Mechanisms of action and therapeutic potential of PCSK9-regulating drugs

Abstract

Context

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) metabolism and is a key target for cardiovascular therapies. It also plays roles in inflammation, cancer, and metabolic disorders, prompting interest in repurposing PCSK9-targeting drugs for non-lipid conditions.

Objective

This review comprehensively summarizes PCSK9-regulating medications, delves into their mechanisms of action, and explores their increasingly expanding therapeutic potential across multiple organ systems, such as the liver, immune system, small intestine, heart, brain, and pancreas.

Methods

A comprehensive literature search was carried out in databases such as PubMed, with keywords like ‘PCSK9 inhibitors’, ‘lipid metabolism’, ‘liver’, ‘immune system’, ‘neoplasms’ and ‘PCSK9-related diseases’. The search was meticulously designed to cover relevant research extensively. Only those studies that delved into the molecular mechanisms underlying PCSK9 regulation and the practical clinical applications of PCSK9-targeting therapies were selected for inclusion.

Results

PCSK9-regulating drugs, encompassing monoclonal antibodies, small peptides, antisense oligonucleotides, small interfering RNAs, and vaccines, modulate PCSK9 expression or activity at different levels. These drugs are effective in lowering LDL-C levels and demonstrate potential benefits in the treatment of inflammation, non-alcoholic fatty liver disease, renal lipotoxicity, and various metabolic disorders. They mainly exert their effects by controlling PCSK9 gene transcription, influencing mRNA translation, and blocking the interaction between PCSK9 and LDL-R.

Conclusions

PCSK9-regulating drugs hold great promise for treating a diverse array of diseases. Future research should focus on optimizing their application in personalized therapies that target multiple pathways.

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as a critical regulator in maintaining blood cholesterol levels and is closely linked to familial hypercholesterolemia (Ahamad et al. 2022). Given its regulatory impact on plasma low-density lipoprotein cholesterol (LDL-C) levels, PCSK9 has been extensively investigated in the liver (Zaid et al. 2008). Mechanistically, PCSK9 specifically binds to the low-density lipoprotein receptor (LDL-R) on the cell surface, forming a complex that is subsequently internalized and transported to the lysosome. This process facilitates the degradation of LDL-R, consequently raising blood LDL-C levels (Qian et al. 2007; Peterson et al. 2008). Furthermore, PCSK9 is expressed across various organs, such as the brain, heart, kidney, liver, pancreas, immune cells, and small intestine (Beppu et al. 2012; van Poelgeest et al. 2013; Mbikay et al. 2018; Gai et al. 2019; O’Connell and Lohoff 2020; Laudette et al. 2023). These findings, particularly its role in cholesterol homeostasis, have established PCSK9 as a prominent target in the clinical management of atherosclerotic cardiovascular disease (ASCVD).

The extensive expression of PCSK9 highlights its versatility and significance. Aberrant PCSK9 expression has been linked to impaired renal function, neuronal death, and dysregulated islet cell activity (Wang et al. 2018; Marku et al. 2022; Feng et al. 2023). Current PCSK9-regulating agents can be classified into three primary groups: natural medicines, chemical drugs, and biological drugs. PCSK9-regulating drugs play a crucial role not only in maintaining blood cholesterol homeostasis but also in ameliorating various pathological conditions. This review provides a comprehensive overview of the latest developments in PCSK9-regulating drugs, summarizing agents that modulate PCSK9.

PCSK9-regulating drugs for the management of lipid-lowering therapy

Natural products

Natural PCSK9-regulating agents comprise phenols, terpenoids, alkaloids, glycosides, and compound preparations. The majority of natural substances exhibiting PCSK9-inhibitory activity demonstrate exceedingly low bioavailability, thereby substantially constraining their practical therapeutic efficacy in the human body. Furthermore, a substantial proportion of these natural compounds have yet to be clinically tested in humans (see Table 1). Thus, for the bioactive molecules that have already exhibited activity in human studies, it is imperative that we undertake more extensive and profound research and exploration.

Table 1.

Natural products reduce LDL-C by regulating PCSK9 in vitro or in non-clinical settings.

