Affinage

PCSK9

Proprotein convertase subtilisin/kexin type 9 · UniProt Q8NBP7

Length
692 aa
Mass
74.3 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK9 is a secreted proteinase K-like subtilase that governs LDL cholesterol metabolism by controlling the surface abundance of the LDL receptor (LDLR), and human gain-of-function mutations (S127R, D374Y) in PCSK9 cause autosomal dominant hypercholesterolemia (PMID:12730697). The protein matures by Ca2+-independent autocatalytic intramolecular cleavage of its prosegment at an (Y,I)VV(V,L)(L,M) motif in the ER, with hydrophobic residues at P1/P3/P5 critical for recognition, after which the mature convertase is secreted (PMID:12552133, PMID:15358785, PMID:14622975). Its proteolytic activity is dispensable for LDLR regulation: instead PCSK9 acts as a chaperone, binding LDLR and routing it to lysosomal degradation rather than recycling (PMID:15358785, PMID:18649882). Mechanistically, the PCSK9 catalytic domain engages the EGF-A domain of LDLR at the cell surface; after clathrin-mediated co-internalization, an acidic-pH electrostatic interaction with the LDLR ligand-binding domain holds the complex together and blocks the conformational change LDLR needs to recycle (PMID:25222343), specifically preventing LDLR from binding the recycling adaptor SNX17 and thereby diverting it to lysosomal destruction (PMID:40071387). The C-terminal Cys/His-rich domain (CHRD) is a second functional module required for full activity; it is bound and inhibited by Annexin A2 and engages CAP1 in support of LDLR degradation (PMID:35552680, PMID:19063703). Beyond LDLR, PCSK9 drives lysosomal degradation of MHC class I on tumor cells, dampening cytotoxic T-cell infiltration so that its blockade potentiates anti-PD1 therapy (PMID:33177715), and it activates LDLR-independent pro-inflammatory signaling through cell-surface CAP1, triggering a Syk–PKCδ–NF-κB axis that upregulates TLR4, scavenger receptors, and cytokines (PMID:38555386). PCSK9 secretion is itself induced by NLRP3 inflammasome/IL-1β signaling (PMID:32641981), and its expression level in pancreatic cancer cells reprograms cholesterol metabolism to dictate metastatic organ tropism between liver and lung (PMID:40399683).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Established the enzymatic identity of PCSK9, answering how the newly identified protein matures and what cleavage specificity governs its zymogen processing.

    Evidence Biosynthetic analysis, microsequencing, in vitro peptide processing, and Ala-scanning across P1-P5 of recombinant enzyme

    PMID:12552133 PMID:14622975

    Open questions at the time
    • Did not identify physiological substrates beyond the prosegment
    • Did not connect the protease activity to a cellular function
  2. 2003 High

    Connected PCSK9 to human disease, answering whether the protein has a physiological role in lipid homeostasis by linking specific mutations to hypercholesterolemia.

    Evidence Linkage mapping and mutation identification in autosomal dominant hypercholesterolemia kindreds

    PMID:12730697

    Open questions at the time
    • Did not establish the molecular mechanism by which mutations raise LDL
    • Did not distinguish gain- versus loss-of-function consequences mechanistically
  3. 2003 High

    Showed PCSK9 acts on the LDLR and operates in vivo, answering whether PCSK9 controls LDL by degrading the receptor and whether the effect is LDLR-dependent.

    Evidence Stable HepG2 overexpression with ammonium chloride inhibition, adenoviral hepatic overexpression in WT and LDLR-/- mice, and characterization of mutant zymogen processing

    PMID:15358785

    Open questions at the time
    • Did not resolve whether catalytic activity was required for LDLR loss
    • The LDLR-independent ~2-fold effect in LDLR-/- mice was unexplained
  4. 2003 Medium

    Localized the maturation and trafficking of PCSK9, addressing where processing occurs and how the secreted protein intersects the LDLR endocytic route.

