The Asialoglycoprotein Receptor (ASGPR) was the first mammalian lectin discovered, initially identified by Ashwell and Morell and colleagues through their research on mammalian plasma glycoprotein metabolism (2, 3). The human ASGPR gene is located on chromosome 17 (9) and consists of a hetero-oligomeric complex of two homologous but structurally distinct subunits, named ASGR1 (H1 subunit, approximately 46 kDa) and ASGR2 (H2 subunit, approximately 50 kDa). Each subunit is a type II single-pass transmembrane protein, composed of a short N-terminal cytoplasmic domain (~40 amino acids), a transmembrane region (~20 amino acids), an extracellular stalk region (~80 amino acids), and a calcium-dependent Carbohydrate Recognition Domain (CRD, ~140 amino acids) (10, 11). Among the two subunits, ASGR1 (H1 subunit) is widely regarded as the primary functional subunit, mainly responsible for ligand recognition and mediating the endocytosis process (12–14). H2 itself lacks the ability to bind glycan ligands and is unstable when expressed alone, leading to rapid degradation (15). However, the H2 subunit is not redundant; rather, it plays a crucial role in high-affinity ligand binding. It is thought to act as a structural scaffold or bridge that helps organize multiple CRDs into an optimally spaced recognition platform for ligand binding (13) (Figure 1). ASGR1 and ASGR2 can form various receptor complexes, including ASGR1–ASGR2 heterooligomers, ASGR1 homooligomers, and ASGR2 homooligomers. These different oligomeric forms on the plasma membrane provide the structural basis for substrate recognition and endocytosis (16). Each form exhibits distinct ligand-binding specificities, suggesting that modulation of ASGPR oligomerization may be a potential strategy to diversify its ligand recognition capabilities and enable targeted therapeutic applications for related diseases (13, 16).

ASGR1 is primarily expressed on the surface of hepatic parenchymal cells, with each cell containing about (1−5) ×10⁵ binding sites (17–19). Its classical physiological function is to recognize terminal galactose (Gal) and N-acetylgalactosamine (GalNAc) residues in a calcium-dependent manner through its extracellular CRD (2, 3). The high-affinity binding between ASGR1 and glycoproteins depends on calcium ions (Ca²⁺), which enhance the thermal stability of ASGR1 and prevent denaturation (3, 20, 21). Structural studies have shown that calcium ions coordinate with conserved amino acid residues (such as glutamate and asparagine) within the CRD, stabilizing carbohydrate binding. These interactions enable ASGR1 to form hydrogen bonds and coordination bonds with the 3- and 4-hydroxyl groups of Gal/GalNAc, thereby conferring high specificity (22). However, the affinity between a single CRD and a monosaccharide is relatively weak. Therefore, multivalent ligands, by simultaneously engaging multiple CRDs, can significantly enhance binding strength and increase overall affinity (23, 24). An important feature of protein–glycan interactions is multivalency (23). In addition to enhancing binding affinity (25), multivalency can also greatly improve binding selectivity. So-called super-selective binding occurs when the density of the target ligand on the cell surface exceeds a certain threshold (26, 27), enabling discrimination between target cell types that display different numbers of specific glycans or lectins, and laying the foundation for the exceptional liver-targeting specificity of GalNAc-conjugated therapeutics (28).

Multivalency has also been shown to influence the mechanism of ligand internalization. Nanoparticles with low ligand density tend to enter cells via caveolae-mediated endocytosis, which directs them toward perinuclear compartments such as the Golgi apparatus and endoplasmic reticulum, thereby avoiding lysosomal degradation. In contrast, nanoparticles with high ligand density predominantly enter cells via clathrin-mediated endocytosis and are delivered to lysosomes for degradation (29, 30).