Natural products		Mechanisms of action	Models	References
Phenols	Black raspberry extract, Cajanus cajan (L.) Millsp. leaves	Inhibiting HNF-1α leads to suppressed PCSK9 expression.	HepG2 Cells	Song et al. 2018; Chang et al. 2019
	Penthorum chinense Pursh. (Penthoraceae)	Downregulation of PCSK9.		Chae et al. 2021
	Sesamin, moracin C	Suppress PCSK9 transcription.	Hepatocellular carcinoma cells	Pel et al. 2017; Dong et al. 2024
	Rhubarb(Rhei Radix et Rhizoma) free anthraquinones	Down-regulated PCSK9 mRNA.	Dyslipidemia rat model	Wang et al. 2022
	Epigallocatechin gallate	Induce an early reduction in extracellular PCSK9.	HepG2 cells	Kitamura et al. 2017; Adorni et al. 2020
	Curcuin nicotinate	Reduce PCSK9 protein levels.		Huang et al. 2024
	Polydatin	Inhibit PCSK9-LDLR interaction.		Li et al. 2018
	3,7,2′-trihydroxy-5-methoxy-flavanone, skullcapflavone II	Inhibit PCSK9 mRNA expression.		Nhoek et al. 2018
	Resveratrol	Attenuate the abnormally rapid secretion of PCSK9.	APP/PS1 mice	Dong et al. 2023
	Quercetin	Reduce PCSK9 expression.	Macrophages	Lara-Guzman et al. 2012; Li et al. 2018
	Quercetin-3-glucoside	Inhibit PCSK9 secretion.	Mice on a high-cholesterol diet	Mbikay et al. 2018
Terpene	Protium heptaphyllum (Burseraceae) gum resin extract	Reduce PCSK9 expression.	Human hepatocytes	Mannino et al. 2021
	Hexanorisocucurbitacin D, isocucurbitacin D	Reduce PCSK9 expression.	HepG2 cells	Zhang et al. 2020
	Antirrhinoside	Activate the transcription of SREBP-regulated genes (LDL-R and PCSK9).	Huh7 cells	Sut et al. 2022
	Supercritical carbon dioxide extracts of Mentha. longifolia L. (Lamiaceae (Labiatae)) leaves	Suppress PCSK9 expression.	Huh7 and HepG2 cells	Sut et al. 2021
	Difluoromethyl oleanolate	Lower HNF1α to decrease PCSK9.	HepG2 cells	He 2017
	Plant stanol	Regulate through SREBP-2 and target genes (HMGCR, LDLR, PCSK9).	C57BL/6J mice	De Smet et al. 2015
Glycosides	Tetrahydroxydiphenylethylene-2-O-glucoside	Inhibit PCSK9-LDLR interaction.	HepG2 cells	Li et al. 2018
	Astragalus polysaccharide	Reduce PCSK9 via PPAR-β/δ pathway.	THP-1-derived macrophages	Zou and Liu 2017
	Fucoidan F3	PCSK9 suppression & other unknown mechanisms.	C57BL/6J mice fed a high-fat diet	Zhang et al. 2024
	Gynostemma pentaphyllum (Thunb.) Makino	Suppressing the PCSK9/LOX-1 signaling pathway.	VitD3 plus high cholesterol diet-induced AS rats	Huang et al. 2022
	Gypenoside LVI	Downregulate PCSK9 mRNA and protein levels.	HepG2 cells	Su et al. 2021; Wang et al. 2021
	Euphorbia helioscopia (Euphorbiaceae), Celastrus orbiculatus (Celastraceae), Trichosanthes cucumeroides (Ser.) Maxim. (Cucurbitaceae)	Reduce PCSK9 protein.		Li 2018
	Pseudoprotodioscin	Promote LDLR by reducing PCSK9 levels.	THP-1 macrophages, HepG2 cells	Gai et al. 2019
Lignan derivatives	Welsh onion (Allium fistulosum L. [family Amaryllidaceae])	Downregulation of PCSK9.	HepG2 Cells	Choi et al. 2017
Compound preparation	Huazhuo Qushi Decoction	Regulate through SREBP-2 and target genes (HMGCR, LDLR, PCSK9).	Hyperlipidemic SD rats models	Sui 2016
	Imperatae rhizoma and Hedyotis diffusa Willd.	Reduce PCSK9 expression.	Nephrotic syndrome rats	Zou et al. 2021
	Combination containing monacolin K, Berberine and 1-deoxynojirimycin	Decrease PCSK9 mRNA, protein, and promoter activity.	HepG2 and Huh7 cells	Lupo et al. 2019
	Shoushen granules	Antagonize PCSK9, TLR4/NF-κB key factors.	ApoE-knockout (ApoE-/-) mice	Li et al. 2019

Curcumin

Curcumin, a polyphenolic compound extracted from Curcuma longa L. (Zingiberaceae), has been extensively investigated as a chemopreventive agent (Cong et al. 2025). Subsequent research has demonstrated that curcumin nicotinate (CurTn) regulates LDL-R distribution on hepatocyte surfaces by downregulating PCSK9/IDOL (inducible degrader of the LDL-R), thus promoting LDL-C uptake in the liver (Huang et al. 2024). In vitro studies have demonstrated that curcumin reduces the nuclear levels of hepatocyte nuclear factor 1α (HNF1α). This reduction subsequently attenuates the interaction between HNF1α and the PCSK9 promoter, ultimately resulting in the downregulation of PCSK9 expression and exerting a lipid-lowering effect (Tai et al. 2014). To overcome the limited bioavailability of native curcumin, micellar curcumin has been synthesized. A double-blind, randomized, crossover trial involving 15 healthy volunteers was conducted to compare the effects of micellar curcumin and natural curcumin. The study revealed that, compared with blood samples stimulated with lipopolysaccharide, participants who consumed micellar curcumin showed a notable decrease in PCSK9 concentrations after 7 days. Furthermore, micellar curcumin demonstrated favorable oral bioavailability (Grafeneder et al. 2022).

Berberine

Berberine, an isoquinoline alkaloid and the primary active component of Coptis, is widely used in the treatment of hyperlipidemia in traditional Chinese medicine (Bao et al. 2015). It has been reported that berberine operates through a mechanism of action distinct from that of statins (Wu et al. 2023). Specifically, berberine upregulates LDL-R and suppresses PCSK9 expression in liver cells to modulate LDL-C levels by regulating the extracellular signal–regulated protein kinase pathway (Cao et al. 2019). Accumulating evidence shows that exposure to berberine downregulates PCSK9 expression in liver cells in a dose- and time- dependent manner, thereby leading to an increase in LDL-R on hepatocyte surfaces (Cameron et al. 2008). Berberine has been demonstrated to inhibit PCSK9 transcription by downregulating the expression of HNF-α and/or SREBP-2 (Li et al. 2009). In addition, randomized controlled trials in adults have shown that berberine can modestly reduce LDL-C, triglyceride, and apolipoprotein B levels compared to placebo (Blais et al. 2023). Further meta-analysis showed that, when compared with the placebo group, berberine could significantly reduce the total cholesterol and low-density lipoprotein levels (Zhang et al. 2019).

