From November 7-10, 2025, the American Heart Association (AHA) Scientific Sessions were grandly held in New Orleans, USA. During the conference, the Merck Research Laboratories team unveiled the Phase III results for the world's first novel oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, MK0616 (Enlicitide). This achievement marks a significant step forward in the field of lipid-lowering therapy, with Enlicitide decanoate demonstrating substantial efficacy in lowering lipids alongside a favorable safety profile.The PCSK9 target, as a highly popular focus of research, holds immense value in both its research progress and application prospects. Let's explore it in detail!
 

PCSK9 Target IntroductionPCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease encoded by the PCSK9 gene, primarily synthesized and secreted by the liver, with minor presence in the small intestine, pancreas, kidneys, lungs, and central nervous system. It plays a crucial role in regulating blood cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C). The PCSK9 protein contains multiple domains, such as a signal peptide, an inhibitory prodomain, a subtilisin-like catalytic domain, a hinge region, and a cysteine- and histidine-rich C-terminal domain, which determine its proteolytic activity and receptor-binding functions.
 

(Image placeholder: PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity)

 

I) Hypercholesterolemia: The "Regulatory Switch" of Cholesterol Metabolism
 

In the liver, low-density lipoprotein receptors (LDLR) on the surface of hepatocytes bind and internalize LDL-C. Under normal conditions, after LDL-C is degraded in lysosomes, LDLR can be recycled. However, PCSK9 specifically binds to the EGF-A domain of LDLR, forming a stable complex. Once internalized, within the acidic endosomal environment, PCSK9 acts as a "degradation signal," directing the complex to the lysosome, leading to the irreversible degradation of LDLR and preventing its recycling. This results in a reduced number of LDLRs on the hepatocyte surface, decreased hepatic clearance of LDL-C, and elevated plasma LDL-C levels, thereby inducing hypercholesterolemia.

(Image placeholder: PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity)

 

II) Atherosclerosis: Driving Pathology Through Multiple MechanismsPCSK9 promotes atherosclerosis through various mechanisms. Primarily, it binds to and degrades LDLR on hepatocyte surfaces, leading to elevated plasma LDL-C levels. The increased LDL-C infiltrates the arterial intima and becomes oxidized to oxidized LDL (ox-LDL), which is phagocytosed by monocytes to form foam cells, constituting the early atherosclerotic lesion—the fatty streak.
 

A key mechanism involves PCSK9, secreted by macrophages and vascular smooth muscle cells (VSMCs), acting on these cells in an autocrine/paracrine manner. PCSK9 binds to Toll-like receptor 4 (TLR4) on the cell membrane, activating the nuclear factor kappa B (NF-κB) signaling pathway, which induces the release of pro-inflammatory cytokines (such as IL-6, TNF-α), exacerbating local inflammatory responses. This inflammatory environment further promotes the proliferation and migration of VSMCs and leads to apoptosis of foam cells, forming a necrotic core. Ultimately, PCSK9 synergistically amplifies the two core processes of "hypercholesterolemia" and "local vascular wall inflammation," driving the formation, progression, and increased instability of atherosclerotic plaques.
 

 

(Image placeholder: PCSK9 as an Atherothrombotic Risk Factor)

 

III) Cancer Immunity: An Emerging Star MechanismNumerous studies indicate abnormal PCSK9 expression in various cancers (e.g., hepatocellular carcinoma, colorectal cancer, rectal adenocarcinoma, esophageal cancer, gastric adenocarcinoma, stomach cancer, lung cancer, breast cancer). PCSK9 can promote cancer cell proliferation, inhibit apoptosis, and enhance invasion and metastasis capabilities, with mechanisms involving regulation of cholesterol metabolism, induction of endoplasmic reticulum stress, and influence on MAPK/PI3K and other signaling pathways.
 

PCSK9 drives tumor progression through dual mechanisms: within cancer cells, it activates pro-survival signaling pathways such as KRAS-MAPK and PI3K-Akt and upregulates HSP70 expression, thereby promoting proliferation and invasion. Simultaneously, it effectively blocks the apoptotic process by modulating the Bax/Bcl-2 ratio, inhibiting caspase activity, and downregulating molecules like XIAP. Furthermore, PCSK9 can degrade tumor suppressor proteins such as PTEN, inducing therapy resistance. In the tumor microenvironment, PCSK9 degrades MHC-I molecules on cancer cell surfaces, weakening antigen presentation and aiding tumor immune evasion. Concurrently, it directly binds to LDLR on T cell surfaces, interfering with T cell receptor recycling to the membrane, thereby inhibiting T cell activation and cytotoxic functions. These mechanisms collectively lead to immune escape and may enhance resistance to immune checkpoint inhibitors.

(Image placeholder: Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside)

 

Gene Therapy
 

Gene Editing Technology: Utilizes lipid nanoparticles (LNP) encapsulating gene-editing components, which are administered intravenously, taken up by hepatocytes, achieving liver-targeted editing to permanently inactivate the PCSK9 gene within liver cells.

RNA Interference Therapy: Employs N-acetylgalactosamine (GalNAc) conjugated to small interfering RNA (siRNA), which specifically binds to the asialoglycoprotein receptor (ASGPR) on hepatocyte surfaces for precise delivery to the liver, degrading PCSK9 mRNA and preventing its protein synthesis.

Gene-Editing Enzyme Technology: Uses meganucleases delivered via adeno-associated virus (AAV) vectors to the liver, which specifically cleave the PCSK9 gene, causing loss-of-function mutations.