For ASGR1, its endocytic mechanism specifically belongs to receptor-mediated endocytosis (RME) and is classified as clathrin-mediated endocytosis (31, 32). Notably, neither H1 nor H2 subunit alone is sufficient for ligand binding or internalization; co-expression is essential (15). ASGR1-mediated endocytosis is extensively studied, with receptor internalization half-life of approximately 5–6 min without ligands, accelerated to 2.5–3 min in the presence of ligands, followed by receptor recycling to the cell surface within 5–7 min (33). This efficient cycle involves clathrin-coated pits-mediated endocytosis, ligand dissociation in early endosomes, receptor recycling to the plasma membrane, and ligand degradation in lysosomes, a process known as RME (31, 32, 34). ASGR1 surface levels are regulated by endocytosis and recycling efficiency (35, 36) (Figure 1).

The ligands recognized by ASGR1 possess specific glycan features. ASGR1 belongs to the C-type lectin family, which typically recognizes sugar residues such as mannose or galactose; however, ASGR1 specifically binds to terminal galactose (Gal) and N-acetylgalactosamine (GalNAc) residues (37, 38). Glycans are crucial components for endogenous glycoprotein homeostasis and circulating clearance. Modulating glycan patterns can alter glycoprotein concentration and half-life, thereby changing their clearance rate from circulation (39). A key factor in plasma glycoprotein clearance is desialylation, where sialic acid residues are removed by circulating sialidases (NEU1, NEU3, NEU4) (40). This process exposes terminal Gal or GalNAc residues, making them recognizable by ASGR1, thus initiating glycoprotein clearance (41). Interestingly, α2,3-sialylation abolishes ASGR1 affinity, whereas α2,6-sialylation does not (42). O-acetylation of sialic acids protects them from desialylation by reducing sialidase activity (43, 44).

Although the role of ASGR1 in clearing desialylated glycoproteins is confirmed, its overall impact on circulating glycoprotein metabolism remains debated (45). A mouse glycomics study revealed no significant accumulation of terminally desialylated or galactose-exposed glycoproteins in ASGR1 deficiency, suggesting compensatory regulatory mechanisms (46). Thus, the critical role of ASGR1 in glycoprotein homeostasis remains inconclusive.

Beyond these classical functions, recent studies indicate the involvement of ASGR1 in various biological processes. For example, ASGR1 may play roles in immune regulation (47). Moreover, recent studies have revealed that ASGR1 also participates in lipid metabolism regulation (48, 49).

Several studies have identified ASGR1 homologs in various non-hepatic cell types, such as DC-ASGPR and Rat Hepatic Lectin-1 (RHL-1) (50, 51). These proteins exhibit a certain degree of structural or functional similarity to hepatic ASGR1 (52, 53). It should be noted that the hepatic-type ASGPR expressed in Caco-2 cells (54), the ASGPR-like receptor in human renal proximal tubular epithelial cells (RPTEC) (55), and RTG-r in rat testis (which is antigenically related to RHL-2/3) (56) currently lack comprehensive amino acid sequence comparisons. Therefore, whether these proteins are truly homologous to hepatic ASGR1 remains to be further investigated.

C-type lectin receptors (CLRs) play a crucial role in the activation of innate immunity (38). Acting as pattern recognition receptors (PRRs) and endocytic receptors, CLRs recognize pathogen-associated glycan structures, facilitating pathogen-receptor complex internalization and activating innate immune responses (57). ASGR1, as a C-type lectin receptor, is expressed in DCs (38). Studies have shown that the expression and function of glycan-recognizing receptors differ between immature and mature DCs, DC-ASGR1 is highly expressed only in immature DCs and is rapidly downregulated upon maturation, indicating a close association between DC-ASGR1 and the maturation status of DCs. However, whether DC-ASGR1 directly regulates dendritic cell maturation requires further investigation (52).