    Evidence Subcellular fractionation and confocal double-immunofluorescence with LDLR and clathrin antibodies

    PMID:16462892

    Open questions at the time
    • Colocalization was partial and correlative
    • Did not demonstrate direct co-trafficking of a PCSK9-LDLR complex
  5. 2006 Medium

    Probed non-hepatic roles, testing whether PCSK9 has functions outside cholesterol metabolism in the nervous system.

    Evidence Morpholino knockdown in zebrafish with neuroanatomical phenotyping, and overexpression with active-site/deletion mutants in primary cerebellar granule neurons

    PMID:16893422 PMID:17051583

    Open questions at the time
    • Morpholino specificity and off-target effects not fully excluded
    • Mechanistic link between protease activity and neuronal apoptosis not defined
    • Relevance to mammalian CNS unestablished
  6. 2008 High

    Resolved the central mechanistic question of whether PCSK9 needs its protease activity, establishing that it acts as a non-enzymatic chaperone for LDLR degradation.

    Evidence Catalytic-site mutagenesis combined with crystal structure determination and LDLR degradation assays

    PMID:18649882

    Open questions at the time
    • Did not define the endosomal trafficking step that commits LDLR to lysosomes
    • Did not explain how the complex evades recycling
  7. 2009 Medium

    Identified the CHRD as a functional domain and an endogenous regulator, addressing how PCSK9 activity can be modulated post-secretion.

    Evidence Domain mapping and binding assays with Annexin A2, plus LDLR degradation assays

    PMID:19063703

    Open questions at the time
    • Structural basis of Annexin A2-CHRD binding not resolved
    • Physiological extent of Annexin A2 regulation in vivo unquantified
  8. 2014 High

    Assembled the molecular model of how PCSK9 traps LDLR, answering how a surface-binding event is converted into lysosomal diversion and how circulating PCSK9 is buffered.

    Evidence Mechanistic synthesis of structural/biochemical data on EGF-A binding and acidic-pH C-terminal interaction; biochemical apoB100-PCSK9 binding and LDLR competition assays

    PMID:25110901 PMID:25222343

    Open questions at the time
    • Identity of the recycling-blocking adaptor not yet defined
    • In vivo relevance of the apoB100 feedback not quantified
  9. 2015 Medium

    Extended PCSK9 into vascular inflammation, addressing whether PCSK9 participates in atherogenic signaling independent of hepatic lipid handling.

    Evidence Reciprocal siRNA/overexpression and LOX-1 and PCSK9 knockout mice with mtROS manipulation; NF-kB/VCAM-1 readouts

    PMID:26092101

    Open questions at the time
    • Direct physical interaction not demonstrated
    • Causal direction of the LOX-1/PCSK9 loop incompletely resolved
  10. 2020 High

    Defined an immune function for PCSK9, answering whether it regulates antigen presentation and could be leveraged in cancer immunotherapy.

    Evidence Co-immunoprecipitation, PCSK9 deletion and neutralizing antibody in syngeneic tumors, MHC-I flow cytometry, and T-cell depletion epistasis

    PMID:33177715

    Open questions at the time
    • Domain of PCSK9 mediating MHC-I binding not mapped
    • Whether MHC-I degradation uses the same trafficking machinery as LDLR unknown
  11. 2020 Medium

    Identified an upstream regulator of PCSK9 release, addressing how inflammation controls PCSK9 levels.

    Evidence NLRP3, IL-1b, IL-18 and caspase-1 knockout mice, macrophages, and high-fat diet model measuring PCSK9 secretion

    PMID:32641981

    Open questions at the time
    • Mechanism by which IL-1b drives secretion not defined
    • Tissue source contributions not fully separated
  12. 2021 Medium

    Linked PCSK9 to macrophage lipid uptake and secretion, addressing partners that act with PCSK9 in foam-cell formation.

    Evidence Co-IP and siRNA of LRP5 and PCSK9 in primary human macrophages with cholesterol ester and NF-kB assays

    PMID:32991689

    Open questions at the time
    • Single-lab Co-IP without structural mapping
    • Whether LRP5 is a PCSK9 degradation substrate or a secretion cofactor unresolved
  13. 2022 High

    Identified the receptor for LDLR-independent inflammatory signaling, answering how secreted PCSK9 transmits a pro-inflammatory signal at the cell surface.

