of a visible cell mass at the injection site, the zebrafish were transferred to a 24-well plate in 500 uL of a 0.3X Danieaus solution incubator and maintained at 34 . The zebrafish with already formed metastasis at 1 hour post-injection (hpi) were discarded.

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Response regulation The disruption of PCSK9 inhibits the anti-ferroptosis p62-Keap1-Nrf2 pathway, one could speculate that a combination therapy of anti-PCSK9 with sorafenib would alleviate drug resistance and improve prognosis. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat hepatocellular carcinoma.
Hepatocellular carcinoma [ICD-11: 2C12]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Proprotein convertase subtilisin/kexin type 9 (PCSK9) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
HuH-6 cells Hepatoblastoma Homo sapiens CVCL_4381
In Vivo Model
Zebrafish were maintained at 28 and in light cycle conditions (12 h). The Casper mutant fish line was purchased from the Zebrafish International Resource Center (ZIRC). For zebrafish xenotransplantation, 48 hours post-fertilization (hpf) zebrafish embryos were dechorionated and anesthetized in egg water solution containing 0.04 mg/mL tricaine (Sigma-Aldrich, St. Louis, MO, USA) before human cell injection. Approximately 200 to 500 fluorescent cells were injected (Eppendorf Femtojet microinjector) into the ducts of Cuvier of each embryo, and the zebrafish were maintained in 0.3X Danieaus solution for 1 h at 28 . After confirmation of a visible cell mass at the injection site, the zebrafish were transferred to a 24-well plate in 500 uL of a 0.3X Danieaus solution incubator and maintained at 34 . The zebrafish with already formed metastasis at 1 hour post-injection (hpi) were discarded.

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Response regulation The disruption of PCSK9 inhibits the anti-ferroptosis p62-Keap1-Nrf2 pathway, one could speculate that a combination therapy of anti-PCSK9 with sorafenib would alleviate drug resistance and improve prognosis. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat hepatocellular carcinoma.
References
Ref 1 Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis. Cells. 2022 Dec 23;12(1):62. doi: 10.3390/cells12010062.