{"gene":"ASGR1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2022,"finding":"ASGR1 deficiency decreases lipid levels by stabilizing LXRα: loss of ASGR1 blocks endocytosis and lysosomal degradation of glycoproteins, reduces lysosomal amino-acid levels, inhibits mTORC1 and activates AMPK. AMPK then (1) increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1, and (2) suppresses SREBP1. LXRα upregulates ABCA1 and ABCG5/G8, promoting cholesterol transport to HDL and excretion to bile/faeces. Anti-ASGR1 neutralizing antibody recapitulates this effect and shows synergy with atorvastatin or ezetimibe.","method":"Asgr1-knockout mouse model, anti-ASGR1 neutralizing antibody treatment, Western blot, pathway rescue experiments (AMPK inhibition, BRCA1/BARD1 modulation), in vitro and in vivo cholesterol/lipid measurements","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and in vitro methods with genetic KO, antibody treatment, and pathway rescue across a rigorous single study in a high-impact journal","pmids":["35922515"],"is_preprint":false},{"year":2021,"finding":"ASGR1 deficiency reduces VLDL/LDL secretion and increases uptake via decreased expression of MTTP and PCSK9 (SREBP targets), linked to increased INSIG1 that traps SREBPs in the ER and prevents their nuclear translocation. INSIG1 knockdown independently reversed ASGR1-deficient lipid phenotypes, establishing an ASGR1/INSIG1/SREBP axis in lipid homeostasis.","method":"Asgr1-knockout mice, INSIG1 overexpression and knockdown in multiple cell/animal models, SREBP nuclear fractionation, apolipoprotein B secretion assay, LDL uptake assay","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, multiple rescue/knockdown interventions, two orthogonal cellular readouts (secretion + uptake), pathway validated in vivo and in vitro","pmids":["34622799"],"is_preprint":false},{"year":2024,"finding":"ASGR1 binds the ER-stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73, which then interacts with BIP to activate ER stress, leading to liver injury. Neutralization of GP73 attenuates ASGR1 deficiency-induced liver injury.","method":"Co-IP (ASGR1–GP73 interaction), ASGR1 KO and overexpression mouse models (acetaminophen-induced acute and CCl4-induced chronic injury), GP73 neutralizing antibody, Western blot for ER stress markers","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for binding, KO + overexpression genetic models with defined phenotype, antibody rescue experiment, multiple orthogonal methods in single study","pmids":["38459023"],"is_preprint":false},{"year":2021,"finding":"ASGR1 and KREMEN1 are sufficient for ACE2-independent SARS-CoV-2 entry in vitro and in vivo; they were identified by screening 5054 human membrane proteins for interaction with the SARS-CoV-2 spike (S) protein. SARS-CoV-2 uses distinct ACE2/ASGR1/KREMEN1 (ASK) receptor combinations to enter different cell types.","method":"Genomic receptor profiling screen (5054 membrane proteins), S-protein binding assays, pseudovirus and live-virus entry assays in vitro and in vivo, neutralizing antibody blockade in human lung organoids","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — large-scale receptor screen plus functional entry assays in multiple cell types and in vivo, with antibody blockade validation","pmids":["34837059"],"is_preprint":false},{"year":2024,"finding":"ASGR1 deficiency reduces VLDL production by inhibiting MTTP and ANGPTL3/ANGPTL8, increases LPL activity, increases LDL uptake via elevated LDLR, and promotes cholesterol efflux through upregulation of LXRα, ABCA1, ABCG5, and CYP7A1. Conversely, ASGR1 overexpression augments VLDL production and reduces fecal cholesterol. Confirmed in both KO and overexpression mouse models on ApoE background.","method":"Asgr1/ApoE double-KO mice, ASGR1-overexpressing ApoE mice, Western diet feeding, VLDL production assay, LPL activity assay, fecal cholesterol measurement, hepatic gene expression analysis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (KO and overexpression), multiple molecular and functional readouts, in vivo atherosclerosis model","pmids":["39387120"],"is_preprint":false},{"year":2021,"finding":"ASGR1 deficiency in pigs reduces hepatic de novo cholesterol synthesis by downregulating HMGCR and increases cholesterol clearance by upregulating LDLR, together lowering non-HDL-C. CRISPR/Cas9-generated ASGR1-deficient pigs on atherogenic diet show lower non-HDL-C and less atherosclerotic lesions.","method":"CRISPR/Cas9-generated ASGR1-deficient