PCSK9 was originally identified because of its role in lipid metabolism. However, recent data is demonstrating its involvement in other pathologies such as sepsis and acute respiratory distress syndrome. CLI chatted with Emma Crossley (Queen’s University Belfast, UK) to find out more about the roles of PCSK9 in these diseases.

What is the normal role of proprotein convertase subtilisin-kexin type 9 (PCSK9)?

The classical role of PCSK9 was identified in lipid metabolism. However, before we introduce the role of PCSK9, we need to describe normal low density lipoprotein cholesterol (LDLc; also called cholesterol) metabolism. Here, LDLc binds to the LDL receptor at the surface of hepatocytes and becomes internalized. Then, during the descent towards the lysosome, there’s a drop in pH that induces dissociation of the receptor from its target. This means that while the cholesterol is taken to the lysosome and degraded, the receptor is recycled back to the cell surface. So, one receptor can clear a lot of cholesterol in its 10- to 15-minute period of this recycling.

When PCSK9 is involved, the CAT domain of PCSK9 binds to the EGFR-A domain of the LDL receptor, which changes the structure of the LDL receptor and prevents the dissociation of LDLc from the receptor and the entire complex is directed to the lysosome for degradation. Additionally, nascent PCSK9 can also bind the LDL receptor in the Golgi network and target it to the lysosome for degradation. Hence, the presence of PCSK9 reduces the expression of LDL receptor at the cell surface and results in an increase in plasma levels of LDLc.

If the reduction of the LDL receptor at the cell surface is persistent, an individual has a gain of function mutation in PCSK9 or they produce too much PCSK9, this results in a higher plasma LDLc concentration and an increased risk of cardiovascular events in the future.

How is PCSK9 linked to disease?

The discovery of PCSK9’s role in disease came about by happy accident, as the result of a collaboration between two research groups. Nabil Seidah identified the protein because he was looking at the entire PCSK family and found the 9th member – he was contacted by Catherine Boileau, who was looking into familial hypercholesterolemia, and they identified gain of function mutations within the protein as causes of familial hypercholesterolemia. After that discovery, in 2003, they identified the role of PCSK9 in actually degrading the LDL receptor and so linked it to wider cardiovascular disease – dyslipidemia or atherosclerosis, for example. Loss of function mutations do exist. At the minute, and I stress at the minute, there doesn’t seem to be any adverse effects associated with loss of function mutations. Those individuals will have a lower concentration of plasma LDLc, but they don’t seem to suffer any adverse effects from that. We’re discovering new things every day, but at the minute, loss of function mutations don’t seem to do anything too worrying or strange to the body, which is why PCSK9 inhibition was actually pursued in research.

What are the implications of this for treatment of hypercholesterolemia?

Again, loss of function mutations don’t seem to have any adverse effects, which is what led to the pursuit of PCSK9 inhibitors as a treatment for hypercholesterolemia. Currently, the only clinically approved therapeutics are temporary.

Monoclonal antibody therapy

The two most popular options used in the clinic are the monoclonal antibodies, evolocumab and alirocumab. They have established safety and efficacy profiles and long-term morbidity and mortality benefits. They essentially act to block the function of PCSK9 and so they stop that interaction between the PCSK9 and the LDL receptor, thereby increasing the amount of LDL receptor at the cell surface and increasing the amount of LDLc removed from circulation. The limitations with them is that they’re quite expensive and their dosing regimens are quite frequent, once every two weeks or once a month (depending on the concentration). This means that there’s a lot of discontinuation with patients, which is obviously not a good thing when you’re trying to stop cardiovascular events from happening. In light of that, development has begun on methods of inhibition that are longer lasting and/or can have slightly longer intervals in the dosing regimens.

Small interfering RNA therapy
The only other clinically approved inhibitor that I’m aware of is inclisiran, which is a small interfering (si)RNA and so blocks the synthesis of PCSK9. The siRNA has a moiety on the end of it which means that it’s specifically taken up by hepatocytes. The current literature suggests that it’s not quite as effective as the monoclonal antibody therapy, as around 30% of circulating PCSK9 remains. This is possibly because it is taken up solely by hepatocytes and a lot of current research, including my own, would suggest that more cells than hepatocytes actually make PCSK9. So rather than just blocking circulating PCSK9, it stops the synthesis in the liver. It’s slightly less frequently dosed. After the initial injection there is another at three months but after that maintenance doses are given every 6 months (so twice a year). This is good, but more permanent solutions are also being investigated.

Longer lasting and more permanent strategies
Vaccination strategies are still in the preclinical stage. And actually recently in the New England Journal of Medicine, they published a phase one trial of the CRISPR-based therapeutic VERVE-102to permanently inhibit PCSK9 synthesis. In my opinion, proceed with caution, as permanently knocking out anything could have implications, but it is certainly very exciting. There is some evidence that permanently knocking out PCSK9 could affect the ability of the liver to regenerate and things like that. So while very, very exciting, it’s still very much in its infancy. More work needs to be done to ensure that no adverse effects due to a lack of PCSK9 would be waiting years down the line.

High levels of PCSK9 protein or activity result in reduced clearance of low density lipoprotein (cholesterol) from the blood and an increased risk of cardiovascular disease

Are there other roles for PCSK9?