    Evidence Unbiased transcriptomics, recombinant PCSK9 stimulation of LDLR-/- macrophages, CAP1 identification with CAP1-Fc antagonism, and AAV PCSK9 in Ldlr-/- mice with molecular imaging

    PMID:38555386

    Open questions at the time
    • Structural basis of PCSK9-CAP1 engagement not solved
    • How CAP1 couples to Syk activation mechanistically unclear
  14. 2022 Medium

    Connected the CHRD to CAP1 in LDLR degradation, addressing the role of the second PCSK9 domain in receptor turnover.

    Evidence Domain-deletion and binding studies summarized with primary data

    PMID:35552680

    Open questions at the time
    • Review-level synthesis rather than single primary dataset
    • Quantitative contribution of CHRD-CAP1 versus catalytic-EGF-A binding not separated
  15. 2024 Medium

    Revealed a hepatic bile-acid axis controlled by PCSK9, addressing downstream metabolic consequences of PCSK9 inhibition.

    Evidence Hepatocyte PCSK9 inhibition, PPARa nuclear/lysosomal fractionation, CYP7A1 promoter-reporter, and gallstone mouse model with alirocumab

    PMID:38191052

    Open questions at the time
    • Whether PCSK9 directly degrades PPARa or acts indirectly unresolved
    • Single-lab in vivo model
  16. 2025 High

    Pinpointed the recycling step PCSK9 blocks, answering precisely how PCSK9 converts endosomal LDLR from recycling to degradation.

    Evidence SNX17 knockdown in cells and in vivo, LDLR-/- HuH7 cells and mice reconstituted with FH variants, pH-dependent conformational and co-IP assays

    PMID:40071387

    Open questions at the time
    • Structure of the LDLR-SNX17 interface not solved
    • Why some FH variants are intrinsically PCSK9-unresponsive at atomic detail unclear
  17. 2025 High

    Established PCSK9 as a determinant of cancer metastatic tropism, addressing how PCSK9 expression reprograms cholesterol metabolism to dictate organ colonization.

    Evidence In vivo PDAC metastasis modeling with PCSK9 overexpression/ablation, mTORC1 assays, oxysterol quantification, and ferroptosis assays

    PMID:40399683

    Open questions at the time
    • Whether tropism control depends on secreted versus intracellular PCSK9 unresolved
    • Generalizability beyond pancreatic cancer untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PCSK9 selects and traffics its non-LDLR targets (MHC-I and other receptors) and whether a single structural mechanism unifies its chaperone, inflammatory, and metabolic-reprogramming functions remain unresolved.
  • No shared structural model linking LDLR, MHC-I, and CAP1 engagement
  • Domain requirements for non-LDLR cargo degradation unmapped
  • Relative in vivo contribution of intracellular versus secreted PCSK9 to each function unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0016787 hydrolase activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005764 lysosome 3 GO:0005576 extracellular region 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9609507 Protein localization 2 R-HSA-162582 Signal Transduction 1
Partners
ANXA2APOBCAP1LDLRLOX-1LRP5MHC CLASS ISNX17