pigs, atherogenic diet feeding, hepatic transcriptome analysis, in vivo cholesterol metabolism tracing","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in a large-animal model with transcriptome and functional metabolic readouts, independent replication of lipid-lowering phenotype","pmids":["34762653"],"is_preprint":false},{"year":2011,"finding":"ASGR1 on porcine liver sinusoidal endothelial cells mediates binding and phagocytosis of human platelets. siRNA knockdown of ASGR1 reduced its protein by ~20%, correlating with a 21% decrease in human platelet binding. Anti-ASGR1 antibodies and the ASGR1 substrate asialofetuin inhibited platelet binding in a dose-dependent manner.","method":"siRNA knockdown, anti-ASGR1 inhibition assay, substrate competition with asialofetuin, flow cytometry, quantitative PCR, immunoblot, confocal microscopy","journal":"Xenotransplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus antibody/substrate competition in primary cells, single lab, two orthogonal inhibition approaches","pmids":["21848542"],"is_preprint":false},{"year":2023,"finding":"ASGR1 promotes monocyte-to-macrophage differentiation by upregulating CD68, F4/80, and CD86. Mechanistically, ASGR1 increases ATF5 expression by promoting phosphorylation of NF-κB and IKBα. ASGR1 physically interacts with ATF5 (demonstrated by co-IP). ASGR1 knockdown in mice suppressed inflammatory monocytes and macrophages in liver and improved survival in LPS-induced sepsis.","method":"ASGR1 knockdown/overexpression in THP-1 cells and BMDMs, flow cytometry, RNA-seq, co-IP (ASGR1–ATF5), Western blot (NF-κB and IKBα phosphorylation), ASGR1-knockdown mouse LPS sepsis model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for physical interaction, KD/KO with defined cellular phenotype and in vivo validation, single lab with multiple orthogonal methods","pmids":["36621538"],"is_preprint":false},{"year":2024,"finding":"Paraoxonase-2 (PON2) interacts with ASGR1 and promotes its degradation in a dose-dependent manner, as identified by immunoprecipitation combined with mass spectrometry (IP-MS). PON2-mediated ASGR1 degradation reduced lipid levels in mice.","method":"IP-MS (immunoprecipitation + mass spectrometry), dose-dependent co-expression experiments, lipid level measurement in mice","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS for physical interaction with dose-dependent degradation readout and in vivo lipid outcome, single lab","pmids":["39055948"],"is_preprint":false},{"year":2025,"finding":"ASGR1 (lectin) and DC-SIGN, acting jointly with TMEM106B, allow ACE2-independent entry of SARS-CoV-2 spike mutant E484D. ASGR1 alone or TMEM106B alone was insufficient; the combination directed viral entry to an ACE2-independent, TMEM106B-dependent endosomal pathway that is not inhibited by the neutralizing antibody imdevimab.","method":"S protein-pseudotyped particle entry assays, cell lines with single and combinatorial expression of ASGR1/DC-SIGN/TMEM106B, imdevimab neutralization assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pseudovirus entry assay with combinatorial genetic expression, single lab","pmids":["39791910"],"is_preprint":false},{"year":2024,"finding":"ASGR1 deficiency improved hepatic insulin sensitivity in HFD-fed mice, evidenced by enhanced PI3K-AKT insulin signaling in liver (but not muscle or adipose tissue), reduced hepatic gluconeogenesis and glycogenolysis. ASGR1−/− HepG2 cells showed enhanced insulin signal transduction, and transcriptome analysis showed enrichment in PI3K-AKT signaling.","method":"ASGR1-KO mice fed HFD, ASGR1−/− HepG2 cells, insulin tolerance tests, insulin signaling pathway assays (phospho-AKT), transcriptome analysis, glucose/glycogen metabolism assays","journal":"Diabetes & metabolism journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo and in vitro with multiple metabolic readouts and transcriptome support, single lab","pmids":["38310881"],"is_preprint":false},{"year":2024,"finding":"ASGR1 deficiency in ALI exacerbates liver injury via the NOXs-ROS-PANoptosis-like axis: ASGR1 KO hepatocytes show elevated ROS and reduced mitochondrial membrane potential under LPS/D-Gal challenge, activating apoptosis (BAX/BCL-2, cleaved caspase-8) and necroptosis (p-RIPK1, p-RIPK3, p-MLKL). Inhibiting NOXs or scavenging ROS reversed these effects.","method":"ASGR1-KO mice (LPS/D-Gal ALI model), primary hepatocyte KO/overexpression, cell death inhibitors, ROS inhibitor NAC and NOXs inhibitor DPI, electron microscopy, proteomics, Western