Hepatic targeting in ASCVD: integrating lipid lowering and inflammation modulation from statins to gene editing

Background

Atherosclerotic cardiovascular disease (ASCVD) continues to be a major global health burden, with substantial residual cardiovascular risk remaining. Growing evidence highlights the liver’s pivotal role in the onset and development of ASCVD through multiple interconnected pathways.

Main body

As the metabolic center of the body, the liver regulates the synthesis, secretion, and clearance of several atherogenic lipoproteins while simultaneously serving as a systemic inflammation amplifier, producing cytokines, acute-phase proteins, and coagulation factors. Traditional liver-targeted therapies, such as statins, have demonstrated that regulating liver metabolism can confer significant cardiovascular benefits. Subsequently, advances in nucleic acid-based drugs and in vivo gene-editing tools have broadened this strategy, enabling accurate and durable modulation of hepatic gene expression. However, recent clinical trials suggest that improvements in laboratory biomarkers do not always translate into proportional reductions in major adverse cardiovascular events. Moreover, the long-term safety and durability of lipid nanoparticles and gene-editing platforms remain ongoing concerns. Future research should focus on the classification of patients based on multiple omics data, and distinguish those whose main problem is metabolic disorder from those who are mainly at high risk of inflammation, thereby facilitating personalized therapeutic targeting.

Conclusion

Overall, current evidence indicates that the liver represents a convergent therapeutic target for modulating both lipid metabolism and inflammation, offering a promising opportunity for deeper and more durable cardiovascular risk reduction.

Highlights

The liver acts as a central regulator integrating lipoprotein metabolism and systemic inflammation in the pathogenesis of ASCVD.

Traditional liver-targeted therapies, including statins and bempedoic acid, improve lipid profiles but do not fully eliminate residual cardiovascular risk.

Nucleic acid therapeutics and in vivo gene editing enable precise modulation of hepatic gene expression and offer deeper intervention across lipid and inflammatory pathways.

Reductions in biomarkers, including LDL-C, Lp(a) and hs-CRP, do not consistently translate into cardiovascular event reduction, emphasizing the need for outcome-driven evaluation of liver-targeted therapies.

Safety concerns and patient heterogeneity highlight the need for individualized liver-targeted treatment in ASCVD.

Introduction

Atherosclerotic cardiovascular disease (ASCVD) represents a major global health challenge, causing about 18 million deaths every year [1]. Although the traditional treatment is effective in reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events, a number of patients with LDL-C reaching the target still have significant residual cardiovascular risk [2, 3]. Triglyceride-rich lipoproteins (TRLs) and remnant cholesterol (RC) are now recognized as key contributors to this residual risk, which may remain elevated even when LDL-C is optimally controlled. These remnant particles trigger harmful responses in the arterial wall and facilitate the development of atherosclerotic plaques [4]. Meanwhile, accumulating evidence indicates that persistent activation of the interleukin-6-C-reactive protein (IL-6–CRP) axis and hepatic production of prothrombotic mediators can sustain vascular inflammation and plaque instability, and plaque instability driven by inflammation constitutes a key mechanism linking these remnant particles to residual risk in ASCVD [5]. Given that these metabolic and inflammatory drivers arise largely from hepatic pathways, therapeutic strategies capable of more precisely modulating liver function are indispensable for addressing residual ASCVD risk beyond LDL-C lowering alone [6]. In this review, we present a comprehensive perspective on the liver’s role in atherogenesis, highlighting its function as a metabolic and inflammatory regulator. Subsequently, we analyze the unique advantages of liver-targeted therapy in modulating lipid metabolism and inflammatory pathways. We also discuss the evolution of treatment strategies in recent years, focusing on how these strategies precisely regulate liver metabolism and inflammatory functions, overcome limitations of traditional therapy, and address the persistent residual risk in ASCVD.

The dual role of the liver in ASCVD

The liver occupies a unique integrative position in the pathophysiology of ASCVD, as hepatocytes coordinate the synthesis, remodeling, and clearance of systemic atherogenic lipoproteins while initiating acute-phase and thrombotic responses in reaction to upstream inflammatory signals. Within hepatocytes, lipid overload and inflammatory signals interact to create a vicious cycle, which amplifies the risk of vascular injury and accelerates atherogenesis (Fig. 1).

Fig. 1.

The dual role of the liver in lipid metabolism and systemic inflammation in ASCVD. On the metabolic side (left), the liver regulates the life cycle of atherogenic lipoproteins through four key processes: (1) Endogenous lipid export: synthesis and secretion of VLDL and TRLs; (2) Circulating lipid hydrolysis: regulation of LPL activity by ANGPTL3 and ApoC3; (3) Hepatic lipid clearance: receptor-mediated uptake and degradation of circulating lipids; and (4) Synthesis and clearance of Lp(a): the liver as the exclusive source of circulating Lp(a). On the inflammatory side (right), the liver amplifies systemic inflammation and thrombosis through two interconnected pathways: (1) Systemic inflammation amplifier: inflammatory cytokines (IL-6, IL-1β) induce hepatocyte-derived CRP production; and (2) Inflammation–thrombosis axis: hepatic synthesis of procoagulant and complement proteins promotes vascular inflammation and thrombotic risk. Together, these processes position the liver as a central integrator of metabolic and immune regulation in ASCVD, linking lipid metabolism to systemic inflammation and thrombosis

The central hub of circulating lipoprotein metabolism

The liver plays a central role in our body’s processing of fat. It is responsible for managing several kinds of lipoproteins, such as LDL-C, very low-density lipoprotein (VLDL), lipoprotein (a) [Lp(a)] and TRLs, including synthesizing, modifying and cleaning them.

The liver occupies a central position in systemic lipid homeostasis by coordinating the synthesis, remodeling, and clearance of multiple atherogenic lipoproteins, including LDL-C, very-low-density lipoprotein (VLDL), lipoprotein(a) [Lp(a)], and TRLs [7]. Consequently, hepatic dysregulation of lipoprotein metabolism constitutes a major pathophysiological mechanism underlying the initiation and progression of ASCVD [8] (Fig. 2).