The meta-analysis of randomized, controlled clinical trials has demonstrated that the combination of berberine with other lipid reducers, such as red yeast rice and silymarin, may be more effective than using berberine alone (Hernandez et al. 2024). Specifically, the coadministration of berberine and silymarin can effectively improve the lipid and glucose profile, exerting the most significant impact on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides (Fogacci et al. 2019; Bertuccioli et al. 2020). The greater efficacy may be ascribed to silymarin increasing the bioavailability of berberine (Bertuccioli et al. 2020). A 2-month study evaluated the ability of a nutraceutical containing monacolin K, berberine, and silymarin to reduce LDL-C levels in 53 patients with polygenic hypercholesterolemia. The nutraceutical was found to be as effective as 10 mg of atorvastatin, thereby significantly changing PCSK9 levels and improving the lipoprotein functional profile (Formisano et al. 2020). Furthermore, a 3-month randomized trial explored the effects of a nutraceutical combination containing red yeast rice and berberine in HIV-infected patients undergoing antiretroviral therapy. The results demonstrated that, compared to the group receiving no treatment, the nutraceutical combination safely reduced cholesterol and PCSK9 levels and improved arterial stiffness in 30 patients (Pirro et al. 2019). In a phase II study, a nutraceutical combination composed of berberine, monacolin K, chitosan, and coenzyme Q successfully reduced non-HDL cholesterol levels. This combination maintained stable PCSK9 levels and demonstrated good tolerability, thus providing benefits to individuals suffering from dyslipidemia (Spigoni et al. 2017). For instance, a study assessed the efficacy of a berberine-containing nutraceutical in combination with ezetimibe in hypercholesterolemic patients who were intolerant to statins or had refused to take them (Pisciotta et al. 2012). The findings indicated that the combined treatment was as effective as moderate-dose statins, and it is suggested that berberine might exert its effects in vivo by enhancing the expression and stability of low-density lipoprotein receptors (LDLRs) and/or suppressing PCSK9 expression.

Xuezhikang

Xuezhikang, an extract derived from red yeast rice, has been demonstrated to be effective in reducing the incidence of cardiovascular events in Chinese patients with diabetes and coronary heart disease (Xu et al. 2023). Research has indicated that Xuezhikang and statins alone or in combination can increase PCSK9 levels through the SREBP-2 pathway (Zhang et al. 2014; Jia et al. 2016). Furthermore, the combination of Xuezhikang and ezetimibe significantly attenuated increase in PCSK9 compared to ezetimibe plus pitavastatin, thereby suggesting that the former combination may hold greater potential than the latter in future clinical application (Zhang et al. 2014).

Chemicals

In humans, statin and fibrate drugs significantly alter plasma PCSK9 levels (Mayne et al. 2008; Chan et al. 2010; Costet et al. 2010; Noguchi et al. 2011; Arsenault et al. 2018; Altunkeser et al. 2019). Studies have demonstrated that the combination treatment of ezetimibe and statin led to an increase in PCSK9 concentration (Gouni-Berthold et al. 2008; Zhang et al. 2014). It has been shown that ezetimibe activates the SREBP-2 pathway, and the administration of rosuvastatin further enhances the effects of ezetimibe on this pathway (Zhang et al. 2014). Furthermore, atorvastatin inhibits HMG-CoA reductase (HMG-CoAR)-mediated stimulation of PCSK9 expression in the intestine and increases cholesterol absorption, possibly through upregulation of SREBP-2 and HNF-4α (Tremblay et al. 2011). Statins and fibrates can significantly elevate PCSK9 levels, yet this increase is negatively correlated with the reduction in LDL-C levels. To address this issue, metformin, evolocumab, and walnuts have been shown to inhibit statin-induced PCSK9 expression and can serve as adjuncts in statin therapy (Robinson et al. 2014; Amadi et al. 2022; Hu et al. 2024). Another study has also demonstrated that niacin can counteract the increase in PCSK9 levels induced by statins and fibrates in hypercholesterolemic patients (Khera et al. 2015). A clinical trial has shown that polyunsaturated fatty acids (PUFA) can lower cholesterol levels in abdominally obese subjects by downregulating PCSK9 (Bjermo et al. 2012). Specifically, dietary high-oleic canola oil supplemented with docosahexaenoic acid has been shown to reduce plasma PCSK9 levels in participants at risk of cardiovascular disease (Pu et al. 2016). Moreover, marine-3 PUFA have been found to decrease plasma PCSK9 levels in both pre- and postmenopausal women (Graversen et al. 2016). Research has shown that active benzofurans, as well as natural products capable of upregulating TRIB1, also modulate hepatic cell cholesterol metabolism by increasing the expression of LDLR transcripts and LDL receptor proteins, while concurrently reducing the levels of PCSK9 transcripts and secreted PCSK9 proteins and stimulating LDL uptake (Nagiec et al. 2015). Notably, this effect of benzofuran is independent of the SREBP-2 regulatory pathway and is not masked by cholesterol depletion (Nagiec et al. 2015). In contrast, estradiol therapy (ER) reduces atherogenesis and cholesterol levels following ovariectomy without altering LDLR expression, yet unexpectedly increases PCSK9 levels (Maarouf et al. 2020). This represents the first report of estradiol-induced PCSK9 expression, which highlighting the need to investigate the balance between estrogen and PCSK9 in women.

