ANGPTL3: From Mechanisms to Clinics, Exploring a Novel Therapeutic Target for Cardiometabolic Diseases

ANGPTL3 (Angiopoietin-like protein 3) is a hepatocyte-derived secreted protein that plays a central role in the regulation of lipoprotein metabolism. Substantial evidence from human genetics, molecular mechanism studies, and clinical interventions indicates that ANGPTL3 regulates the distribution and clearance of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL), and by acting in concert with ANGPTL8. Compared to the ANGPTL4/LPL pathway, ANGPTL3 exhibits a unique metabolic fingerprint and displays non-canonical roles in inflammation, cancer, hepatic metabolism, and multi-organ diseases.

In recent years, various therapeutic strategies targeting ANGPTL3, including monoclonal antibodies, nucleic acid silencing, and gene editing, have entered clinical or preclinical stages, demonstrating significant lipid-lowering potential while also revealing safety challenges such as increased hepatic lipids and immune compensation. This article elucidates the biological characteristics, signaling pathways, disease associations, and drug development progress of ANGPTL3, aiming to provide assistance for your research.

1. Discovery and Research Significance of ANGPTL3

2. Biological Characteristics and Signaling Pathways of ANGPTL3

3. ANGPTL3 and Associated Diseases

4. Research Progress on ANGPTL3-Targeting Drugs

5. ANGPTL3 Research Tools

1. Discovery and Research Significance of ANGPTL3

ANGPTL3 (Angiopoietin-like protein 3) is a hepatocyte-derived secreted protein first identified through human genetic studies. Its loss-of-function mutations are closely associated with a characteristic phenotype of "familial combined hypolipidemia." Individuals carrying homozygous inactivating mutations exhibit synchronously and significantly reduced levels of TG, HDL-C, and LDL-C. This phenomenon prompted researchers to validate its causality in animal and cellular models using RNA interference and CRISPR/Cas9 technology, confirming the pivotal role of ANGPTL3 in systemic lipoprotein metabolism ^[1].

At the molecular level, ANGPTL3 explains the decrease in TG and HDL-C through the inhibition of LPL and EL activity. The reduction in LDL-C involves more complex mechanisms, including decreased ApoB lipoprotein secretion and enhanced clearance, suggesting that ANGPTL3's actions are not confined to a single enzyme inhibition pathway ^[1].

Studies based on metabolomics and Mendelian randomization have further revealed differences between ANGPTL3 and other lipid metabolism targets. Inhibition of ANGPTL4 or enhancement of LPL produces highly consistent metabolic effects, correlating with improved insulin sensitivity and reduced risk of coronary heart disease. In contrast, inhibition of ANGPTL3 presents unique alterations in lipoprotein subtypes and signals related to renal function, and its metabolic signature has a more complex relationship with cardiovascular outcomes ^[2][3].

Although drug-target Mendelian randomization analyses of common variants have not consistently predicted a reduction in CAD risk, both protein-truncating variants and pharmacological inhibition show significant reductions in atherosclerotic cardiovascular disease risk ^[4][5]. Research on specific loci (e.g., rs1748195) suggests ANGPTL3 may be involved in disease pathogenesis by affecting HDL functionality, but this evidence requires larger-scale validation ^[6].

In summary, ANGPTL3 combines clear genetic causality and druggable characteristics. However, the heterogeneity of its metabolic effects indicates that its optimal application scenarios must be clarified through comprehensive mechanism studies and stratified clinical trials.

2. Biological Characteristics and Signaling Pathways of ANGPTL3

2.1 Molecular Structure and Functional Features

The C-terminal fibrinogen-like domain (ANGPTL3-FLD) of ANGPTL3 is its key functional module. In vitro studies show that ANGPTL3-FLD significantly amplifies the lipolytic response under β-adrenergic stimulation, accompanied by increased HSL activity. This effect depends on the MAPK-ERK pathway rather than simply superimposing on adrenergic signaling ^[7]. This domain can also activate signals such as AKT in different cell types, suggesting ANGPTL3 possesses trans-tissue signaling regulatory capacity.

In the circulatory system, ANGPTL3 regulates TG metabolism by inhibiting LPL, a physiological significance validated in various models. Inhibiting ANGPTL3 expression enhances LPL activity and improves hyperlipidemia, but may also induce upregulation of hepatic lipogenesis and lipid accumulation, a phenomenon observed in both cellular experiments and ASO clinical trials ^[8][9].

ANGPTL3 does not function in isolation; its complex with ANGPTL8 significantly enhances LPL inhibitory activity in the postprandial state, thereby redistributing fatty acid uptake between muscle and adipose tissue ^[10]. This mechanism explains ANGPTL3's seemingly opposite effects on local lipolysis and systemic lipid distribution.