Fig. 2.

Hepatic regulation of lipoprotein metabolism and inflammation in the pathogenesis of ASCVD. The liver integrates multiple metabolic and inflammatory pathways that drive the development and progression of ASCVD. Left panel: Hepatic synthesis and secretion of VLDL are initiated by ApoB and MTTP, forming nascent VLDL particles that are secreted into the circulation. Circulating VLDL is hydrolyzed by LPL, a process inhibited by ApoC3 and ANGPTL3, to generate IDL and LDL. Hepatic LDLR mediates LDL uptake and recycling, while proprotein PCSK9 promotes LDLR degradation, elevating plasma LDL-C. Middle panel: The liver exclusively synthesizes Apo(a) and assembles Lp(a), a highly atherogenic and proinflammatory lipoprotein particle that contributes to monocyte recruitment, foam cell formation, and atherosclerotic plaque development. Right panel: Inflammatory cytokines, such as IL-1β and IL-6, activate hepatocyte gp130/IL-6 receptor (IL-6R) complexes, triggering the JAK/STAT3 signaling axis and transcription of CRP. Hepatocyte-derived CRP, along with complement and coagulation factors, amplifies vascular inflammation and endothelial dysfunction, forming the inflammation–thrombosis axis. Collectively, these processes establish the liver as a central hub that couples lipid metabolism with systemic inflammation, amplifying residual cardiovascular risk in ASCVD

Synthesis and secretion of VLDL and trls: the gateway for endogenous lipid export

As the origin of the endogenous lipid transport system, the liver coordinates the packaging of fatty acids and triglycerides synthesized de novo or derived from the circulation into VLDL particles [9]. Under conditions of nutrient excess, hepatocytes convert surplus carbohydrates into fatty acids through the de novo lipogenesis (DNL) pathway. These fatty acids, together with circulating non-esterified fatty acids (NEFAs), are esterified into triglycerides [10]. Subsequently, in the hepatocyte endoplasmic reticulum (ER), the VLDL precursor is assembled by incorporating cholesterol esters, triglycerides, and phospholipids onto apolipoprotein B (ApoB). Microsomal triglyceride transfer protein (MTTP) acts as an important lipid transporter, which binds to ApoB and transfers lipids to ApoB [11]. Newly formed VLDL are secreted into the circulation via the Golgi apparatus. The rate of VLDL generation directly determines the total flux of ApoB particles in plasma [12]. VLDL particles are hydrolyzed by lipoprotein lipase (LPL) located on vascular endothelial surfaces, releasing fatty acids for utilization by the surrounding tissues such as muscle and adipose tissue [10]. This metabolic cascade progressively transforms VLDL into VLDL remnants and intermediate-density lipoproteins (IDLs) with relatively increased cholesterol ester content. These TRL remnants can easily cross the endothelial barrier and accumulate within the arterial wall, exhibiting potent atherogenic potential [3, 13].

Generation and clearance of LDL-C: the ultimate determinant of atherogenic burden

LDL-C is one of the most well-established contributors for ASCVD [14]. Most plasma LDL particles are the final degradation products of VLDL hydrolysis. Therefore, excessive production of liver-derived VLDL represents one of the major upstream drivers of elevated LDL-C levels [4]. Meanwhile, the level of circulating LDL-C is tightly controlled by the efficiency of hepatic clearance [15]. The liver efficiently removes LDL particles from the circulation via the low-density lipoprotein receptor (LDLR) on its cell surfaces [16]. LDLR recognizes apolipoprotein B-100 (ApoB100) on the surface of LDL particles and internalizes the LDL-receptor complex through clathrin-mediated endocytosis [17]. In an acidic endosome, LDLR is released from LDL and returns to the cell surface for reuse, while LDL particles remain within the endosomal compartment and are subsequently transported to lysosomes for degradation [18].

Sterol regulatory element-binding protein 2 (SREBP-2) regulates the transcription of LDLR, and this process is tightly governed by intracellular cholesterol concentrations via a negative feedback loop [18]. Furthermore, recent studies have revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9), synthesized and secreted by the liver, serves as an important negative regulator of LDLR protein levels [19]. PCSK9 latches onto LDLR extracellularly and directs the entire complex to lysosomal degradation following internalization, effectively blocking LDLR recycling and ultimately causing a substantial elevation in circulating LDL-C concentrations [20]. Therefore, PCSK9 inhibitory therapies have evolved as one of the cornerstones of modern lipid-lowering treatment [21].

Synthesis and clearance of Lp(a): a unique genetic risk factor

Lipoprotein(a) (Lp(a)) shares many characteristics with LDL-C, which is recognized as an independent, inherited risk factor for ASCVD [22]. Lp(a) is similar to LDL-C in size, lipid composition, and the presence of ApoB100. However, Lp(a) contains large glycoprotein, apolipoprotein(a) [Apo(a)] [23]. Apo(a) is almost entirely synthesized in the liver, and the expression of the LPA gene is the most significant factor determining an individual’s plasma Lp(a) concentration, which is over 90% genetically determined and remains relatively stable throughout an individual’s life [24].

The precise assembly site of Lp(a), whether intracellular or extracellular, remains under investigation. Nevertheless, the liver is firmly established as the sole source of Lp(a) entering the circulation [25]. Furthermore, the clearance mechanisms of Lp(a) are not yet fully elucidated and are largely independent of the classical LDL receptor pathway [26]. This characteristic explains why therapies primarily targeting LDL-C reduction (such as statins) have minimal impact on Lp(a) levels [27].

Current research indicates that the liver may participate in the clearance of Lp(a) through multiple alternative pathways, including scavenger receptors, lectin receptors, and potentially plasminogen receptors. However, the overall clearance efficiency of these processes is substantially lower than that of LDL [28]. Due to Lp(a) exhibiting multifaceted pathological properties, including atherogenic, proinflammatory, and potentially prothrombotic properties, elevated plasma Lp(a) concentrations are now recognized as an important and independent genetic risk factor for ASCVD [29].