 

Mouse Models
 

PCSK9 KO Mice: The most notable phenotype is extremely low plasma LDL-C levels (reduced by approximately 40%-60%) and a significant increase in the number of LDL receptor (LDLR) proteins on hepatocyte surfaces.

PCSK9 Humanized Mice: Express human PCSK9 with normal metabolism, specifically used to evaluate the in vivo efficacy of antibodies, RNAi drugs, and small molecules targeting human PCSK9.

PCSK9 HU / ApoE KO Double Gene Mice: Introduce the human PCSK9 gene into a disease background of ApoE knockout (causing severe hyperlipidemia and spontaneous atherosclerosis).

Liver-Specific PCSK9 Knockout Mice: Specific knockout of PCSK9 in hepatocytes, primarily used to precisely verify the in vivo mechanisms of liver-targeted drugs.

 

MingCeler Biotech Facilitates Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech can customize various PCSK9-related mouse models according to client needs, such as PCSK9 KO mice, PCSK9 humanized mice, PCSK9 HU / ApoE KO double gene mice, and liver-specific PCSK9 knockout mice. We welcome inquiries!

 

 

QuickMice™ PCSK9 Humanized Mice
 

Strain Name: C57BL/6N-PCSK9tm1Cin(PCSK9)/MC
 

Strain Description
 

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key protein regulating cholesterol metabolism. Inhibiting PCSK9 is an effective method to enhance the efficacy of immune checkpoint inhibitors, and the combination therapy strategy of "PCSK9 inhibitor + immune checkpoint inhibitor" has shown promising results in tumor immunotherapy experiments. Targeting PCSK9 to develop new inhibitors or gene therapies holds bright prospects in both cardiovascular disease treatment and tumor immunotherapy. The hPCSK9 humanized mouse is an important model for PCSK9 inhibitor or gene therapy research and development.
 

The C57BL/6N-hPCSK9 humanized mouse, independently developed by MingCeler Biotech, uses the genomic sequence corresponding to the human PCSK9 transcript NM_174936.4 (5'UTR-3'UTR) to precisely replace the genomic sequence corresponding to the mouse mPCSK9 transcript NM_153565.2 (5'UTR-3'UTR). This design ensures the specific expression of the human PCSK9 gene in mice, providing an important experimental model for studying PCSK9 in cholesterol metabolism and related diseases.

 

Modeling Principle
 

The entire PCSK9 gene of C57BL/6N mice is replaced with the full-length sequence of the human PCSK9 gene. This model ensures specific expression of the human PCSK9 gene in mice.

 

Model Advantages
 

Precisely Mimics Human Gene Expression Patterns: In situ replacement of the mouse PCSK9 gene locus with the full-length human PCSK9 genomic sequence ensures that the expression pattern and tissue specificity of the human PCSK9 gene in mice are consistent with the endogenous state.

Meets Specific Targeted Therapy Research Needs: If the target site of a gene-targeting therapeutic drug is located within the promoter region of the human sequence, MingCeler Biotech's exclusively developed PCSK9 human promoter + full-length gene humanized mouse can be used.

 

Application Areas:
 

Cholesterol metabolism-related research

Cardiovascular disease research

Development of PCSK9-targeted gene therapy drugs

Screening and evaluation of humanized PCSK9 antibodies

Evaluation of PCSK9 antibody combination therapy with statin lipid-lowering drugs

Hypercholesterolemia-related research

 

Validation Data:  (Image Placeholder)

 

References:

1.Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet.34, 154–156 (2003).

2.Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet.37, 161–165 (2005).

3.Lagace, T. A. PCSK9 and LDLR degradation. Curr. Opin. Lipidol.25, 387–393 (2014).

4.Liu, X. et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature588, 693–698 (2020).

5.Seidah, N. G. & Prat, A. The Multifaceted Biology of PCSK9. Endocr. Rev.43, 558–582 (2022).

6.Mahboobnia, K. et al. PCSK9 and cancer: Rethinking the link. Biomed. Pharmacother.140, 111758 (2021).

 

References:

[1] Sotler T, Šebeštjen M. PCSK9 as an Atherothrombotic Risk Factor. Int J Mol Sci. 2023 Jan 19;24(3):1966. doi: 10.3390/ijms24031966. PMID: 36768292; PMCID: PMC9916735.

[2] Bao, X., Liang, Y., Chang, H. et al. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Sig Transduct Target Ther 9, 13 (2024). https://doi.org/10.1038/s41392-023-01690-3

[3] Liu X, Bao X, Hu M, Chang H, Jiao M, Cheng J, Xie L, Huang Q, Li F, Li CY. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature. 2020 Dec;588(7839):693-698. doi: 10.1038/s41586-020-2911-7. Epub 2020 Nov 11. PMID: 33177715; PMCID: PMC7770056.

[4] Mei W, Faraj Tabrizi S, Godina C, Lovisa AF, Isaksson K, Jernström H, Tavazoie SF. A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor. Cell. 2025 Jan 23;188(2):371-389.e28. doi: 10.1016/j.cell.2024.11.009. Epub 2024 Dec 9. PMID: 39657676; PMCID: PMC11770377.

[5] Rademaker G, Hernandez GA, Seo Y, Dahal S, Miller-Phillips L, Li AL, Peng XL, Luan C, Qiu L, Liegeois MA, Wang B, Wen KW, Kim GE, Collisson EA, Kruger SF, Boeck S, Ormanns S, Guenther M, Heinemann V, Haas M, Looney MR, Yeh JJ, Zoncu R, Perera RM. PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer. Nature. 2025 Jul;643(8074):1381-1390. doi: 10.1038/s41586-025-09017-8. Epub 2025 May 21. PMID: 40399683.

 

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