Biological drugs

Polypeptide vaccines

Recent progress in polypeptide vaccines has broadened the application of this approach in the management of lipid metabolism disorders (Momtazi-Borojeni et al. 2019; Surma et al. 2024). A recent study has shown that the anti-PCSK9 vaccine can induce a long-lasting immune response against PCSK9, resulting in persistently low levels of PCSK9 in the serum (May et al. 2022). VXX-401 is a peptide-based vaccine against PCSK9, which has demonstrated immunogenicity in nonhuman primates with a favorable safety profile (Vroom et al. 2024). Moreover, a vaccine that uses keyhole limpet hemocyanin as the peptide carrier can significantly stimulate the production of antibodies targeting PCSK9, thereby concurrently upregulating LDL-R expression on the cell surface (Kawakami et al. 2018). Additionally, two AFFITOPE^® peptide vaccine candidates, AT04A and AT06A, have been found to induce PCSK9-specific antibodies. Nevertheless, AT04A showed only a modest cholesterol-lowering effect when administered alone (Zeitlinger et al. 2021).

Nanoliposome vaccines

A PCSK9 nanoliposome vaccine has demonstrated notable effects in reducing PCSK9 levels and enhancing LDL-R expression in hypercholesterolemic mice. This vaccine contains a peptide construct named immunogenic fused PCSK9-tetanus (IFPT). The IFPT is presented on the surface of liposome nanoparticles (L-IFPT) and then mixed with an alum adjuvant (L-IFPTA+) (Momtazi-Borojeni et al. 2019; Surma et al. 2024).

Virus-like particles (VLP) vaccines

Investigations conducted on macaques revealed that VLP vaccines targeting a single PCSK9 epitope were ineffective in reducing LDL-C levels unless statins were co-administered. Conversely, the bivalent VLP vaccine, targeting two distinct PCSK9 epitopes, induced a robust antibody response and was effective in reducing cholesterol levels when used independently (Fowler et al. 2023). Researchers have demonstrated that VLP vaccines featuring full-length PCSK9 antigens surpassed those with shorter antigens in lowering total cholesterol, TG, and plasma PCSK9 levels in vivo (Goksøyr et al. 2022). Significantly, the PCSK9Qβ-003 vaccine, a VLP-peptide vaccine, has the potential to augment the expression of SREBP-2, HNF-1α, and hepatic LDL-R (Pan et al. 2017; Wu et al. 2020).

Monoclonal antibody

The molecular mechanism through which human monoclonal PCSK9 antibodies decrease LDL-C levels involves interrupting the binding between PCSK9 and LDL-R (Berger et al. 2017). Some examples of these monoclonal antibodies are alirocumab (REGN727/SAR236553), evolocumab (AMG145), bococizumab, and frovocimab (LY3015014) (Yoon and Watson 2014; Liberale et al. 2017). Among them, frovocimab (LY3015014) is a human IgG4 monoclonal antibody that has finished phase II clinical trials (Kastelein et al. 2016). Bococizumab is a humanized monoclonal antibody. However, its clinical trials were halted because patients developed antidrug antibodies (McCush et al. 2023).

Adnectins

Adnectins constitute a class of engineered proteins that, much like PCSK9 monoclonal antibodies, disrupt the interaction between PCSK9 and LDL-R (Mitchell et al. 2014). For instance, BMS-962476, a small polypeptide, has been shown to rapidly reduce cholesterol and free PCSK9 levels (Mitchell et al. 2014; White et al. 2016; Gill and Hegele 2023). LIB003, which consists of the PCSK9-binding domain and human serum albumin, shows strong effectiveness in reducing LDL-C. At present, this recombinant fusion protein has concluded phase III clinical studies (Raal et al. 2023; Chen et al. 2024).

PCSK9 gene silencing and editing

VERVE-101 is a single-administration liver-targeted gene editing drug. It silences the PCSK9 gene to lower LDL-C levels. Reportedly, VERVE-101 is employed for the prevention and treatment of cardiovascular diseases, including heterozygous familial hypercholesterolemia (Lee et al. 2023; Oostveen et al. 2023). Through the use of lipid nanoparticles to deliver the gene-editor mRNA and the PCSK9-targeting guide RNA, VERVE-101 inhibits the expression of hepatic PCSK9 (Oostveen et al. 2023). Antisense oligonucleotides (ASOs) are single-stranded RNA or DNA molecules that primarily function within the cell nucleus (Gupta et al. 2023). Examples such as CiVi007, AZD8233, BMS-84442, and SPC5001 target the liver. They bind to the target mRNA (PCSK9 mRNA), leading to its cleavage (van Poelgeest et al. 2013; Gennemark et al. 2021; Chen et al. 2024). CiVi007 and AZD8233 have advanced phase 2 clinical trials. However, BMS-84442 and SPC5001 were terminated due to renal toxicity. Furthermore, inclisiran, a small interfering RNA (siRNA), has been shown to inhibit the expression of PCSK9 at the mRNA level in hepatic cells, thus reducing LDL-C levels (German and Shapiro 2020). STP135G and RBD7022 are GalNAc-siRNAs that target PCSK9. They treat hyperlipidemia by lowering LDL-C (Oostveen et al. 2023) (Table 2).

Table 2.

Biological drugs regulating PCSK9.