The liver: an amplifier of systemic inflammation and thrombosis

Beyond its central role in metabolic regulation, the liver also serves as a key organ in host defense and inflammatory responses. It functions both as a sensor of numerous pro-inflammatory and anti-inflammatory mediators and as the principal site for the synthesis of systemic acute-phase reactants (APRs) [30]. The liver translates inflammatory signals originating from atherosclerotic plaques or from systemic sources into a systemic pro-inflammatory and pro-thrombotic state, thereby substantially amplifying cardiovascular risk [31] (Fig. 2).

The liver functions as the effector hub for systemic inflammation and thrombotic risk

Hepatocytes are the primary producers of acute-phase proteins in the body. When stimulated by upstream inflammatory cytokines, particularly interleukin 6 (IL-6) and interleukin 1β (IL-1β), the liver initiates a robust acute-phase response, synthesizing and secreting a wide range of bioactive proteins into the circulation. Among these, high-sensitivity C-reactive protein (hs-CRP) has been firmly established as an independent predictor of future cardiovascular events and serves as an important biomarker for clinical risk stratification and therapeutic monitoring [30, 32]. Hs-CRP is synthesized almost exclusively by hepatocytes in response to stimulation from IL-6 and related cytokines [33]. Plenty of epidemiological studies and meta-analyses have consistently demonstrated that elevated hs-CRP levels independently predict myocardial infarction, ischemic stroke, and cardiovascular mortality, even among individuals whose LDL-C levels are well controlled [34, 35].

The liver is also responsible for synthesizing nearly all components of the circulating complement system, as well as most coagulation factors and fibrinogen [36]. During inflammatory activation, the complement system not only contributes to pathogen clearance but also generates cleavage products such as C3a and C5a, which exacerbate endothelial inflammation and promote platelet activation [37]. Meanwhile, inflammatory mediators upregulate hepatic production of coagulation factors, including fibrinogen and factor VIII, thereby disrupting the balance between anticoagulant and procoagulant pathways [38]. This imbalance establishes a vicious cycle within the inflammation–thrombosis axis (immuno-thrombosis), markedly increasing the risk of atherothrombosis [39]. Therefore, the liver acts as a key effector organ linking inflammatory sensing to downstream vascular events [40].

The IL-6/JAK/STAT3/CRP axis: a critical signaling pathway linking inflammation to ASCVD risk

Within the liver, the IL-6 signaling pathway is the core mediator of inflammatory responses, which triggers acute phase reactions and bolstering infection defenses. Circulating IL-6 binds to the IL-6 receptor (IL-6R) on the surface of hepatocytes, activating the intracellular Janus kinase (JAK) [41]. The activated JAK further phosphorylates and activates Signal Transducer and Activator of Transcription 3 (STAT3). The phosphorylated STAT3 forms dimers and translocases into the nucleus [42]. These STAT3 dimers attach to the promoter regions of multiple acute-phase protein genes, including CRP, thereby strongly promoting their transcription [30]. The classical IL-6/JAK/STAT3 signaling axis not only forms the foundation of hepatic inflammatory responses but also represents the biological core linking inflammation to cardiovascular disease [43]. Large-scale clinical investigations, including the CANTOS trial, have revealed that targeting IL-1β, an upstream activator of IL-6, successfully reduces hs-CRP levels and mitigates the risk of recurring cardiovascular incidents. This finding provides the clinical validation of the “inflammation hypothesis”, demonstrating that inhibition of inflammation can confer cardiovascular benefits independently of lipid-lowering effects [44].

Established liver-targeted therapies: metabolic enzyme inhibition

Liver is a major target for pharmacological interventions of dyslipidemia in clinical settings [45]. The classic therapeutic approach is to inhibit key enzymes in the cholesterol synthesis pathway, which not only effectively lowers atherogenic lipoprotein levels but also partly inhibits liver-mediated inflammatory pathways (Fig. 3; Table 1).

Fig. 3.

Liver-targeted therapeutic strategies integrating lipid lowering and inflammation modulation from statins to gene editing. The liver serves as the primary target for multiple generations of therapeutic interventions in ASCVD, encompassing small-molecule inhibitors, nucleic acid–based drugs, and in vivo gene-editing technologies. Conventional metabolic enzyme inhibitors such as statins and bempedoic acid act on the cholesterol synthesis pathway by inhibiting HMGCR and ACL, respectively, thereby reducing intracellular cholesterol synthesis and upregulating LDLR expression to enhance LDL clearance. Nucleic acid–based drugs utilize GalNAc conjugation for efficient hepatocyte delivery via the ASGPR. Key therapeutics include Olezarsen (ApoC3 ASO), Solbinsiran (ANGPTL3 siRNA), Inclisiran (PCSK9 siRNA), and Olpasiran (LPA siRNA). These agents selectively silence hepatic mRNAs, leading to degradation of their targets through RNase H1 or RNA-induced silencing complex (RISC) pathways, resulting in reduced synthesis of atherogenic proteins and improved lipoprotein metabolism. Gene-editing strategies represent the next frontier, exemplified by VERVE-101, an in vivo ABE therapy targeting the PCSK9 gene in hepatocytes to achieve permanent suppression of PCSK9 expression. Parallel anti-inflammatory approaches, including Canakinumab (IL-1β antibody) and Colchicine, target the IL-1β/IL-6/JAK/STAT3/CRP axis, attenuating systemic inflammation. Collectively, these approaches illustrate the liver-directed therapeutics that concurrently modulate lipid metabolism and inflammatory signaling, establishing the liver as a convergent target for comprehensive ASCVD risk reduction

Table 1.