2.2 Regulatory Mechanisms and Signaling Networks

ANGPTL3 influences remnant cholesterol and VLDL metabolism via the LPL pathway, closely relating to coronary heart disease risk. Genetic evidence indicates that enhancing LPL-mediated lipolysis can simultaneously reduce the risk of coronary heart disease and type 2 diabetes, while the cardiovascular benefit from ANGPTL3 inhibition is partly independent of LDL-C reduction ^[11]. In clinical trials, inhibiting ANGPTL3 synthesis significantly reduces remnant cholesterol and VLDL-C, establishing a causal chain from molecular inhibition to clinical phenotype improvement ^[12].

At the regulatory level, the ANGPTL3-ANGPTL4-ANGPTL8 model elucidates the regulation of TG flow between tissues during fed and fasting states ^[13]. Furthermore, transcription factors like ChREBP and miRNAs (e.g., miR-181d) are involved in its expression regulation, tightly coupling glucose metabolism, obesity status, and lipid homeostasis ^[14][15].

Notably, ANGPTL3 also possesses intracellular functions; it can inhibit NF-κB signaling by interacting with IL1R1/IL1RAP, suggesting its potential role in inflammation regulation ^[17].

3. ANGPTL3 and Associated Diseases

3.1 Metabolic Diseases and Cardiovascular Diseases

In the field of metabolic diseases, elevated ANGPTL3 is closely associated with dyslipidemia related to nephrotic syndrome. Serum ANGPTL3 levels are increased in PNS patients and positively correlated with TG and LDL-C; animal models show that ANGPTL3 overexpression exacerbates hypertriglyceridemia and proteinuria, while knockout has a protective effect ^[20][21]. In diabetes and obesity, ANGPTL3 often co-elevates with ANGPTL8, together determining an adverse lipid profile. Its diagnostic value as a single biomarker is limited but holds potential in multi-indicator panels ^[23][24].

In cardiovascular diseases, ANGPTL3 is not only a lipid-regulating factor but also directly participates in atherosclerotic plaque inflammation. Its C-terminal domain can act as a ligand for integrin αvβ3, promoting macrophage activation within plaques; combined blockade of ANGPTL3 and CD47 can achieve plaque regression and improve phagocytic function in animal models ^[21][22].

3.2 Cancer, Inflammation, and Other Diseases

In cancer, ANGPTL3 exhibits context-dependent roles. Ovarian cancer research shows that downregulation of ANGPTL3 is associated with chemotherapy resistance, while restoring its expression can inhibit the PI3K-AKT-mTOR pathway and enhance NK cell killing ^[25]. Conversely, the hypolipidemic environment caused by ANGPTL3 deficiency can promote Treg expansion and induce an immunosuppressive phenotype ^[18], suggesting systemic inhibition may have adverse effects in the context of cancer or infection.

In organ repair models, ANGPTL3 inhibition can synergize with autophagy-modulating drugs to ameliorate nephropathy, while local delivery of ANGPTL3 can promote angiogenesis after spinal cord injury via PI3K/AKT ^[16]. These studies collectively emphasize that ANGPTL3 has distinct, even opposite, biological effects in different tissues.

4. Research Progress on ANGPTL3-Targeting Drugs

As a key target for regulating lipid metabolism, the development of ANGPTL3-targeting drugs has progressed rapidly in recent years, encompassing various technological approaches such as monoclonal antibodies, siRNA, gene editing, and small molecule drugs. Multiple drugs have entered different clinical stages. Among them, evinacumab, as the first approved monoclonal antibody for treating diseases like homozygous familial hypercholesterolemia, marks a substantive breakthrough in the therapeutic application of this target. Concurrently, nucleic acid-based drugs represented by siRNA have advanced to Phase III clinical trials for indications including familial hyperlipidemia and hypertriglyceridemia, demonstrating sustained therapeutic potential. Furthermore, emerging directions such as gene editing therapies and bispecific antibodies are gradually entering early clinical stages, propelling the field toward precision and long-lasting efficacy. The table below outlines the global R&D status of major ANGPTL3-targeting drugs for reference in related research and clinical practice.