Studies have shown that ASGR1 mediates the differentiation of monocytes into macrophages (58). In the LPS (Lipopolysaccharide)-induced septic mouse model, ASGR1 promotes the phosphorylation of NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) and IκBα (Inhibitor of kappa B alpha). After the phosphorylation of P65 enters the nucleus, it increases the expression of ATF5 (Activating Transcription Factor 5), thereby promoting the differentiation of monocytes into macrophages, elevating the levels of pro-inflammatory cytokines (such as TNF-α, IL-6, IL-1β), and exacerbating liver inflammation (58). Current studies suggest that ASGR1 may act as an upstream regulatory factor promoting the differentiation of pro-inflammatory macrophages, thereby contributing to the onset and progression of inflammatory liver injury. Moreover, in nonalcoholic steatohepatitis (NASH) and other chronic liver diseases, sustained macrophage-driven inflammation is considered a key driver of fibrosis progression (59). The ASGR1-mediated monocyte-to-macrophage differentiation mechanism may also play a pathological role in such conditions. Therefore, targeting ASGR1 or its associated signaling axis holds promise as a novel strategy for controlling hepatic inflammatory responses and blocking macrophage polarization, and warrants further investigation in broader models of inflammatory liver disease.

Apart from its role in immune cells, ASGR1 is closely related to endoplasmic reticulum (ER) stress during liver injury (60). ASGR1 binds to the circulating liver disease biomarker Golgi Protein 73 (GP73) and mediates its endocytosis for subsequent lysosomal degradation. In the absence of ASGR1, elevated levels of GP73 interact with the ER stress marker immunoglobulin heavy chain binding protein (BIP), leading to the activation of ER stress pathways and ultimately exacerbating liver injury (60). Under non-stress conditions, the endoplasmic reticulum (ER) stress marker BIP forms complexes with the three major sensors—inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6)—thereby maintaining these signaling factors in an inactive state (61, 62). Upon cellular stress, BIP dissociates from these sensors, leading to the activation of the unfolded protein response (UPR) (62, 63). This suggests that GP73 is no longer merely a traditional liver disease biomarker (64), but may also act as a pathogenic contributor and potential therapeutic target. As a key regulatory pathway of cellular stress and injury, the UPR plays a critical role in the progression of various liver diseases (65). Targeting the UPR pathway may offer a novel approach for precision therapy in chronic liver diseases.

In addition to its roles in immune cell function and stress regulation, ASGR1 also mediates the clearance and rebalancing of blood components, highlighting its unique contribution to the regulation of blood immune homeostasis. ASGR1 recognizes and clears desialylated platelets, a process that not only participates in platelet clearance but also stimulates hepatic thrombopoietin (TPO) synthesis via the janus kinase/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, maintaining platelet homeostasis (66). Clinically, thrombocytopenia is a common complication in patients with chronic liver disease (67). ASGR1 agonists or multivalent GalNAc ligands may be used to enhance TPO expression, thereby improving liver disease–associated thrombocytopenia. Meanwhile, the expression level or functional status of ASGR1 may also serve as a potential biomarker for predicting platelet production capacity. Additionally, studies in pig models indicate ASGR1 expression beyond the liver, such as peripheral vascular endothelial cells (e.g., aorta, femoral artery), recognizing human platelet surface-exposed Gal/GalNAc residues, leading to platelet phagocytosis. This mechanism may contribute to severe thrombocytopenia in xenotransplantation (human-to-pig transplantation) (68) (Figure 2).

In addition, ASGR1 is involved in the clearance of adaptive immune products, highlighting its unique role in maintaining humoral immune homeostasis. Studies have shown that ASGR1 participates in the clearance of circulating IgA; however, it remains controversial whether this process is primarily mediated through the recognition of N-glycans or O-glycans on the IgA1 subtype (69, 70). ASGR1 is also involved in the clearance of circulating low-density lipoprotein (LDL) (71, 72), chylomicron remnants (73), and cellular fibronectin (74).