Liver-targeted therapies

Drug / platform	Primary targets	Lipid efficacy (typical reduction)	Effect on inflammation markers	Cardiovascular outcomes evidence	Common adverse effects
Statins	Inhibit hepatic HMG‑CoA reductase [46]	LDL‑C :~30–55% decrease [47]	hs-CRP : ~15–25% decrease [48]	Multiple large RCTs show MACE reduction [49]	Liver enzyme elevation, myalgia; rare rhabdomyolysis [50]
	Increase LDLR expression [46]
	Accelerate the clearance of LDL-C [46]
Bempedoic acid	Inhibit ATP- citrate lyase [51]	LDL‑C : ~21% decrease [52]	hs-CRP : ~21.6% decrease [52]	CLEAR Outcomes: reduced composite CV events in statin‑intolerant pts [52]	Hyperuricemia/gout [53]
	Increase LDLR expression [54]
	Accelerate the clearance of LDL-C [51]
Inclisiran (siRNA, GalNAc)	RNAi to suppress hepatic PCSK9 synthesis [55]	LDL‑C : ~50% decrease (twice yearly maintenance) [55]	Neutral	ORION‑4 outcomes trial ongoing : potential benefits for MACE reduction [56]	Mild cough, musculoskeletal pain, nasopharyngitis [57]
	Enhance hepatic LDL receptor recycling and expression [55]
	Accelerate the clearance of LDL-C [55]
Olpasiran (siRNA, GalNAc)	RNAi to suppress hepatic LPA mRNA [58]	Lp(a) :~90–95% decrease [58]	OxPL-apoB: up to 90% decrease [59]	Outcomes trial ongoing [58]	Injection site reactions [58]
	Reduce levels of Lp(a) [58]
Olezarsen (ASO, GalNAc) [60]	ASO to suppress hepatic ApoC3 mRNA	TG: up to 60% decrease	Outcomes trial ongoing	Outcomes trial ongoing	Injection site reactions
	Reduce the synthesis of ApoC3
Solbinsiran (siRNA, GalNAc) [61]	RNAi to suppress hepatic ANGPTL3 mRNA	ApoB: up to 15% decrease TG: ~50% decrease VLDL-C: ~50% decrease LDL-C: ~16% decrease	Outcomes trial ongoing	Outcomes trial ongoing	Injection site reactions, hypersensitivity, gallbladder-related disorders
	Reduce the synthesis of ANGPTL3
	Enhance lipoprotein clearance
Canakinumab	Monoclonal antibody against IL-1β [62]	Neutral	hs-CRP : ~20–40% decrease [63]	CANTOS Outcomes: a significant reduction on the primary cardiovascular end point [63]	Neutropenia, thrombocytopenia [63]
	Inhibit the IL-1β/IL-6/JAK/STAT3/CRP inflammatory axis [63]
VERVE-101 (in vivo CRISPR base-editing delivered via LNP)	PCSK9 gene turned off	LDL‑C: ~50% decrease	Outcomes trial ongoing	Outcomes trial ongoing	Injection site reactions
	A significant and stable decrease in LDL-C levels

Statins: the cornerstone of cholesterol synthesis inhibition

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) serves as the crucial gatekeeper enzyme in the hepatic cholesterol biosynthesis pathway. Statins are competitive inhibitors of HMGCR. Statins reduce cholesterol synthesis within hepatocytes, subsequently upregulating the expression of LDLR via the SREBP-2 pathway, thereby accelerating the clearance of circulating LDL-C [46]. Comprehensive meta-analyses of randomized clinical trials (RCTs) have consistently shown that statin therapy effectively lowers LDL-C levels. For every 1 mmol/L (39 mg/dL) drop in LDL-C, there’s a roughly 20% decrease in the risk of major adverse cardiovascular events [64].

Besides the lipid-lowering effect, statins have been suggested to exhibit pleiotropic effects, including improved endothelial function, antioxidative stress capacity, and significant anti-inflammatory activity [65]. Clinical studies indicate that statin therapy can significantly reduce hs-CRP levels by 15–25% [66]. The JUPITER trial provided landmark evidence that rosuvastatin treatment significantly reduced the incidence of first cardiovascular events in healthy individuals with normal LDL-C levels but elevated hs-CRP, offering direct clinical proof of statins’ anti-inflammatory effects [48]. Thus, the success of statins fundamentally represents an early example of targeting the liver’s “metabolic-inflammatory crosstalk.”

Bempedoic acid: a next-generation, liver-specific inhibitor

Bempedoic acid is a novel therapeutic agent targeting the upstream pathway of cholesterol synthesis. It functions through inhibition of ATP-citrate lyase (ACL). ACL serves as an upstream enzyme of HMGCR, catalyzing the transformation of citrate from mitochondria into acetyl-CoA, which functions as a common substrate for both cholesterol and fatty acid synthesis [67]. Bempedoic acid is a prodrug that is uniquely activated by very long-chain acyl-CoA synthetase-1 (ACSVL1), an enzyme highly expressed in the liver, to form its active metabolite, bempedoyl-CoA. This liver-specific activation mechanism prevents its conversion in skeletal muscle, thereby markedly lowering the incidence of muscle-related side effects commonly seen with statin treatments [51].

The pivotal cardiovascular outcomes trial, CLEAR Outcomes, has validated the clinical value of bempedoic acid in a cohort of over 13,000 statin-intolerant patients. Findings revealed that, compared with placebo, bempedoic acid reduced LDL-C levels by 21.1% and lowered the risk of MACE by 13%. Notably, a prespecified analysis of the study revealed that bempedoic acid markedly reduced the median level of hs-CRP by 21.6% [52]. These findings provide compelling evidence that targeting upstream hepatic metabolic enzymes, such as ACL, can achieve not only effective lipid lowering but also anti-inflammatory effects, reaffirming the central role of the liver as a hub integrating metabolic and inflammatory signaling in the progression of ASCVD. The success of bempedoic acid offers new insights for developing tissue-selective therapeutic strategies [68].