Drug	Drug Type	Indication	Research institutions	Highest Phase
Ivecur monoclonal antibody	Monoclonal antibodies	Homozygous Familial Hypercholesterolemia \| Diabetic nephropathy	Ultragenyx Pharmaceutical, Inc. \| Ultragenyx Germany GmbH \| Ultragenyx Japan KK \| Regeneron Pharmaceuticals, Inc.	Approved for listing
Zodasiran	siRNA	Homozygous Familial Hypercholesterolemia \| Complicated dyslipidemia \| Familial hypercholesterolemia \| Hypertriglyceridemia \| Primary hypercholesterolemia	Viazhen Biotechnology (Shanghai) Co., Ltd. \| Viazhen Biotechnology (Hong Kong) Limited \| Arrowhead Pharmaceuticals, Inc. \| Viazhen Biotechnology (Suzhou) Co., Ltd	Phase 3 clinical trial
SHR-1918	Monoclonal antibodies	Familial Mixed Hyperlipidemia \| Homozygous familial hypercholesterolemia	Beijing Shengdi Pharmaceutical Co., Ltd. \| Suzhou Shengdia Biopharmaceutical Co., Ltd	Phase 3 clinical trial
BW-00112	siRNA	Hypertriglyceridemia \| Lipid disorders \| Metabolic Diseases \| Nutritional disorders	Shanghai Bowang Pharmaceutical Co., Ltd. \| Hangzhou Shipin Pharmaceutical Technology Co., Ltd	Clinical phase 2
Solbinsiran Sodium	siRNA	Hypertriglyceridemia \| Hyperlipoproteinemia	Eli Lilly & Co.	Clinical phase 2
ALN-ANG3	siRNA	Diabetic nephropathy	Alnylam Pharmaceuticals, Inc. \| Regeneron Pharmaceuticals, Inc.	Clinical phase 2
JS401	siRNA	Metabolic Diseases \| Hyperlipidemia \| Hypercholesterolemia \| Hypertriglyceridemia	Shanghai Junshi Biomedical Technology Co., Ltd. \| Runjia (Shanghai) Pharmaceutical Technology Co., Ltd	Clinical phase 1/2
SYH2070	siRNA	Hyperlipidemia \| Familial Mixed Hyperlipidemia \| Hypertriglyceridemia \| Diseases of the endocrine system	CSPC Pharmaceutical Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. \| CSPC Pharmaceutical Group Co., Ltd. \| CSPC Pharmaceutical Group Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd	Clinical phase 1
VERVE-201	Gene editing	Hypercholesterolemia \| Hypertriglyceridemia \| Homozygous familial hypercholesterolemia	Verve Therapeutics, Inc.	Clinical phase 1
AZD-1705	Small molecule chemicals	Lipid disorders \| Cardiovascular disease	AstraZeneca PLC	Clinical phase 1
FY101	siRNA	Hyperlipidemia	Beijing Fuyuan Pharmaceutical Co., Ltd	Clinical phase 1
NNC0491-6075	Monoclonal antibodies	Hypertriglyceridemia	Novo Nordisk A/S	Clinical phase 1
CTX-310	CRISPR/Cas9	Cardiovascular disease	CRISPR Therapeutics AG	The clinical stage is unknown
BAT6024/BAT6034	Bispecific antibodies	Hypertriglyceridemia	Biotech Biopharmaceutical Co., Ltd	Clinical application

(Data as of December 26, 2025, sourced from synapse)

5. ANGPTL3 Research Tools

CUSABIO provides ANGPTL3 recombinant protein, antibodies, and ELISA kits to facilitate your related mechanism research and targeted drug development.

● ANGPTL3 Recombinant Protein

Recombinant Mouse Angiopoietin-related protein 3 (Angptl3); CSB-EP874172MO

● ANGPTL3 Antibody

ANGPTL3 Antibody; CSB-PA05759A0Rb

● ANGPTL3 ELISA Kit

Human angiopoietin-like protein 3, ANGPTL3 ELISA Kit; CSB-E11724h

References

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[20] Fu Zhong, Shurao Liu, Yue Li, Guanyu Li, Ming Liu, Jingzhi Wang, Weijing Cui, Yanhong Suo, Xia Gao.(2022). ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome.

[21] Yuejie Zhang, Cen Yan, Yuan Dong, Jiwei Zhao, Xuanyi Yang, Yalan Deng, Li Su, Jiming Yin, Yang Zhang, Fenghui Sun, Yingmei Feng.(2025). ANGPTL3 accelerates atherosclerotic progression via direct regulation of M1 macrophage activation in plaque.

[22] Xiaozhi Hu, Yanyang Nan, Yuting Zhang, Jiajun Fan, Hanqi Wang, Yu Bai, Yuanzhen Zhang, Xuyao Zhang, Zeguo Zhu, Zhonglian Cao, Xiaomiao Ye, Tao Wu, Shuwen Xu, Zhengyu Wu, Wei Hu, Dianwen Ju.(2024). Simultaneously blocking ANGPTL3 and CD47 prevents the progression of atherosclerosis through regulating lipid metabolism, macrophagic efferocytosis and lipid peroxidation.

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[25] Dandan Wu, Jia Liu, Xin Yang, Zhifen Wu, Tingzhao Wang, Meiqin Xiao.(2024). ANGPTL3 diminishes the resistance of ovarian cancer to paclitaxel by blocking the PI3K-AKT-mTOR signaling pathway.