Drugs			Apply	Mechanism	Research stage	References
Anti-PCSK9 vaccines	Polypeptide vaccines	AT04A, AT06A	Hypercholesterolemia	Induce PCSK9-specific antibodies	Clinical trial: Phase 1	Zeitlinger et al. 2021
		VXX-401	Hypercholesterolemia, atherosclerotic cardiovascular disease	Trigger a safe humoral immune response against PCSK9	Experiment: hepatic cell models, nonhuman primates	Vroom et al. 2024
		L-IFPTA+	LDL-lowering	Induce humoral immune response against PCSK9	Experiment: BALB/c mice	Momtazi-Borojeni et al. 2019; Surma et al. 2024
	Virus-like particles (VLP) vaccines.	Monovalent VLP vaccine	Atherosclerotic cardiovascular disease	Target epitopes found within the LDL receptor binding domain of PCSK9	Experiment: mice and non-human primates	Fowler et al. 2023
		The bivalent VLP vaccine
		Full-length PCSK9 capsid VLP vaccine	Lower cholesterol	Induction anti-PCSK9 antibody response	Experiment: BALB/c mice	Goksøyr et al. 2022
		PCSK9Qβ − 003	Hypercholesterolemia		Experiment: Balb/c mice, LDLR+/-mice and low-density lipoprotein receptor+/–male mice	Pan et al. 2017; Wu et al. 2020
Monoclonal antibody	Alirocumab (REGN727/SAR236553) Evolocumab (AMG145)		Dyslipidemias primary	Interrupting the binding between PCSK9 and LDL-R	Available in 2015	Yoon and Watson 2014
	Bococizumab		Atherosclerotic cardiovascular disease	Target PCSK9	Discontinued	McCush et al. 2023
	Frovocimab (ly 3015014)		Hypercholesteremia	Induce PCSK9-specific antibodies	Phase 2: completed	Kastelein et al. 2016
Adnectins	BMS-962476		Hypercholesterolemia	PCSK9 inhibitor	Clinical trial: Phase 1	White et al. 2016
	LIB003		Lower LDL cholesterol		Clinical trials: Phase 3	Raal et al. 2023; Chen et al. 2024
PCSK9 gene silencing and editing	Liver base editing drugs in vivo	VERVE-101	Heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.	Turning off the expression of PCSK9	Experiment: nonhuman primates and murine F1 progeny	Lee et al. 2023; Oostveen et al. 2023
	Antisense oligonucleotide	AZD8233	Dyslipidemia	Binding to PCSK9 mRNA	Clinical trials	Gennemark et al. 2021
		Civi-007	Hypercholesterolemia		Clinical trials: Phase 2a	Chen et al. 2024
		SPC5001	Dyslipidemia		Discontinued	van Poelgeest et al. 2013; Van Poelgeest et al. 2015
	Small interfering RNA	Inclisiran	Hypercholesterolemia	Prevents translation of PCSK9 messenger RNA	Approved for marketing	German and Shapiro 2020; Lamb 2021
		STP135G	Lipid-lowering		Experiment	Oostveen et al. 2023
		RBD 7022			Clinical trial: Phase 1
Others	DS-9001a		Dyslipidemia	Inhibiting PCSK9-LDL-R pathway	Experiment: cynomolgus monkeys	Masuda et al. 2018
	MK-0616 (Merck)		Hypercholesteremia	PCSK9 Inhibitor	Clinical trial: Phase 2b	Ballantyne et al. 2023
	Small molecule inhibitor based on PF-00932239 206 (R-IMPP)		–	Targeting ribosome to suppress PCSK9 protein translation	Experiment: Sprague–Dawley rats	Ahamad et al. 2022
	P5-met (a metabolite of P5)		Regulate cholesterol metabolism	Block the PCSK9-LDL-R interaction and Downregulate HNF-1α	Experiment: HepG2 cells	Lammi et al. 2021
	HSP27 immune complex		Atherosclerosis	Boost PCSK9 disposal via LDLR synthesis	Experiment: ApoE−/−mice	Chen et al. 2021

Others

In addition to the aforementioned drugs, other compounds, including dextran sulfate, pentosan sulfate, suramin, and phosphorothiorate oligodeoxycytidine S-dC-36, also inhibit PCSK9. They act by disrupting the interaction between PCSK9 and its receptor on the cell surface (Gill and Hegele 2023). In addition, small heat shock proteins, such as those involved in HSP25 vaccination and the HSP27 immune complex, have been shown to reduce both PCSK9 and cholesterol levels. However, the HSP27 immune complex treatment exerts only a transient regulatory effect on PCSK9 expression (Chen et al. 2021). Moreover, DS-9001a, a recombinant fusion protein, has been demonstrated to inhibit the binding between PCSK9 and LDL-R, thereby preventing PCSK9-mediated LDL-R degradation (Masuda et al. 2018). MK-0616 (Merck), an investigational PCSK9 inhibitor that has successfully completed phase II clinical trials, binds to circulating PCSK9 and interrupts its interaction with LDL-R (Ballantyne et al. 2023). P5, a hypocholesterolemic peptide derived from lupin protein, reduces PCSK9 production in the gut by downregulating the expression of HNF-1α (Lammi et al. 2021). Other peptides generated during lupin hydrolysis also modulate cholesterol metabolism and PCSK9 secretion in vitro (Lammi et al. 2021). To date, several small-molecule inhibitors have been developed to reduce PCSK9 levels through various mechanisms. For instance, R-IMPP (PF-00932239) acts on the ribosome to inhibit PCSK9 protein translation (Ahamad et al. 2022).

Notably, although some natural drugs, including glycosides, terpenes, polyphenols, etc., have been reported to modulate PCSK9, most of these compounds are still in the research stage (Adorni et al. 2020; Zhang et al. 2020; Huang et al. 2022; Sut et al. 2022). The research and development of chemical drugs targeting PCSK9 is comparatively limited, and currently, there are no mature chemical drugs available on the market. In contrast, biological agents have emerged as the predominant approach in PCSK9 drug development, with several PCSK9 inhibitor biological agents, such as evolocumab and alirocumab, already successfully launched (Yoon and Watson 2014; Zhang et al. 2018). Clinical studies have shown that these PCSK9 inhibitor biological agents possess good safety and tolerability.