Nucleic acid therapeutics and delivery platforms: a new paradigm for dual targeting of metabolism and inflammation

With the rapid advances in molecular biology and medicinal chemistry, nucleic acid–based drugs, particularly small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have emerged as revolutionary tools for targeting gene expression [69]. These drugs silence mRNA at the post-transcriptional level, thereby inhibiting the synthesis of pathogenic proteins with conspicuous specificity. Coupled with advanced liver-targeted delivery technologies, nucleic acid therapeutics have opened a new frontier for simultaneously modulating the metabolic and inflammatory drivers of ASCVD (Fig. 3; Table 1).

The GalNAc-ASGPR delivery system: a cornerstone of efficient hepatocyte targeting

The clinical translation of nucleic acid therapeutics has long been limited by off-target effects and inefficient delivery. The advent of the N-acetylgalactosamine (GalNAc) delivery platform revolutionarily overcomes these challenges [70]. By covalently conjugating GalNAc ligands to ASO or siRNA molecules, the drugs can be efficiently recognized and internalized by the asialoglycoprotein receptor (ASGPR), which is highly expressed on the surface of hepatocytes [71]. This ligand–receptor–mediated delivery strategy enables precise hepatic enrichment of the drugs while reducing systemic exposure, thereby greatly enhancing the therapeutic index [72]. The development of this technology has established a solid foundation for liver-targeted nucleic acid therapies aimed at modulating hepatic protein synthesis.

PCSK9-targeting siRNA (Inclisiran): a revolution in long-acting lipid Lowering and adherence

Inclisiran is a siRNA therapeutic delivered via GalNAc conjugation, targeting hepatic PCSK9 mRNA to achieve long-term suppression of PCSK9 protein synthesis [73]. The ORION studies demonstrated that twice-yearly subcutaneous injections of inclisiran can steadily and persistently reduce LDL-C levels by approximately 50% [55, 74]. This low-frequency dosing regimen offers a breakthrough solution to the long-standing challenge of medication adherence in cardiovascular prevention [75]. Although there is currently no direct evidence indicating that Inclisiran exerts anti-inflammatory effects independent of lipid lowering, Inclisiran provides a highly effective and easily adherent lipid-lowering strategy that fundamentally ensures the successful implementation of both primary and secondary prevention of ASCVD [56, 76].

Lp(a)-targeting therapeutics: aiming at a pro-inflammatory and pro-thrombotic lipoprotein

Given Lp(a)’s multiple pathological characteristics and its resistance to conventional lipid-lowering drugs, developing specific Lp(a)-lowering therapies holds significant clinical importance [77]. Several therapeutic agents targeting hepatic LPA mRNA have entered late-stage clinical development. The siRNA drug Olpasiran has demonstrated high efficacy in lowering Lp(a) levels in clinical trials, with reductions exceeding 90% [58]. Although the primary clinical benefit of Olpasiran is expected to result from attenuating the atherogenicity of Lp(a) particles, it also holds promise for indirectly alleviating vascular wall inflammation by eliminating oxidized phospholipids (OxPL), a pro-inflammatory mediator carried by Lp(a) [25, 59].

Targeting ANGPTL3: modulating triglycerides and the inflammatory microenvironment

Angiopoietin-like protein 3 (ANGPTL3) is a pivotal lipid regulatory factor synthesized and secreted by the liver. It inhibits the activities of LPL and endothelial lipase (EL), leading to the accumulation of TRLs and their remnants, which possess atherogenic and proinflammatory properties [78]. Human genetic studies have firmly established that individuals with mutations that disrupt the ANGPTL3 gene tend to have notably lower lipid levels and a substantially decreased chance of suffering from coronary artery disease [79]. ANGPTL3 functions not only as a metabolic regulator but also as an indirect amplifier of inflammation [3]. Based on this, liver-targeted nucleic acid therapies against ANGPTL3 mRNA, such as the ANGPTL3 siRNA drug Solbinsiran, have been developed. Clinical trials have demonstrated that Solbinsiran significantly reduces ApoB, TG, non-HDL-C, and ANGPTL3 levels in adults with mixed dyslipidemia, with an overall favorable safety profile, representing a new precision therapy strategy for simultaneously modulating metabolic abnormalities and inflammatory microenvironments through a single molecular target [61].

APOC3 ASO (Olezarsen): confirmed dual effects on triglycerides and inflammation

Apolipoprotein C-III (ApoC3) is a well-recognized regulator of triglyceride metabolism [80]. ApoC3 promotes the accumulation of TRLs and their remnants in plasma through multiple mechanisms. It directly inhibits the activity of LPL, thereby impairing triglyceride hydrolysis. It can also interfere with apolipoprotein E (ApoE)-mediated receptor recognition, which reduces the clearance of TRL remnants by LDLR and LDLR-related protein 1 (LRP1) [81]. Recent genetic research has revealed that individuals with inherited ApoC3 gene mutations experience consistently lower triglyceride levels throughout their lives, resulting in a significantly diminished likelihood of developing coronary heart disease [82]. In addition, ApoC3 and its associated TRL remnants can activate endothelial cells and monocytes, which in turn boost the production of proinflammatory cytokines and adhesion molecules, ultimately fueling vascular inflammation [3].

Olezarsen, an ASO conjugated with GalNAc, specifically targets hepatic ApoC3 mRNA to block its translation and suppress ApoC3 synthesis. In individuals with moderate hypertriglyceridemia or elevated cardiovascular risk, Olezarsen produces significant and dose-dependent decreases in both APOC3 and triglyceride levels [60]. In patients with familial chylomicronemia syndrome (FCS), Olezarsen also markedly reduces the risk of pancreatitis [83]. Overall, by reducing TRL remnant burden and attenuating vascular inflammation, Olezarsen represents an innovative liver-targeted therapeutic strategy that integrates metabolic correction with anti-inflammatory potential.