Early studies indicated ASGR1 specifically binds hepatitis B virus (HBV) particles, mediating hepatic endocytosis and potentially facilitating hepatocyte infection by HBV (75). Numerous studies confirm that ASGR1 enhances HBV infectivity by binding to the viral preS1 region, facilitating viral uptake into hepatocytes. This interaction represents a key mechanism in liver-specific HBV infection, underscoring the role of ASGR1 in viral entry (76, 77). Similarly, ASGR1 facilitates hepatitis E virus (HEV) infection through interaction with viral open reading frame 2 (ORF2) protein, enhancing hepatocyte entry (78).

After the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), further research revealed that ASGR1 mediates viral entry into various tissues, including liver and lungs (79). Multiple independent groups confirmed ASGR1 as an alternative receptor to Angiotensin-Converting Enzyme 2 (ACE2), mediating SARS-CoV-2 entry through interactions with the receptor-binding domain (RBD) and N-terminal domain (NTD) of the spike glycoprotein, promoting ACE2-independent cellular entry and resistance to certain antibodies (5, 80, 81). Particularly in hepatocytes, high ASGR1 expression markedly enhances SARS-CoV-2 binding and infection, suggesting ASGR1-mediated pathways contribute significantly to viral infection and pathogenic mechanisms (82). ASGR1 also participates in virus-induced inflammation and immune modulation, potentially collaborating with other CLRs to exacerbate inflammation, enhancing viral-induced immunopathological damage (83) (Figure 3).

Studies have found that HBV, hepatitis C virus (HCV), and SARS-CoV-2 can partially rely on ASGR1-mediated glycan recognition to facilitate their attachment to and entry into hepatocytes (76, 78, 82). This mechanism may provide important insights into the molecular basis of viral hepatotropism, inform the development of glycan-targeted antiviral strategies, and guide the design of ASGR1-based liver-targeting viral vectors. Given that multiple viruses can exploit ASGR1 to mediate cellular entry, future research may explore the development of broad-spectrum ASGR1 inhibitors to block diverse viral infection pathways. Moreover, from the perspective of genetic polymorphism, identifying expression variations or splicing isoforms of ASGR1 through techniques such as single-cell RNA sequencing (84) and long-read transcriptome analysis (85) may help predict individual susceptibility to viral infections, offering new insights for precision prevention and control strategies.

Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, characterized by high invasiveness and poor prognosis, representing a significant global health burden. The primary risk factors for HCC vary by region. In most high-risk areas, chronic HBV infection is the main contributor. In regions with lower HCC incidence, the rising number of cirrhosis patients largely explains the increasing HCC rates, driven by factors such as higher HCV-related cirrhosis incidence, HBV-related cirrhosis (to a lesser extent), and improved overall survival among cirrhosis patients (86).

Tumor cells typically exhibit highly sialylated glycan structures on their surfaces, a feature that facilitates immune evasion by preventing recognition and clearance by the immune system (87). In most tumor tissues, truncated O-glycans are abnormally overexpressed (88). The Tn antigen, a type of immature O-glycan, consists of a single N-acetylgalactosamine (GalNAc) residue attached to the serine (Ser) or threonine (Thr) residue of a protein, and is classified as one of the truncated O-glycans (88, 89). The Tn antigen promotes immune tolerance by engaging with immunosuppressive receptors, thereby contributing to tumor immune evasion (90). Notably, its structural characteristics closely resemble the ligand recognition pattern of ASGR1 (2, 3). Whether ASGR1 can effectively recognize the Tn antigen and mediate relevant biological functions remains to be further investigated. It is worth noting that the antigenicity of Tn has been validated in mice; antibodies induced by Tn-modified glycopeptides have been shown to effectively inhibit the growth of transplanted tumor cells, thereby exerting protective anti-tumor effects (91).