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PCSK9 (NARC-1) is a proteinase K-like subtilase that undergoes autocatalytic intramolecular processing of its prosegment at the (Y,I)VV(V,L)(L,M) motif; in vitro peptide processing studies and Ala substitutions of P1–P5 sites established that hydrophobic/aliphatic residues are critical at P1, P3, and P5 for substrate recognition. Biosynthetic analysis, microsequencing of WT and mutant enzyme, in vitro peptide processing assays, Ala-scanning mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 12552133
2003 Gain-of-function mutations in PCSK9 (S127R and D374Y) cause autosomal dominant hypercholesterolemia, establishing PCSK9 as a genetic determinant of LDL cholesterol metabolism. Human genetic linkage mapping and mutation identification in ADH kindreds Nature genetics High 12730697
2003 PCSK9 autocatalytic zymogen processing is Ca2+-independent; Val at P4 and Pro at P3′ are critical for processing at the SSVFAQ↓SIP site. Gain-of-function mutants S127R and D374Y reduce zymogen processing by ~50–60% and ≥98%, respectively, whereas F216L, R218S, and double D374Y+N157K mutants show normal processing. Biosynthetic analysis of WT and natural mutant NARC-1, site-directed mutagenesis, Ca2+-depletion experiments The Journal of biological chemistry High 15358785
2003 Overexpression of NARC-1/PCSK9 in stable HepG2 cells reduces LDL receptor (LDLR) levels, an effect abrogated by ammonium chloride, indicating PCSK9 increases LDLR turnover via a lysosomal/endosomal pathway. Stable HepG2 cell overexpression, Western blot for LDLR, ammonium chloride inhibition of lysosomal degradation The Journal of biological chemistry High 15358785
2003 Adenoviral expression of human NARC-1 in mice produces up to ~9-fold increase in circulating LDL cholesterol; in LDLR−/− mice a smaller ~2-fold delayed increase occurs, demonstrating both LDLR-dependent and LDLR-independent effects on LDL. Adenoviral hepatic overexpression in WT and LDLR−/− mice, plasma LDL measurement The Journal of biological chemistry High 15358785
2003 NARC-1 autocatalytic processing occurs in the ER, and the mature convertase is secreted from liver and hepatoma cells; PCSK9 shows partial colocalization with clathrin-coated vesicles and LDLR by double immunofluorescence. Subcellular fractionation, Western blotting, confocal immunofluorescence double-labeling with LDLR and clathrin antibodies Biochemistry and cell biology Medium 16462892
2003 Rat Narc1 undergoes autocatalytic intramolecular processing at LVFAQ↓, generating an active protease with a broad alkaline pH optimum and no apparent calcium requirement; both primary and secondary structural determinants influence substrate recognition; the enzyme is classified in the proteinase K subfamily. Functional characterization: recombinant expression, prosegment cleavage assay, pH and calcium-dependence assays, substrate profiling Archives of biochemistry and biophysics High 14622975
2006 Specific morpholino knockdown of zebrafish NARC-1/PCSK9 mRNA causes disorganization of cerebellar neurons and loss of hindbrain-midbrain boundaries leading to embryonic death, establishing a role for PCSK9 in CNS development distinct from its hepatic cholesterol function. Whole-mount in situ hybridization, morpholino-mediated knockdown in zebrafish, phenotypic analysis Journal of neurochemistry Medium 16893422
2006 NARC-1/PCSK9 overexpression in cerebellar granule neurons (CGNs) promotes caspase-dependent and caspase-independent apoptosis; mutation of the active-site serine or deletion of the catalytic domain reduces the BAF-sensitive (caspase-dependent) component of cell death, linking the protease activity to pro-apoptotic signaling. Transfection of EGFP-fusion constructs (WT, active-site mutant, deletion mutants) in primary CGNs; laser scanning cytometry-based cell death scoring; BAF (poly-caspase inhibitor) treatment Cytometry Part A Medium 17051583