Collectively, these nucleic acid–based therapies illustrate a fundamentally new therapeutic paradigm in which hepatocyte-specific modulation of disease-driving genes can be achieved with unprecedented precision and durability. This long-acting profile is particularly advantageous for ASCVD, a lifelong disease in which treatment adherence and consistent risk-factor control remain major challenges. However,

In vivo gene editing: the vision of a one-time, lifelong regulation of hepatic metabolism and inflammation

In vivo gene editing, particularly CRISPR-based gene editing, opens a new avenue for the treatment of ASCVD by enabling one-time administration with long-term efficiency. Such durable control is particularly valuable for a chronic and lifelong disease in which metabolic and inflammatory mechanisms remain persistently active. By irreversibly silencing key hepatic genes, base-editing technologies can achieve sustained lipid lowering together with downstream anti-inflammatory effects without the need for repeated administration. This shift from long-term pharmacologic suppression to permanent reprogramming of hepatocyte function illustrates why gene editing is emerging as one of the most promising future directions in liver-targeted therapy for ASCVD (Fig. 3; Table 1).

PCSK9 base editing (VERVE-101): proof-of-concept and initial clinical success

PCSK9, validated by both genetic and pharmacologic evidence as a key therapeutic target for ASCVD, has emerged as a prime candidate for in vivo gene editing [84]. VERVE-101, produced by Verve Therapeutics, is an innovative in vivo base editing therapy. VERVE-101 employs lipid nanoparticles (LNPs) to deliver mRNA encoding an adenine base editor (ABE) along with a guide RNA (gRNA) specifically to hepatocytes [85]. Inside the hepatocytes, this system precisely converts an A-T base pair into a G-C base pair at a specific site within the PCSK9 gene, introducing an inactivating mutation that permanently switches off PCSK9 protein production [86]. A study in nonhuman primates demonstrated that treatment with VERVE-101 led to a significant and durable reduction in LDL-C levels [87, 88]. In the Heart-1 trial, which enrolled individuals with heterozygous familial hypercholesterolemia (HeFH), a one-time intravenous dose of VERVE-101 produced encouraging preliminary results. Treated patients achieving profound and sustained suppression of plasma PCSK9 protein levels and approximately 50% durable reductions in LDL-C [89, 90]. However, safety-related events were observed, leading to a temporary enrollment pause. These results indicate that in vivo base editing of PCSK9 holds substantial potential for long-term LDL-C reduction, although additional extensive and prolonged research is needed to verify its effectiveness, safety, and clinical value.

Future directions: hepatic gene editing targeting various pathogenic pathways

The potential of in vivo gene editing extends well beyond lipid metabolism. In principle, any protein synthesized by the liver that plays a key pathogenic role in ASCVD could serve as a potential therapeutic target. Among these, the inflammation-amplifying axis driven by the IL-6 signaling pathway represents a particularly compelling focus [91]. In the phase 2 randomized RESCUE trial conducted in high-risk individuals, the IL-6 ligand inhibitor Ziltivekimab markedly reduced levels of hs-CRP and other inflammatory biomarkers, providing pharmacological proof of concept that inhibition of IL-6 signaling can attenuate inflammation [92, 93]. These findings lay the groundwork for the development of hepatic gene editing strategies targeting key components of this pathway, including IL6, IL6R (the IL-6 receptor), and STAT3. Beyond inflammation, in vivo base editing has demonstrated remarkable progress in lipid regulation. In murine models, both adeno-associated virus (AAV)-mediated and LNP-mediated delivery systems efficiently silenced the angiopoietin-like 3 (ANGPTL3) gene, resulting in long-term reductions in plasma triglycerides and LDL-C [94, 95]. The optimized GalNAc-LNP delivery platform has further enabled CRISPR-based editing of ANGPTL3 in nonhuman primates lacking LDL receptors, offering a promising therapeutic avenue for patients with homozygous familial hypercholesterolemia [96]. Moreover, recent preclinical work using LNP-mediated delivery of TALEN mRNA achieved permanent knockdown of the LPA gene in mice, leading to sustained reductions in Lp(a), and demonstrating the feasibility of one-time editing of refractory lipoprotein risk factors [97].

Challenges and outlook: safety as the critical gatekeeper to clinical application

The clinical translation of genome editing technologies is facing substantial challenges, with long-term safety and effective delivery remaining the central concern [98]. Off-target effects represent the foremost issue. Although base editing offers greater precision compared with traditional CRISPR-Cas9 nuclease systems, unintended genomic alterations across the whole genome still pose a potential risk, necessitating comprehensive assessment using ultra-deep sequencing and other high-resolution analytical approaches [99–101]. Delivery-related immunogenicity and long-term effects also warrant scrutiny. LNP systems may elicit immune activation or chronic toxicity, while the editing machinery itself could induce cytotoxicity or immune responses [102]. The challenge is particularly pronounced for strategies targeting inflammatory pathways. Permanently silencing a key immune signaling axis (such as IL-6) raises the concern that host defense mechanisms against infection and tissue injury might be compromised, potentially resulting in immune dysregulation [103, 104]. Therefore, before this revolutionary technology can be widely implemented for the prevention and management of ASCVD, unequivocal evidence of long-term safety and net clinical benefit must be established through large-scale clinical trials that include comprehensive off-target profiling, expanded toxicology studies and prolonged human follow-up [105].

Clinical evidence: definitive proof of the liver as a metabolomic-inflammatory crosstalk point

Recently, accumulating clinical evidence has established the liver as a central amplifier of both metabolic and inflammatory processes in ASCVD. Therapeutic modulation of hepatic metabolic–inflammatory pathways has been shown to yield substantial cardiovascular benefits, offering a solid conceptual and empirical foundation for the next generation of ASCVD interventions.

Success of anti-inflammatory trials

Multiple large-scale cardiovascular outcome trials (CVOTs) have demonstrated that direct inhibition of inflammatory pathways involved in ASCVD effectively reduces the risk of cardiovascular events [106]. Among these, the CANTOS trial was a landmark study showing that Canakinumab, a monoclonal antibody targeting IL-1β, significantly lowered hs-CRP levels and reduced recurrent cardiovascular events without affecting lipid concentrations [107]. Subsequent pivotal studies evaluating the efficiency of Colchicine, namely COLCOT and LoDoCo2, consistently demonstrated that low-dose Colchicine reduced the risk of MACE by more than 20% in secondary prevention populations [108]. Meta-analysis of randomized controlled trials further confirmed that Colchicine significantly reduced the incidence of MACE, myocardial infarction (MI), ischemic stroke, and repeat coronary revascularization compared with placebo, with an overall favorable safety profile [109]. Collectively, these trials provide high-level randomized evidence supporting inflammation-targeted therapy.