blot","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with pharmacological rescue in vivo and in vitro, proteomic pathway analysis, single lab with multiple orthogonal methods","pmids":["41443470"],"is_preprint":false},{"year":2026,"finding":"The natural polyketide enterocin directly binds ASGR1 and promotes its proteasomal (not lysosomal) degradation, leading to AMPKα activation and LXRα-mediated upregulation of cholesterol efflux transporters (ABCA1/G1/G5/G8) in liver cells and in HFD-fed mice.","method":"Direct binding assay (enterocin–ASGR1), proteasomal vs. lysosomal inhibitor experiments, AMPKα/LXRα/ABCA1/G1/G5/G8 protein/RNA assays, ASGR1 KO and HFD mouse models","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus mechanistic pathway with KO rescue, single lab, in vitro and in vivo","pmids":["41580117"],"is_preprint":false},{"year":2000,"finding":"The mouse ASGR1 gene comprises eight coding exons; a minimal 600 bp proximal upstream region exhibits hepatic-specific promoter activity in HepG2 cells, establishing the basis for liver-restricted expression of this receptor.","method":"Gene sequencing, exon mapping, promoter-reporter assay in HepG2 cells","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single reporter assay in cell line, single lab, limited functional follow-up","pmids":["10675034"],"is_preprint":false}],"current_model":"ASGR1 is a liver-expressed endocytic C-type lectin that internalizes and targets asialoglycoproteins (including glycoprotein hormones, lipoproteins, and viral particles) for lysosomal degradation; loss of ASGR1 blocks this pathway, depletes lysosomal amino acids, inhibits mTORC1 and activates AMPK, which in turn stabilizes LXRα (via reduced BRCA1/BARD1 ubiquitin ligase activity) to upregulate ABCA1/ABCG5/G8-mediated cholesterol excretion and suppresses SREBP1-driven lipogenesis; ASGR1 also directly binds and targets the ER-stress mediator GP73 for lysosomal degradation, and physically interacts with ATF5 to modulate NF-κB-dependent monocyte-to-macrophage differentiation; additionally, ASGR1 serves as an alternative entry receptor for SARS-CoV-2 (spike S protein binding) in an ACE2-independent manner, and on liver sinusoidal endothelial cells mediates phagocytosis of desialylated platelets."},"narrative":{"mechanistic_narrative":"ASGR1 is a liver-expressed endocytic C-type lectin that internalizes and targets glycoproteins for lysosomal degradation, and it functions as a master node coupling this clearance pathway to systemic lipid homeostasis [PMID:35922515]. Loss of ASGR1 blocks glycoprotein endocytosis, depletes lysosomal amino acids, inhibits mTORC1 and activates AMPK, which stabilizes LXRα by reducing its BRCA1/BARD1 ubiquitin ligases and suppresses SREBP1, driving ABCA1/ABCG5-G8-mediated cholesterol efflux to HDL and biliary/fecal excretion [PMID:35922515]. The lipid-lowering output is reinforced through an INSIG1/SREBP axis that traps SREBPs in the ER and lowers MTTP and PCSK9 to reduce VLDL/LDL secretion while raising LDLR-mediated uptake [PMID:34622799], and through downregulation of HMGCR de novo cholesterol synthesis, effects confirmed bidirectionally in knockout and overexpression rodent and large-animal models with attenuated atherosclerosis [PMID:39387120, PMID:34762653]. Beyond bulk glycoprotein clearance, ASGR1 directly binds the ER-stress mediator GP73 and routes it for lysosomal degradation, limiting GP73-BIP-driven ER stress and liver injury [PMID:38459023], and it physically interacts with ATF5 to promote NF-κB-dependent monocyte-to-macrophage differentiation [PMID:36621538]. ASGR1 also serves as an ACE2-independent entry receptor for SARS-CoV-2 spike, identified by membrane-protein interaction screening and acting in combination with KREMEN1 or DC-SIGN/TMEM106B [PMID:34837059, PMID:39791910]. Its hepatic abundance is regulated by interacting proteins including PON2, which promotes ASGR1 degradation to lower lipid levels [PMID:39055948].","teleology":[{"year":2000,"claim":"Establishing why ASGR1 is liver-restricted defined the cis-regulatory basis for its tissue-specific receptor function.","evidence":"Exon mapping and promoter-reporter assays in HepG2 cells","pmids":["10675034"],"confidence":"Low","gaps":["Single reporter assay in one cell line","Trans-acting hepatic factors driving the promoter not identified","No link to functional receptor activity"]},{"year":2011,"claim":"Demonstrating ASGR1-mediated platelet phagocytosis extended its role beyond hepatocytes to liver