2008 The enzymatic (protease) activity of PCSK9 is not required for LDLR degradation; instead, PCSK9 acts as a chaperone that binds LDLR and targets it for lysosomal degradation. This was demonstrated by site-directed mutagenesis of the catalytic site and crystal structure determination. Site-directed mutagenesis of catalytic site; crystal structure determination; LDLR degradation assays Atherosclerosis High 18649882
2014 The catalytic domain of PCSK9 binds to the EGF-A domain of LDLR at the cell surface. Following clathrin-mediated endocytosis, an additional electrostatic interaction at acidic pH between the C-terminal domain of PCSK9 and the ligand-binding domain of LDLR keeps the complex intact in the sorting endosome, preventing LDLR from adopting a closed conformation required for recycling. LDLR ectodomain is subsequently cleaved by a cysteine cathepsin in the sorting endosome, directing it to lysosomal degradation. Literature synthesis of structural, biochemical, and cell biology studies; mechanistic model supported by referenced crystal structure and endosomal pH-dependence experiments Atherosclerosis High 25222343
2015 LOX-1 and PCSK9 positively regulate each other's expression in vascular endothelial and smooth muscle cells; siRNA knockdown of each reduces the other's expression, and LOX-1 KO mice show reduced PCSK9 and vice versa. Mitochondrial ROS (mtROS) acts as an upstream initiator of this crosstalk, and PCSK9 regulates VCAM-1 expression via NF-κB signaling. siRNA knockdown, cDNA overexpression, LOX-1 and PCSK9 knockout mice, mtROS inhibition/induction experiments Cardiovascular research Medium 26092101
2020 PCSK9 physically associates with MHC class I proteins on tumor cell surfaces, promotes their relocation and lysosomal degradation, thereby reducing MHC-I cell surface expression; PCSK9 genetic deletion or antibody neutralization increases tumor cell surface MHC-I and enhances intratumoral cytotoxic T cell infiltration, potentiating anti-PD1 immune checkpoint therapy. Co-immunoprecipitation (physical association), PCSK9 gene deletion in mouse cancer cells, PCSK9 neutralizing antibodies, flow cytometry for MHC-I surface levels, T-cell depletion experiments, syngeneic mouse tumor models Nature High 33177715
2020 NLRP3 inflammasome and its downstream signals (ASC, Caspase-1, IL-1β, IL-18) regulate PCSK9 secretion from macrophages and multiple tissues; IL-1β is identified as more important than IL-18 in inducing PCSK9 secretion; MAPKs are involved. High-fat diet-induced PCSK9 secretion is attenuated in IL-1β-deficient mice. Gene deletion mice (NLRP3 KO, IL-1β KO, IL-18 KO, caspase-1 KO), mouse peritoneal macrophages in vitro, high-fat diet in vivo model, PCSK9 secretion measurement Theranostics Medium 32641981
2021 LRP5 forms a physical complex with PCSK9 in lipid-loaded macrophages, and both contribute to macrophage lipid uptake. In the absence of both LRP5 and PCSK9, cholesterol ester accumulation is strongly reduced. LRP5 silencing also reduces soluble PCSK9 release, indicating LRP5 participates in PCSK9 secretion. PCSK9 upregulates TLR4/NF-κB signaling in macrophages after lipid loading. Co-immunoprecipitation, siRNA knockdown of LRP5 and PCSK9 in primary human macrophages, cholesterol ester accumulation assay, NF-κB nuclear translocation assay Cardiovascular research Medium 32991689