MASLD and MASH: the inevitable link between a hepatic metabo-inflammatory syndrome and ASCVD

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction–associated steatohepatitis (MASH), represent the most characteristic clinical manifestations of hepatic metabolic and inflammatory dysregulation [110]. MASH is pathologically defined by hepatic steatosis accompanied by lobular inflammation and hepatocellular ballooning [111]. Extensive epidemiological evidence indicates that patients with MASLD or MASH are at substantially increased risk of ASCVD, independent of traditional metabolic syndrome components such as obesity and type 2 diabetes [112]. In fact, cardiovascular disease, rather than liver-related complications, is the leading cause of death among individuals with MASLD or MASH [113]. This observation highlights the capacity of local hepatic inflammation (steatohepatitis) to translate into systemic cardiovascular risk through the release of multiple pro-atherogenic hepatokines, including pro-inflammatory cytokines, procoagulant factors, and atherogenic lipoproteins [114].

Insights from resmetirom: dual benefits of targeting hepatic metabo-inflammation

Thyroid hormone receptor β (THR-β) is highly expressed in the liver, and its activation promotes hepatic lipid metabolism, enhances mitochondrial function, and exerts anti-inflammatory effects [115]. Resmetirom is a THR-β selective agonist that has recently been approved for the treatment of MASH [116]. In the phase III MAESTRO clinical program, Resmetirom not only achieved histological resolution of MASH and improvement in hepatic fibrosis, but also demonstrated marked benefits in lipid metabolism. Patients receiving Resmetirom exhibited significant reductions in LDL-C, triglycerides, and Lp(a) [117]. The success of Resmetirom provides a compelling clinical paradigm in which selective targeting of a key regulatory pathway within the liver can concurrently ameliorate local pathological processes (inflammation and fibrosis) and systemic metabolic disturbances (dyslipidemia). This dual benefit highlights a promising direction for the future development of integrated liver-targeted therapeutic strategies [118].

Future perspectives: unanswered questions and core challenges

The emergence of liver-targeted therapeutic strategies has introduced new avenues for the prevention and treatment of cardiovascular disease (Fig. 4). However, from basic mechanistic exploration to clinical translation, this field continues to face numerous unresolved scientific and practical challenges.

Fig. 4.

The Evolving Landscape of Therapies for Cardiovascular Risk Reduction. The historical and projected therapeutic evolution for managing cardiovascular risk, stratified into four distinct layers along a timeline from 1987 to 2030 and beyond

The disconnect between lowering biomarkers and reducing events: how to translate biomarker improvement into clinical benefit?

Despite several novel therapeutic approaches have achieved remarkable reductions in key atherogenic biomarkers, the magnitude of cardiovascular event reduction has not always been proportional to these biochemical improvements [119]. This discrepancy highlights the complex and sometimes disconnected relationship between biomarker modulation and clinical outcome benefit [120]. In the PROMINENT trial, Pemafibrate, a new selective PPARα modulator, significantly lowered triglyceride and VLDL-C levels, yet no reduction in cardiovascular events was observed [121]. Similarly, the STRENGTH trial was a clinical study designed to assess whether a combination omega-3 fatty acid formulation (Epanova) could reduce cardiac events in high cardiovascular risk patients with hypertriglyceridemia [122]. The result demonstrated that despite marked improvements in lipid and inflammatory markers, there was no significant effect on MACE [123]. The failure of therapies that produced favorable metabolic or inflammatory changes but did not reduce clinical outcomes underscores the limitations of relying solely on surrogate markers. Therefore, for emerging liver-targeted therapies, definitive assessment of therapeutic value will require adequately powered, rigorously designed outcome trials [124]. These findings also highlight that future research should aim to elucidate the dynamic interplay within this metabolic and inflammatory network and to explore dual or multiple targeting strategies that combine potent lipid-lowering with anti-inflammatory therapy, thereby transforming biomarker improvement into meaningful reductions in clinical events [34].

Long-term safety: will liver-targeted therapies induce unforeseen long-term effects?

Recent developments in liver-targeted therapies have raised hopes for treating metabolic and inflammatory diseases, but long-term safety concerns remain a critical challenge [124]. Systematic studies have indicated that key components of LNPs, including ionizable lipids and polyethylene glycol (PEG), may trigger inflammatory responses through complement activation-related pseudo allergy (CARPA) and the innate immune pathways of dendritic cells and macrophages [102]. In addition, the development of anti-PEG antibodies may increase immunoreactivity and alter drug efficacy [125]. Gene editing presents additional challenges due to its single-administration and long-lasting effects. Permanent silencing of a gene that may have pleiotropic physiological roles could lead to unforeseen long-term consequences [126]. Therefore, establishing comprehensive long-term safety registries and developing biomarkers which can predict hepatic immune activation are essential steps to ensure the sustainable and safe clinical application of these revolutionary therapies.

Precision medicine: how to select the optimal liver-targeted strategy for the right patient?

Risk for ASCVD exhibits considerable heterogeneity, and the dominant pathogenic drivers may differ among individuals, such as those primarily driven by metabolic dysregulation, including elevated lipoprotein(a) or hypertriglyceridemia, and those characterized by predominant residual inflammatory risk [127]. The central challenge of future research is expected to shift from the question of what we can do to the question of for whom we should do it [128]. Future efforts should focus on accurately identifying distinct patient subgroups and selecting the most appropriate liver-targeted therapeutic strategies. Achieving this goal requires moving beyond conventional clinical classifications by integrating multi-omics data, including genomics, transcriptomics, proteomics, and metabolomics, to establish a new molecular framework for disease stratification. This stratification provides the foundation for personalized therapy by maximizing therapeutic benefit while minimizing unnecessary exposure to potent liver-directed agents, thereby improving the overall effectiveness of ASCVD prevention and treatment [129].