PCSK9-regulating drugs in the management of endotoxemia

LDL-R is involved in lipid metabolism and plays a crucial role in lipopolysaccharide (LPS) detoxification in liver cells (Lazaron et al. 2001). It has been observed that curcumin demonstrates an anti-endotoxemia effect in tetrachloride-induced cirrhotic rats. It achieves this by suppressing the expression of hepatic PCSK9 at both the mRNA and protein levels (Cai et al. 2017). The researchers further demonstrated that curcumin, through this mechanism, upregulates LDL-R expression and promotes LPS clearance and detoxification in the livers of these rats.

PCSK9-regulating drugs in the treatment of inflammatory conditions

Recent experimental findings suggest that PCSK9 is involved in the regulation of inflammation (Arsh et al. 2024). For example, in a chemically-induced colitis mouse model, an elevation in PCSK9 levels were observed. Conversely, the inhibition of PCSK9 alleviated the severity of colitis, suppressed the production of proinflammatory cytokines, and inhibited the activation of proinflammatory signaling (Lei et al. 2020). The PCSK9 vaccine (AT04A) also decreased circulating inflammatory biomarkers, thereby mitigating vascular inflammation in atherosclerotic mice (Landlinger et al. 2017). Furthermore, it has been reported that IL-10 can induce the production of PCSK9, which in turn suppresses the lipoprotein receptor 1 (LOX-1) and toll-like receptor 2 (TLR2) -mediated inflammatory responses. This process confers protection to cardiomyocytes against the cellular inflammation and death induced by PAzPC (1-palmitoyl-2-azelaoyl-sn-glycerol-3-phosphocholine) (Bagchi et al. 2020). In patients with familial hypercholesterolemia, monocytes display a pro-inflammatory phenotype. Treatment with PCSK9 monoclonal antibodies (mAbs) to lower LDL-C levels reduces this pro-inflammatory phenotype. This reduction in LDL-C also decreases intracellular lipid accumulation, indicating a direct anti-inflammatory effect on circulating monocytes (Bernelot Moens et al. 2017). Studies further suggest that alirocumab may exhibit therapeutic potential for the treatment of depression and Alzheimer’s disease due to its anti-inflammatory properties (Abuelezz and Hendawy 2021; Hendawy et al. 2023).

PCSK9-regulating drugs as an approach to anti-neoplastic therapy

Recent findings from in vitro studies have demonstrated that PCSK9 promotes M2 macrophage polarization and enhances the proliferation, migration, and invasion of colon cancer cells. It achieves this by inducing epithelial-mesenchymal transition (EMT) and activating the PI3K/AKT signaling pathway (Wang et al. 2022). Thus, the targeting of PCSK9 as an adjuvant treatment represents a promising approach for anti-tumor therapy. For instance, arenobufagin (ARBU), a traditional Chinese medicine, has been shown to inhibit the progression of liver cancer both in vitro and in vivo. Specifically, ARBU reduces cholesterol production in cancer cells through the PCSK9/LDL-R pathway. By doing so, it disrupts the tumor promoting actions of M2 macrophages, thereby inducing apoptosis and suppressing the migration and proliferation of tumor cells (Li et al. 2024). The Actinidia chinensis Planch root extract (acRoots), which is rich in triterpenes, has been demonstrated to enhance PCSK9 expression (He et al. 2017). This increase in PCSK9 expression leads to a reduction in LDL-R expression, which in turn inhibits LDL uptake. As a result, intracellular cholesterol levels decrease, and the proliferation of liver cancer cells is suppressed. These effects highlight the anti-tumor activity of acRoots. Moreover, the inhibition of PCSK9 by drugs such as evolocumab has been found to reduce adenocarcinoma development in mice and is linked to a lower risk of cutaneous melanoma (Yang et al. 2021; Miao et al. 2024).

PCSK9-regulating drugs for the management of hyperinsulinemia and the improvement of glucose metabolism

Researchers have observed that depleting PCSK9 in the pancreas modifies the expression of LDL-R and cholesterol content in β cells. This alteration leads to elevated blood sugar levels and an increased susceptibility to type 2 diabetes (Marku et al. 2022). Consequently, PCSK9 is acknowledged as a pivotal regulator of β-cell secretory function, maintaining homeostasis to prevent cholesterol over accumulation in β cells (Da Dalt et al. 2019; Marku et al. 2022). Investigations using cell and animal models of type 2 diabetes have demonstrated that polydatin could downregulate PCSK9 expression, thereby upregulating glucokinase expression (Wang et al. 2016). Moreover, quercetin-3-glucoside has been shown to reverse the LDL-R/PCSK9 ratio in β cells. Specifically, quercetin-3-glucoside elicited a relatively greater increase in PCSK9 compared to LDL-R. This effectively restricts cholesterol entry into the cells, counteracting the hyperinsulinemia induced by a high-cholesterol diet (Mbikay et al. 2018).

PCSK9-regulating drugs in the prevention and management of non-alcoholic fatty liver diseases

Modulating the expression of PCSK9 has also revealed therapeutic promise in non-alcoholic fatty liver disease (NAFLD), a disorder linked to lipid accumulation-induced endoplasmic reticulum (ER) stress (Frątczak et al. 2022; Cui et al. 2023). Hydrogen sulfide has been proven to decrease PCSK9 expression in liver cells. By doing so, it alleviates lipid deposition and ER stress, thereby improving the condition of NAFLD (Cui et al. 2023). Furthermore, curcumin has been demonstrated to suppress the expression of SREBP-2, NPC1L1, and 3-hydroxy-3-methylglutaryl coenzyme A reductase in both the liver and intestine in vivo. This suppression reduces the cholesterol production in the liver and cholesterol absorption in the gut, both of which are induced by bisphenol A. As a result, hepatic steatosis and NAFLD are alleviated (Hong et al. 2023).