2022 Adenylyl cyclase-associated protein 1 (CAP1) is identified as the main cell-surface binding partner of PCSK9 in macrophages, mediating LDLR-independent pro-inflammatory signaling. PCSK9-CAP1 binding activates spleen tyrosine kinase (Syk) and PKCδ, leading to NF-κB activation and upregulation of TLR4, scavenger receptors, and pro-inflammatory cytokines. In LDLR-knockout mice, AAV-mediated PCSK9 overexpression promotes vein graft lesion development without altering cholesterol levels. Systems biology/transcriptomics, in vitro stimulation of LDLR−/− macrophages with recombinant PCSK9, AAV gain-of-function in Ldlr−/− mice, in vivo molecular imaging, unbiased network analysis identifying CAP1, functional validation with CAP1-Fc fragment Nature communications High 38555386
2022 The C-terminal Cys/His-rich domain (CHRD) of PCSK9 is required (in addition to catalytic domain binding to EGF-A of LDLR) for PCSK9 function; CHRD binds the secreted cytosolic cyclase associated protein 1 (CAP1), and this interaction is necessary for PCSK9-mediated LDLR degradation. Structural and biochemical analyses, domain-deletion studies, binding assays cited in review with primary data Endocrine reviews Medium 35552680
2025 PCSK9 prevents the acidic pH-induced conformational change in the LDLR extracellular domain that is required for LDLR interaction with SNX17 (sorting nexin 17) via the LDLR intracellular domain. SNX17 is required for LDLR recycling; knocking down SNX17 abolishes LDLR recycling and causes lysosomal degradation. PCSK9 blocks SNX17 binding to LDLR, thereby diverting LDLR to lysosomal degradation. FH-associated sequence variations that disrupt LDLR recycling are unresponsive to PCSK9 or PCSK9 inhibitors. SNX17 knockdown in cells and in vivo, LDLR knockout HuH7 cells and mice reconstituted with FH variants, conformational assays, co-immunoprecipitation of LDLR-SNX17 interaction at neutral vs. acidic pH, PCSK9 binding assays Circulation High 40071387
2024 PCSK9 inhibition in hepatocytes enhances the nuclear expression of PPARα by diminishing its lysosomal degradation, which subsequently activates CYP7A1 transcription and increases conversion of cholesterol to bile acids, preventing cholesterol gallstone formation in mice. In vitro PCSK9 inhibition in hepatocytes, nuclear/cytosolic fractionation for PPARα, PPARα lysosomal degradation assay, CYP7A1 promoter-reporter assay, CGS mouse model with alirocumab treatment Metabolism: clinical and experimental Medium 38191052
2025 PCSK9 expression level in pancreatic ductal adenocarcinoma cells determines metastatic organ preference: PCSK9-low cells preferentially colonize the LDL-rich liver (importing LDL-cholesterol to activate mTORC1 and generate signaling oxysterol 24(S)-hydroxycholesterol), whereas PCSK9-high cells colonize the lung by upregulating distal cholesterol synthesis intermediates (7-dehydrocholesterol, 7-dehydrodesmosterol) that protect against ferroptosis. Increasing PCSK9 redirects liver-avid cells to the lung; ablating PCSK9 drives lung-avid cells to the liver. In vivo mouse metastasis modeling, gene expression correlation analysis, PCSK9 overexpression and genetic ablation in PDAC cell lines, mTORC1 activity assays, oxysterol quantification, ferroptosis assays Nature High 40399683
2009 Annexin A2 specifically binds the C-terminal Cys/His-rich domain (CHRD) of PCSK9 and inhibits its function on LDLR degradation, identifying CHRD as a functional domain and Annexin A2 as an endogenous inhibitor. Binding assays, PCSK9 domain mapping, LDLR degradation assay with Annexin A2 Expert opinion on therapeutic targets Medium 19063703
2014 Circulating PCSK9 binds to apolipoprotein B100 on LDL particles, which inhibits PCSK9's ability to bind to cell surface LDLRs, providing a negative feedback mechanism on PCSK9 activity. Biochemical binding assays (PCSK9-LDL interaction), LDLR binding competition assays Current opinion in lipidology Medium 25110901