Conclusions

The liver plays a dual central role in the pathophysiology of ASCVD. It functions both as the metabolic center that governs the life cycle of atherogenic lipoproteins and as a critical effector that amplifies local and systemic inflammatory signaling. Hepatic overproduction and impaired clearance of atherogenic lipoprotein promote endothelial activation, foam cell formation, and local arterial-wall inflammation. Meanwhile, inflammatory cytokines such as IL-6 and IL-1β, originating from atherosclerotic plaques and extrahepatic tissues, feed back to the liver to upregulate acute-phase proteins, complement and procoagulant factors, thereby amplifying systemic inflammatory and prothrombotic tone. Traditional liver-targeted therapies centered on lipid lowering, such as Statins, have already demonstrated substantial cardiovascular benefits through modulation of hepatic metabolism. Meanwhile, the establishment of the inflammatory hypothesis has further clarified the pivotal contribution of liver-derived inflammatory mediators to residual cardiovascular risk. Recent advances in molecular biology and drug delivery have led to the emergence of a new generation of liver-targeted therapies. These include small molecules with liver-selective activity, nucleic acid–based agents capable of precisely regulating gene expression, and in vivo gene editing technologies with the potential for one-time, long-lasting treatment. The common advantage of these approaches lies in their capacity not only to provide durable and precise modulation of hepatic pathways, but also to overcome the metabolic and inflammatory components of residual ASCVD risk.

Nevertheless, several critical issues remain to be addressed in liver-targeted ASCVD therapeutics. First, whether these improvements in metabolic and inflammatory profiles can be translated into durable reductions in cardiovascular events remains to be confirmed in outcome-driven clinical trials. In addition, the long-term safety of nucleic acid therapeutics and in vivo gene editing requires rigorous evaluation. Furthermore, future work must establish and validate omics-based criteria for identifying patients who are most likely to benefit from lipid-focused or inflammation-focused hepatic interventions. Finally, the optimal combination of lipid-lowering and anti-inflammatory liver-targeted therapies remains uncertain, including how these agents should be sequenced or combined to maximize benefit while minimizing risk. Clearly stating these issues will help guide future mechanistic studies and outcome-driven clinical trials.

Collectively, these developments signify the formation of a new therapeutic paradigm. Future strategies for ASCVD management may no longer separate lipid-lowering from anti-inflammatory interventions but rather consider them as integrated processes within a unified pathophysiological framework. Liver-targeted strategies may allow for comprehensive regulation of both pathways and represent a promising direction toward deeper and more sustained cardiovascular risk reduction, ultimately offering new hope in addressing the global burden of ASCVD.

Abbreviations

AAV

Adeno-associated virus

ACL

ATP-citrate lyase

ABE

Adenine base editor

ACSVL1

Very long-chain acyl-CoA synthetase-1

ANGPTL3

Angiopoietin-like protein 3

ApoA / ApoB / ApoE / ApoC3

Apolipoprotein A / B / E / C-III

APRs

Acute-phase reactants

ASGPR

Asialoglycoprotein receptor

ASO

Antisense oligonucleotide

ASCVD

Atherosclerotic cardiovascular disease

CARPA

Complement activation-related pseudo allergy

CAD

Coronary artery disease

CETP

Cholesteryl ester transfer protein

CHD

Coronary heart disease

CRISPR

Clustered regularly interspaced short palindromic repeats

CRP / hs-CRP

C-reactive protein / high-sensitivity C-reactive protein

CVOTs

Cardiovascular outcome trials

DNL

De novo lipogenesis

ER

Endoplasmic reticulum

FCS

Familial chylomicronemia syndrome

GalNAc

N-acetylgalactosamine

gRNA

Guide RNA

HDL-C

High-density lipoprotein cholesterol

HeFH

Heterozygous familial hypercholesterolemia

HMGCR

3-hydroxy-3-methylglutaryl-coenzyme A reductase

hs-CRP

High-sensitivity C-reactive protein

IDL

Intermediate-density lipoprotein

IL

Interleukin

IL-1β

Interleukin-1 beta

IL-6 / IL-6R

Interleukin-6 / Interleukin-6 receptor

JAK

Janus kinase

LDL-C

Low-density lipoprotein cholesterol

LDLR

Low-density lipoprotein receptor

LRP1

LDL receptor-related protein 1

LNP

Lipid nanoparticle

LPA

Lipoprotein(a) gene

Lp(a)

Lipoprotein(a)

LPL

Lipoprotein lipase

MACE

Major adverse cardiovascular events

MASLD

Metabolic dysfunction-associated steatotic liver disease

MASH

Metabolic dysfunction–associated steatohepatitis

MTTP

Microsomal triglyceride transfer protein

NEFAs

Non-esterified fatty acids

OxPL

Oxidized phospholipid

PCSK9

Proprotein convertase subtilisin/kexin type 9

PEG

Polyethylene glycol

PPARα

Peroxisome proliferator-activated receptor alpha

RC

Remnant cholesterol

RCT

Randomized controlled trial / Reverse cholesterol transport

siRNA

Small interfering RNA

SREBP-2

Sterol regulatory element-binding protein 2

STAT3

Signal transducer and activator of transcription 3

TC

Total cholesterol

TG

Triglyceride

THR-β

Thyroid hormone receptor beta

TRLs

Triglyceride-rich lipoproteins

VLDL

Very-low-density lipoprotein

Author contributions

Q.X. and H.D. designed the project. Q.X. wrote the original manuscript and drew the figures. M.W. and S.W. reviewed and edited the manuscript. L.W. and H.D. provided the literature search support. All authors approved the final version of the manuscript.

Funding

This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant number: 2023ZD0503404), the National Natural Science Foundation of China (grant number: 82170348), and the Fundamental Research Funds for the Central Universities, HUST (grant number: 2025JYCXJJ007).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.