PCSK9-regulating drugs in the prevention and management of renal lipotoxicity

In addition to LDL-R, PCSK9 also regulates the uptake of circulating lipids via CD36. This process contributes to kidney injury through various mechanisms (Byun et al. 2022; Németh et al. 2023). In a murine model of renal lipotoxicity, researchers discovered that the depletion of PCSK9 aggravated the renal injury induced by a high-fat diet. This exacerbation was linked to an upsurge in CD36 expression on renal epithelial cells. Moreover, pretreatment with evolocumab, a PCSK9 monoclonal antibody, resulted in a reduction in CD36 expression on renal epithelial cells and attenuated the high-fat diet-induced kidney injury. Subsequent studies revealed that the binding of evolocumab to PCSK9 disrupts the interaction between PCSK9 and LDL-R, yet leaves the interaction between PCSK9 and CD36 intact (Byun et al. 2022).

PCSK9-regulating drugs for the management and improvement of cardio metabolism

Although PCSK9 is sparsely expressed in cardiomyocytes, it exerts an impact on cardiometabolic function (Laudette et al. 2023). Reportedly, elevated PCSK9 levels can disrupt free fatty acid (FFA) metabolism and compromise cardiomyocyte contractility. Consequently, this disruption leads to excessive autophagy and apoptosis of cardiomyocytes (Guo et al. 2021). Moreover, PCSK9 has been discovered to promote platelet activation and blood coagulation in patients with ventricular fibrillation (Cammisotto et al. 2020). PCSK9-targeting drugs, like pep 2-8 or alirocumab, have demonstrated the ability to downregulate PCSK9 expression in cardiomyocytes and enhance cardiac function in vivo (Wolf et al. 2020). SBC-115076, a PCSK9-specific antagonist, has been shown to mitigate myocardial infarction-induced cardiac fibrosis and ventricular remodeling, thereby improving long-term prognosis. Mechanistically, SBC-115076 suppresses myocardial PCSK9 level, which in turn upregulates myocardial Notch1 expression, thereby suppressing collagen deposition and the migration of cardiac fibroblasts (Wu et al. 2023). Meanwhile, preclinical studies have indicated that, compared with atorvastatin, a commonly used drug for restoring lipid profiles in obese patients, PCSK9 inhibitors display superior cardioprotective effects (Amput et al. 2020).

Regulatory mechanism of drugs on PCSK9

Regulating PCSK9 transcription

Research findings indicate that in HepG2 cells, the expression of PCSK9 is regulated at the transcriptional level by sterols. Both SREBP-1 and SREBP-2 transcriptionally activate PCSK9 expression through the sterol-regulatory element present in the proximal promoter region of PCSK9 in HepG2 cells. Nevertheless, under in-vivo conditions, it is proposed that SREBP-2 predominantly mediates the sterol-dependent regulation of PCSK9 (Jeong et al. 2008). The transcription factors HNF1α and HNF1β are capable of binding to the HNF1 site on the PCSK9 promoter, thereby activating transcription in HepG2 cells. This particular study demonstrates that in mouse liver, HNF1α, rather than HNF1β, serves as the primary positive regulator of PCSK9 transcription (Shende et al. 2015).

Drugs mainly regulate PCSK9 transcription by modulating the expression, post-translational modifications, or activities of SREBP-1, SREBP-2, and HNF1α. Some drugs are designed to target multiple pathways for regulating PCSK9 expression. For instance, plant stanol downregulates SREBP-2 expression in the liver yet activates the SREBP-2 pathway in the intestine (De Smet et al. 2015).

Apart from modulating transcription factors, certain drugs are designed to regulate PCSK9 mRNA levels through alternative mechanisms. For example, estradiol activates estrogen-response elements in the PCSK9 promoter, thus increasing PCSK9 expression (Maarouf et al. 2020). Hydrogen sulfide promotes SIRT1-mediated FoxO1 deacetylation. FoxO1 then binds to the PCSK9 promoter region, leading to a reduction in its transcription (Cui et al. 2023). Moreover, VERVE-101 entirely silences PCSK9 expression by precisely modifying the coding sequences of the PCSK9 gene (Lee et al. 2023).

Regulating the translation of PCSK9 mRNA

Besides modulating PCSK9 transcription, certain drugs directly exert regulatory effects on PCSK9 mRNA. Examples include PCSK9-targeting antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). ASOs, which are single-stranded RNA or DNA molecules, bind to PCSK9 mRNA, thereby causing its degradation (Liao et al. 2017). The N-acetylgalactosamine (GalNAc)-conjugated AZD8233 (ASO) attaches to the asialoglycoprotein receptor expressed on hepatocytes. This binding facilitates the uptake of AZD8233 into hepatocytes (Rekić et al. 2022). SPC5001 (ASO) is a short synthetic DNA oligonucleotide. It has conformationally stabilized (‘locked’) RNA nucleotides at both ends. This modification aims to enhance the sensitivity and specificity of binding (van Poelgeest et al. 2013). On the other hand, siRNAs, such as inclisiran (German and Shapiro 2020), STP135G, and RBD7022 (Oostveen et al. 2023), are also synthesized to silence PCSK9 expression at the mRNA level. Distinct from ASOs, siRNAs are short double-stranded RNA molecules. They integrate into the RNA-induced silencing complex (RISC) and specifically bind to their target mRNA, triggering its degradation (Kaczmarek et al. 2017).