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature genetics 2308 12730697
2003 The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proceedings of the National Academy of Sciences of the United States of America 989 12552133
2016 A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. The New England journal of medicine 601 27959715
2004 NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. The Journal of biological chemistry 541 15358785
2014 PCSK9: a key modulator of cardiovascular health. Circulation research 492 24625727
2020 Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature 387 33177715
2012 The PCSK9 decade. Journal of lipid research 369 22811413
2014 PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Current opinion in lipidology 286 25110901
2019 PCSK9 inhibitors: clinical evidence and implementation. Nature reviews. Cardiology 264 30420622
2015 Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovascular research 205 26092101
2022 The Multifaceted Biology of PCSK9. Endocrine reviews 184 35552680
2014 Lipid lowering with PCSK9 inhibitors. Nature reviews. Cardiology 178 24958078
2019 PCSK9 and inflammation: a review of experimental and clinical evidence. European heart journal. Cardiovascular pharmacotherapy 172 31236571
2008 Molecular basis of PCSK9 function. Atherosclerosis 164 18649882
2021 PCSK9 Biology and Its Role in Atherothrombosis. International journal of molecular sciences 135 34070931
2011 Clinical aspects of PCSK9. Atherosclerosis 133 21596380
2003 Functional characterization of Narc 1, a novel proteinase related to proteinase K. Archives of biochemistry and biophysics 132 14622975
2024 Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal transduction and targeted therapy 127 38185721
2018 Inhibiting PCSK9 - biology beyond LDL control. Nature reviews. Endocrinology 119 30367179
2019 Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1. International journal of molecular medicine 118 31524223
2009 PCSK9 as a therapeutic target of dyslipidemia. Expert opinion on therapeutic targets 112 19063703
2017 Regulation of PCSK9 by nutraceuticals. Pharmacological research 107 28363723
2023 Targeting PCSK9 to tackle cardiovascular disease. Pharmacology & therapeutics 106 37331523
2018 Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clinical pharmacokinetics 103 29353350
2006 Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system. Journal of neurochemistry 102 16893422
2017 Lipid Lowering Therapy and Circulating PCSK9 Concentration. Journal of atherosclerosis and thrombosis 100 28804094
2019 PCSK9 inhibition and inflammation: A narrative review. Atherosclerosis 99 31404822
2013 Targeting PCSK9 for hypercholesterolemia. Annual review of pharmacology and toxicology 94 24160703
2021 Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications. Frontiers in cardiovascular medicine 90 34782856
2021 PCSK9 and cancer: Rethinking the link. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 83 34058443
2022 PCSK9 Inhibition: From Current Advances to Evolving Future. Cells 82 36230934
2020 An Update on the Role of PCSK9 in Atherosclerosis. Journal of atherosclerosis and thrombosis 81 32713931
2017 Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease. Basic research in cardiology 77 28439730
2017 A Therapeutic Peptide Vaccine Against PCSK9. Scientific reports 77 28970592
2021 PCSK9 and LRP5 in macrophage lipid internalization and inflammation. Cardiovascular research 73 32991689
2020 PCSK9 and atherosclerosis: Looking beyond LDL regulation. European journal of clinical investigation 73 33236356
2022 Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis. Journal of the American Heart Association 72 35048716
2022 A Comprehensive Review of PCSK9 Inhibitors. Journal of cardiovascular pharmacology and therapeutics 72 35593194
2015 Role of PCSK9 beyond liver involvement. Current opinion in lipidology 71 25887680
2014 Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis 71 25222343
2018 PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety. Reviews in cardiovascular medicine 70 30207556
2013 PCSK9: From discovery to therapeutic applications. Archives of cardiovascular diseases 70 24373748
2019 PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention. Thrombosis and haemostasis 68 30605918
2020 NLRP3 inflammasome via IL-1β regulates PCSK9 secretion. Theranostics 67 32641981
2022 Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms. Circulation research 66 36263780
2017 PCSK9 and Atherosclerosis - Lipids and Beyond. Journal of atherosclerosis and thrombosis 64 28302950
2020 PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects. Frontiers in physiology 63 33304274
2022 Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond. Current atherosclerosis reports 62 35904732
2017 Hypercholesterolemia: The role of PCSK9. Archives of biochemistry and biophysics 62 28587771
2017 PCSK9 inhibition in the management of familial hypercholesterolemia. Journal of cardiology 62 28784313
2008 PCSK9 function and physiology. Journal of lipid research 61 18663786
2017 PCSK9 at the crossroad of cholesterol metabolism and immune function during infections. Journal of cellular physiology 60 28063230