Research indicates that ASGR1 exerts tumor-suppressive effects by inhibiting phosphorylation of the STAT3 signaling pathway. Specifically, ASGR1 interacts with Nemo-like kinase (NLK) to inhibit glycoprotein 130/janus kinase 1 (GP130/JAK1)-mediated STAT3 phosphorylation, thereby blocking the activation of STAT3-related pro-tumor signaling pathways (92). Additionally, ASGR1 interacts with longevity assurance homolog 2 (LASS2) to suppress vacuolar-type H⁺-ATPase (V-ATPase) activity, reducing HCC cell migration and invasion, further supporting the role of ASGR1 as a metastasis suppressor in liver cancer (93). Multiple studies have reported significant downregulation of ASGR1 expression in HCC tissues, with expression levels decreasing further as tumor progression and grading advance (94). ASGR1 mRNA and protein levels are markedly reduced in Edmondson grade III-IV HCC tissues (95).

In addition, based on liquid biopsy technology, recent studies have analyzed the phenotypic and genetic markers of ASGR1 expression in circulating epithelial cells (CECs) from the peripheral blood of patients with liver cirrhosis (LC) and HCC. Findings reveal that ASGR1-negative CECs significantly increase the risk of developing HCC, particularly strong predictive power in patients with pre-existing LC. Further analysis revealed that ASGR1 expression in CECs remains detectable in the early stages of HCC, such as in LC patients with lower Child-Pugh scores, suggesting its potential as a non-invasive tool for early tumor monitoring. In addition, the combined loss of ASGR1 and miR-122-5p in CECs indicates a dedifferentiation tendency of tumor cells and is closely associated with poorer progression-free survival (PFS). Collectively, this study proposes that ASGR1 holds promise as a precise biomarker for early risk stratification and prognostic assessment in HCC, with potential application in cancer interception (96).

Meanwhile, ASGR1⁺ tumor-associated microparticles (taMPs) are significantly elevated in the peripheral blood of patients with HCC and cholangiocarcinoma, suggesting their potential as a novel non-invasive diagnostic tool for distinguishing liver cancer from liver cirrhosis (94). ASGR1 expression is also closely associated with immune cell infiltration, including B cells, CD8⁺ T cells, and DCs, indicating its role in tumor microenvironment immune modulation. A low methylation level in the promoter region is positively correlated with low ASGR1 expression, suggesting that its expression is influenced by epigenetic regulation (6).

Collectively, these findings underscore the potential of ASGR1 as a biomarker for HCC diagnosis and prognosis. Beyond acting as a tumor suppressor during HCC development, ASGR1 expression on circulating cells may serve as an effective liquid biopsy marker for early screening, risk stratification, and treatment monitoring. Future large-scale cohort studies are needed to validate its clinical translational value (Figure 4).

The clearance of low-density lipoprotein cholesterol (LDL-C) from plasma is primarily mediated by low-density lipoprotein receptors (LDLR) on hepatocyte surfaces (97). Proprotein convertase subtilisin/kexin type 9 (PCSK9), highly expressed in the liver, binds LDLR non-enzymatically after being secreted into the plasma, promoting LDLR degradation within cells, thereby reducing LDLR levels on hepatocyte surfaces and ultimately increasing plasma LDL-C levels (98–100). Interestingly, like PCSK9, ASGR1 can also directly target LDLR. Both proteins independently interact with LDLR and promote its degradation, thus regulating the number of LDLRs on hepatocyte surfaces and influencing plasma LDL-C levels (101). Studies have shown that in ASGR1-deficient conditions, PCSK9 expression at both mRNA and protein levels is significantly reduced (102). Further research indicates that the increased LDL uptake in ASGR1-deficient hepatocytes is associated with decreased PCSK9 levels, suggesting that the enhanced LDL uptake may result from stabilized LDLR due to reduced PCSK9 (102, 103). However, it is currently only known that ASGR1 may indirectly affect LDLR stability, while its precise regulatory mechanisms on PCSK9 expression, secretion, or function have not been fully elucidated and require further scientific investigation.