Interrupting the PCSK9/LDL-R interaction

Drugs are also applied to inhibit PCSK9 at the post-translational stage. Certain drugs bind to PCSK9, inducing a conformational alteration that obstructs its interaction with LDL-R. Consequently, this prevents the PCSK9-mediated degradation of LDL-R. Dextran sulfate, pentosan sulfate, suramin, and phosphorothioate oligodeoxycytidine S-dC-36 inhibit the PCSK9-LDL-R interaction in liver cells by binding to PCSK9 (Gustafsen et al. 2017; Shrestha et al. 2021). Polydatin can impede the PCSK9-LDL-R interaction in tumor cells through the formation of hydrogen bonds with PCSK9 (Wang et al. 2016; Li et al. 2018). Likewise, BMS-962476 (Mitchell et al. 2014), LIB003 (Raal et al. 2023), DS-9001a (Masuda et al. 2018), and MK-0616 (Ballantyne et al. 2023) also inhibit the PCSK9-LDL-R interaction by binding to PCSK9.

Anti-PCSK9 vaccines trigger an anti-PCSK9 antibody response, which leads to a reduction in PCSK9 levels and inhibits its binding to LDL-R. These vaccines can be categorized into several types. First, there are polypeptide vaccines, including AT04A, AT06A, and VXX-401 (Zeitlinger et al. 2021; Vroom et al. 2024). Second, there are nano-liposome vaccines such as L-IFPTA+ (Momtazi-Borojeni et al. 2019). Third, there are VLP vaccines, which include monovalent and bivalent VLP vaccines, full-length PCSK9 and shorter PCSK9 VLP vaccines, as well as PCSK9Qβ-003, and they play a significant role in this area (Pan et al. 2017; Wu et al. 2020; Goksøyr et al. 2022; Fowler et al. 2023).

ARBU suppresses cholesterol synthesis in tumor-associated macrophages through the PCSK9-LDL-R signaling pathway (Li et al. 2024). The peptide Pep 2-8 inhibits the catalytic domain of PCSK9, which is responsible for LDL-R interaction in cardiomyocytes. As a result, it blocks the binding between PCSK9 and LDL-R (Wolf et al. 2020).

Multiple action mechanisms

Some drugs employ multifaceted mechanisms to modulate PCSK9 levels. For instance, the saponin fucoidan F3 upregulated PPARα and LXRα/β while simultaneously downregulating SREBP-1c and SREBP-2 in the mouse liver (Zhang et al. 2024). Furthermore, polydatin not only inhibits the expression of the PCSK9 protein but also blocks the binding between PCSK9 and LDL-R (Wang et al. 2016). Rhubarb free anthraquinone can modify the PPARα signaling pathway, thereby modulating lipid metabolism and reducing the expression of SREBP-2 in the liver (Wang et al. 2022). Additionally, P5-met, a metabolite of P5, has been reported to block the interaction between PCSK9 and LDL-R and downregulate HNF-1α, consequently reducing PCSK9 secretion (Lammi et al. 2021) (Figure 1).

Figure 1.

Regulation mechanism of drugs on PCSK9. (the figure is the property of the author.).

Conclusions and future perspectives

The revelation of PCSK9’s participation in multiple physiological processes unfolds promising prospects for drug repurposing. As our comprehension of PCSK9 continues to deepen, drugs that modulate PCSK9 have transcended the realm of cholesterol homeostasis. PCSK9 is expressed across a diverse range of organs and tissues. In this article, we comprehensively summarize the regulatory impacts that various drugs have on the expression of PCSK9 within distinct organs, tissues, and cells (Figure 2). These drugs now exhibit great potential in the treatment of diabetes, tumors, inflammation, cardiovascular diseases, and neurodegenerative disorders. This ever-expanding application scope vividly demonstrates the potential for repurposing currently available lipid-lowering medications.

Figure 2.

PCSK9-regulating drugs in different organs, tissues and cells. (the figure is the property of the author.).

Certain PCSK9 inhibitors possess a distinct property: they disrupt the PCSK9-CD36 interaction without influencing LDL-R levels. This characteristic lays the foundation for combination therapies, which hold the promise of offering more comprehensive lipid management while minimizing side effects. Numerous studies have indicated that, apart from liver cancer cells, tumors originating from other organ systems also exhibit high-level expression of PCSK9. This finding implies that these drugs could potentially benefit a much broader cohort of cancer patients. Considering the intricate interactions between PCSK9 and diverse cellular pathways, the identification and development of biomarkers to predict treatment efficacy holds the key to devising more customized and effective treatment strategies. In future research, efforts should be directed towards optimizing drug delivery mechanisms, enhancing target specificity, and establishing personalized PCSK9-targeting therapies.

A substantial number of these drugs are currently either in the preclinical research phase or undergoing clinical trials. As a result, remarkable progress is anticipated in the upcoming years. The ever-evolving panorama of PCSK9-targeted therapies holds great promise for making significant headway in treating a diverse spectrum of diseases. This has the potential to revolutionize patient care across numerous medical disciplines, bringing about a paradigm shift in the way healthcare is delivered and received.

Funding Statement

This work was supported by the Shandong Provincial Natural Science Foundation of China (ZR202210300051), the Jinan Science and Technology Bureau (202430030, 202134050), the Youth Science Fund Cultivation and Support Program of Shandong First Medical University (202201-136), and the Shandong Provincial Adverse Drug Reaction Monitoring Research Project (2021SDADRKY01).

Ethical approval

This study does not involve human participants, human data or human tissues. No consent to participate is required.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data referenced in this study are primarily sourced from publicly accessible databases: PubMed and China National Knowledge Infrastructure (CNKI). Specific literature and datasets can be accessed as follows:

PubMed: A DOI has been provided after each reference.

China National Knowledge Infrastructure (CNKI): The Chinese literature has been translated into English, and links have been placed after the references.

As this study did not generate new datasets or raw data, there are no additional data to share. All necessary data and analysis results are described in detail within the article and can be accessed through the aforementioned links.