2016 PCSK9: Regulation and Target for Drug Development for Dyslipidemia. Annual review of pharmacology and toxicology 56 27575716
2018 Role of PCSK9 in lipid metabolism and atherosclerosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 29758414
2018 PCSK9: A novel inflammation modulator in atherosclerosis? Journal of cellular physiology 54 30246446
2006 Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding a novel serine proteinase. Cytometry. Part A : the journal of the International Society for Analytical Cytology 51 17051583
2021 Proprotein convertase subtilisin/kexin type 9 (PCSK9): A potential multifaceted player in cancer. Biochimica et biophysica acta. Reviews on cancer 50 34144130
2021 PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology. Biomedicines 50 34356856
2016 Statins and Their Effect on PCSK9-Impact and Clinical Relevance. Current atherosclerosis reports 48 27315084
2023 PCSK9 attenuates efferocytosis in endothelial cells and promotes vascular aging. Theranostics 47 37284459
2017 PCSK9 and diabetes: is there a link? Drug discovery today 47 28111330
2016 Targeting PCSK9 for therapeutic gains: Have we addressed all the concerns? Atherosclerosis 47 26987067
2022 Safety of PCSK9 inhibitors. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 46 36411665
2020 New Pharmacological Approaches to Target PCSK9. Current atherosclerosis reports 46 32495301
2008 PCSK9: an enigmatic protease. Biochimica et biophysica acta 46 18280815
2024 PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor. Nature communications 45 38555386
2020 microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production. JCI insight 45 33119548
2021 Pleiotropic Effects of PCSK-9 Inhibitors. International journal of molecular sciences 43 33808697
2020 Safety and Tolerability of PCSK9 Inhibitors: Current Insights. Clinical pharmacology : advances and applications 42 33335431
2020 Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall. Journal of cellular physiology 41 32875580
2017 PCSK9 in chronic kidney disease. International urology and nephrology 41 28084558
2017 PCSK9 targets important for lipid metabolism. Clinical research in cardiology supplements 40 28176216
2018 PCSK9 and neurocognitive function: Should it be still an issue after FOURIER and EBBINGHAUS results? Journal of clinical lipidology 39 30318062
2013 PCSK9 inhibitors. Current opinion in lipidology 39 23652470
2018 PCSK9: from biology to clinical applications. Pathology 38 30522786
2017 Nutritional and Lipid Modulation of PCSK9: Effects on Cardiometabolic Risk Factors. The Journal of nutrition 37 28179493
2018 Beyond LDL: What Role for PCSK9 in Triglyceride-Rich Lipoprotein Metabolism? Trends in endocrinology and metabolism: TEM 36 29665987
2014 PCSK9: A key factor modulating atherosclerosis. Journal of atherosclerosis and thrombosis 35 25410128
2022 PCSK9: A emerging participant in heart failure. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 36535197
2018 Potentiation of Psoriasis-Like Inflammation by PCSK9. The Journal of investigative dermatology 34 30395847
2014 Antihyperlipidemic therapies targeting PCSK9. Cardiology in review 34 24407047
2025 PCSK9 Promotes LDLR Degradation by Preventing SNX17-Mediated LDLR Recycling. Circulation 33 40071387
2025 PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer. Nature 32 40399683
2024 PCSK9 in metabolism and diseases. Metabolism: clinical and experimental 32 39547595
2022 PCSK9 promotes arterial medial calcification. Atherosclerosis 32 35135698
2023 The evolving landscape of PCSK9 inhibition in cancer. European journal of pharmacology 31 37059376
2022 Gene Therapy Targeting PCSK9. Metabolites 31 35050192
2020 Characterization of PCSK9 in the Blood and Skin of Psoriasis. The Journal of investigative dermatology 31 32615123
2021 The role of PCSK9 in inflammation, immunity, and autoimmune diseases. Expert review of clinical immunology 30 34928185
2015 PCSK9 and triglyceride-rich lipoprotein metabolism. Journal of biomedical research 30 26320603
2006 Expression and localization of PCSK9 in rat hepatic cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 30 16462892
2024 Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation. Metabolism: clinical and experimental 29 38191052
2020 PCSK9: Associated with cardiac diseases and their risk factors? Archives of biochemistry and biophysics 29 33307067
2017 PCSK9 and infection: A potentially useful or dangerous association? Journal of cellular physiology 29 28574577
2023 Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system. Neuroscience and biobehavioral reviews 28 37019248
2023 PCSK9 and the nervous system: a no-brainer? Journal of lipid research 28 37586604
2018 Proprotein Convertase Subtilisin-Kexin type-9 (PCSK9) and triglyceride-rich lipoprotein metabolism: Facts and gaps. Pharmacological research 28 29428206
2023 PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice. Brain, behavior, and immunity 27 37967665
2014 PCSK9 and lipid lowering drugs. Clinica chimica acta; international journal of clinical chemistry 27 25036764
2014 PCSK9 and its modulation. Clinica chimica acta; international journal of clinical chemistry 27 25444750

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