Studies have shown that ASGR1 deficiency increases the expression of insulin-induced gene 1 (INSIG1), thereby inhibiting sterol regulatory element-binding proteins (SREBPs) and reducing cholesterol synthesis (102). Similarly, a study by the team of Song Baoliang at Wuhan University reported comparable findings. Specifically, they demonstrated that ASGR1 deficiency suppresses mechanistic Target of Rapamycin Complex 1 (mTORC1) activity and activates 5’-AMP-activated protein kinase (AMPK), leading to reduced expression of the liver X receptor alpha (LXRα) ubiquitin ligase complex breast cancer type 1 susceptibility protein/BRCA1 associated ring domain protein 1 (BRCA1/BARD1). This reduction decreases the ubiquitination and degradation of LXRα, resulting in elevated LXRα levels. The upregulation of LXRα subsequently increases the expression of cholesterol transport-related genes such as ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette sub-family G members 5 and 8 (ABCG5/G8), promoting cholesterol efflux and reducing plasma and hepatic lipid levels. In addition, ASGR1 deficiency suppresses SREBP1-mediated fatty acid synthesis, thereby reducing triglyceride (TG) production and hepatic lipid accumulation, contributing to the maintenance of liver metabolic homeostasis. Furthermore, ASGR1 is also involved in lipoprotein metabolism. It may play a role in high-density lipoprotein (HDL)-mediated cholesterol efflux, and its deficiency appears to enhance HDL-mediated cholesterol uptake and promote bile acid synthesis (48) (Figure 5).

Beyond regulating lipid metabolism, ASGR1 is also closely associated with lipid redistribution and transport. ASGR1 deficiency affects lipid distribution in adipose tissue. In obesity, ASGR1-deficient mice show increased visceral adipose tissue (VAT) lipid accumulation but decreased plasma lipid levels, potentially due to ASGR1-mediated lipid redistribution (104).

The role of ASGR1 in lipid regulation may have profound implications for atherosclerosis (AS) and cardiovascular disease (CVD) (7, 105). Independent studies conducted by multiple research groups have consistently demonstrated that ASGR1 knockout effectively reduces LDL levels and improves lipid profiles, indicating high reproducibility and mutual support of these findings (48, 49, 106). Moreover, studies in both pig and mouse models have consistently shown that ASGR1 deficiency improves lipid metabolism and attenuates atherosclerotic phenotypes, further confirming the cross-species consistency of these results (106, 107). Given its multiple roles in lipid regulation, ASGR1 may represent a novel therapeutic target for cardiovascular disease. Since ASGR1 deficiency can reduce non-HDL-C and lower CVD risk, small molecules or antibodies that inhibit ASGR1 may serve as promising new lipid-lowering agents (48).

However, some studies have shown that ASGR1 deficiency in ApoE⁻/⁻ mice leads to reductions in plasma cholesterol and triglyceride levels and alleviates atherosclerotic lesions. Nevertheless, this is also accompanied by an increase in immune cell populations and widespread alterations in hepatic metabolic pathways, despite the absence of overt liver morphological abnormalities (106). Similarly, ASGR1-deficient pigs fed a high-fat diet exhibit reduced non-HDL-C levels and attenuated atherosclerosis, with underlying mechanisms involving downregulation of cholesterol synthesis and enhanced clearance. However, mild to moderate liver injury was also observed (107).

Therefore, during the development of ASGR1-targeted therapeutics, close attention must be paid to the potential systemic metabolic remodeling and associated toxic effects, with comprehensive assessments of safety and tolerability (108). Although no apparent organ-specific lesions have been observed in current ASGR1-deficient animal models (106), the predominant hepatic expression of ASGR1 suggests that its loss of function may impair glycoprotein clearance and the stability of bile components (108, 109), potentially increasing the burden on the hepatobiliary system. Hence, as ASGR1 inhibitors—whether antibody-based or nucleic acid-based—progress toward clinical translation, their multisystem effects should be thoroughly evaluated to ensure effective lipid-lowering and anti-atherosclerotic activity while maintaining a favorable safety margin and therapeutic window.