We know that bacterial phospholipids such as lipopolysaccharide (LPS) exacerbate critical illnesses such as sepsis or acute respiratory distress syndrome (ARDS); however, we don’t know the exact mechanisms behind the pathogenesis of these illnesses and pharmacological intervention is limited. As PCSK9 was originally identified as a lipid regulatory protein, this invited the question of whether PCSK9 could reduce the clearance of bacterial phospholipids. Some of the pre-liminary work found that it did indeed: in a dose-dependent study, PCSK9 was able to significantly reduce the ability of the cultured hepatocytes to remove fluorescent LPS. It was a very elegant study, which advanced the field and was very exciting. It has also been shown that PCSK9 in itself can have inflammatory effects– by acting via toll-like receptor 4 (TLR4), which is the classical receptor for the NF-κB pathway. Additionally, there’s quite a lot of good work investigating the role of PCSK9 in macrophage activation, which, of course, is a key contributor to the dysregulated inflammatory response that we see in sepsis and ARDS. Physiologically relevant levels of PCSK9 can induce inflammatory responses from macrophages. It has therefore been shown that PCSK9 has an inflammatory effect in and of itself, as well as exacerbating the inflammation associated with these critical conditions.

Sepsis
Investigations into a cohort of sepsis patients revealed that that PCSK9 levels were indeed elevated in the plasma of these patients. Crucially, it was also found that elevated PCSK9 levels were related to poor clinical outcomes, such as 28-day mortality. Additionally, it was associated with the development of organ failure, which, of course, has huge implications in sepsis. So, not only are PCSK9 levels elevated, but it is possible that this might actually be contributing to or associated with the severity of the condition.

ARDS
Then, Metkus and co-workers showed that PCSK9 was elevated in the plasma of acute respiratory distress syndrome patients. So far, that is the only real evidence of the involvement of PCSK9 in ARDS that has been published and validated apart from a pilot clinical trial that was done in COVID-19 ARDS patients. Now, COVID-19 ARDS is considered separate to classical ARDS, but in a pilot clinical trial using the PCSK9 inhibitor, evolocumab, (even though it wasn’t powered for outcomes) they found a trend towards reduced mortality in the treatment group, which was very exciting. There is actually some very limited evidence that PCSK9 can reduce the expression of the epithelial sodium channel, the disruption of which is a big contributor to the reduced fluid clearance seen in ARDS. So it could be that PCSK9 is not just an inflammatory protein but it might also have a mechanistic role in ARDS. So, yes, the field is very much in its infancy but is very exciting right now!

What future developments do you envisage in this field?

A study has been done that involved PCSK9 as part of a multilocus risk score that identified individuals at increased risk of coronary artery disease events. ARDS, however, is a complex condition. In recent years, different sub-phenotypes of ARDS based on the plasma concentration of different biomarkers or inflammatory cytokines have been identified. So, with further research it may be that PCSK9 could be used in a multi-marker panel with ARDS also, but probably not as a single biomarker.

In addition to the clinical trial that investigated the use of PCSK9 inhibitors in COVID-19 ARDS, the results of two trials using anti-PCSK9 monoclonal antibodies in sepsis are about to be published and we are excited to see those. A lot of further work is needed before we get to the point of a clinical trial of PCSK9 inhibitors in ARDS patients, but it does constitute a potential therapeutic target, which is exciting for conditions such as ARDS or sepsis that don’t have many specific pharmacological therapies, which is one of the reasons the mortality rates are so high.

 Bibliography
1. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100(3):928–933. PMID: 12552133 (https://doi.org/10.1073/pnas.0335507100).
2. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–156. PMID: 12730697 (https://doi.org/10.1038/ng1161).
3. Zhang D, Lagace T, Garuti R, Zhao Z, McDonald M et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282:18602–18612. PMID: 17452316 (https://doi.org/10.1074/jbc.m702027200).
4. Seidah N. The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol. Glob Cardiol Sci Pract. 2017;2017(1):e201702. PMID: 28971102 (https://doi.org/10.21542/gcsp.2017.2).
5. Vafai SB, Täubel J, Ashdown T, Patel RS, Diamondali S et al. In vivo base editing of PCSK9 with VERVE-102 for hypercholesterolemia. N Engl J Med. 2026;395(7):648–659. PMID: 42187087 (https://doi.org/10.1056/nejmoa2601283).
6. Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ et al. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014;6:258ra143. PMID: 25320235 (https://doi.org/10.1126/scitranslmed.3008782).
7. Boyd JH, Fjell CD, Russell JA, irounis D, Cirstea MS, Walley KR. Increased plasma PCSK9 levels are associated with reduced endotoxin clearance and the development of acute organ failures during sepsis. J Innate Immun. 2016;8:211–220. PMID: 26756586 (https://doi.org/10.1159/000442976).
8. Boyd J. Randomized, Double-blind, Placebo-controlled Phase 2a Trial of Efficacy and Safety of Evolocumab for PCSK9 Lowering in Early Acute Sepsis. NIH National Library of Medicine; National Center for Biotechnology Information; ClinicalTrials.gov 2019 (https://clinicaltrials.gov/study/NCT03869073).
9. Navarese E, Podhajski P, Gurbel P, Grzelakowska K, Ruscio E et al. PCSK9 inhibition during the inflammatory stage of SARS-COV-2 Infection. J Am Coll Cardiol. 2023;81:224–234. PMID: 36653090 (https://doi.org/10.1016/j.jacc.2022.10.030).
10. Metkus TS, Kim BS, Jones SR, Martin SS, Schulman SP, Leucker TM. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) in the acute respiratory distress syndrome. Front Med. 2022;9:876046. PMID: 35770004  (https://doi.org/10.3389/fmed.2022.876046).

The interviewee

Emma Crossley BSC, MSc PhD student
Wellcome-Wolfson Institute for Experimental Medicine, Queen’s
University Belfast, Belfast, UK

Email: ecrossley01@qub.ac.uk

For further information, see:

Crossley E, Silversides JA, O’Kane CM, Hamilton PK. PCSK9 in critical illness – It’s not all about lipids. Ann Clin Biochem. 2026 63(4):287–300. PMID: 41145237 (https://doi.org/10.1177/00045632251395579).