sinusoidal endothelial clearance of desialylated cells.","evidence":"siRNA knockdown, anti-ASGR1 and asialofetuin competition, flow cytometry in primary porcine cells","pmids":["21848542"],"confidence":"Medium","gaps":["Only ~20% knockdown achieved","Single lab and species (porcine)","Downstream fate of phagocytosed platelets not characterized"]},{"year":2021,"claim":"Genetic knockout in mice and pigs established ASGR1 as a regulator of VLDL/LDL handling and de novo cholesterol synthesis, connecting receptor loss to an INSIG1/SREBP axis and reduced atherosclerosis.","evidence":"Asgr1-KO mice with INSIG1 knockdown/overexpression rescue; CRISPR ASGR1-deficient pigs on atherogenic diet with transcriptomics","pmids":["34622799","34762653"],"confidence":"High","gaps":["Mechanism linking ASGR1 endocytosis to INSIG1 induction not fully resolved","Relative contributions of synthesis vs secretion vs uptake not quantified"]},{"year":2021,"claim":"Receptor profiling identified ASGR1 as an ACE2-independent SARS-CoV-2 entry receptor, revealing a non-canonical viral-tropism function.","evidence":"Screen of 5054 membrane proteins, S-protein binding, pseudovirus/live-virus entry in vitro and in vivo with antibody blockade","pmids":["34837059"],"confidence":"High","gaps":["Structural basis of spike-ASGR1 binding not defined","Physiological relevance versus ACE2 in vivo not quantified"]},{"year":2022,"claim":"A single integrated study defined the core ASGR1 lipid-lowering pathway: glycoprotein clearance blockade → lysosomal amino-acid depletion → mTORC1 inhibition/AMPK activation → LXRα stabilization and SREBP1 suppression → cholesterol efflux.","evidence":"Asgr1-KO mice, anti-ASGR1 neutralizing antibody, AMPK and BRCA1/BARD1 pathway rescue, in vivo/in vitro lipid measurements","pmids":["35922515"],"confidence":"High","gaps":["Direct glycoprotein cargo whose clearance limits lysosomal amino acids not enumerated","Whether BRCA1/BARD1 directly ubiquitinate LXRα versus indirect regulation unresolved"]},{"year":2023,"claim":"Identifying ASGR1-ATF5 binding and NF-κB activation defined a function in innate immune cell differentiation distinct from lipid metabolism.","evidence":"Co-IP (ASGR1-ATF5), KD/OE in THP-1 and BMDMs, RNA-seq, ASGR1-knockdown mouse LPS sepsis model","pmids":["36621538"],"confidence":"Medium","gaps":["Single lab","How a hepatic lectin signals to NF-κB/ATF5 mechanistically unclear","Co-IP not reciprocally validated for directness"]},{"year":2024,"claim":"ASGR1 was shown to directly clear the ER-stress mediator GP73, linking its endocytic activity to protection from ER-stress-driven liver injury.","evidence":"Reciprocal Co-IP, ASGR1 KO/OE in acetaminophen and CCl4 injury models, GP73 neutralizing antibody rescue","pmids":["38459023"],"confidence":"High","gaps":["Glycan determinant on GP73 recognized by ASGR1 not defined","Quantitative contribution of GP73 clearance to total ASGR1 cargo unknown"]},{"year":2024,"claim":"Bidirectional genetic manipulation extended the lipid phenotype to ANGPTL3/8, LPL, LDLR and CYP7A1, and identified PON2 as an interactor that degrades ASGR1, while KO improved hepatic insulin sensitivity — broadening ASGR1's metabolic regulatory scope.","evidence":"Asgr1/ApoE double-KO and overexpression mice; IP-MS identification of PON2; HFD-fed KO mice and HepG2 insulin signaling assays","pmids":["39387120","39055948","38310881"],"confidence":"Medium","gaps":["PON2-driven degradation route (proteasomal vs lysosomal) not defined","Insulin sensitivity mechanism downstream of ASGR1 loss unresolved","Liver-specific PI3K-AKT enhancement mechanism unknown"]},{"year":2024,"claim":"ASGR1 deficiency was linked to a NOXs-ROS-PANoptosis-like cell death axis, indicating a hepatoprotective role under acute inflammatory challenge.","evidence":"ASGR1-KO mice (LPS/D-Gal), primary hepatocytes, ROS/NOX inhibitors, proteomics, electron microscopy","pmids":["41443470"],"confidence":"Medium","gaps":["Single lab","Direct molecular link between ASGR1 and NOX/ROS regulation undefined","Apparent conflict with protective roles elsewhere not reconciled"]},{"year":2025,"claim":"ASGR1 was shown to cooperate with DC-SIGN and TMEM106B to route a spike mutant into an ACE2-independent endosomal entry pathway resistant to a neutralizing antibody, refining the combinatorial receptor model.","evidence":"Pseudovirus entry assays with single and combinatorial ASGR1/DC-SIGN/TMEM106B expression, imdevimab neutralization","pmids":["39791910"],"confidence":"Medium","gaps":["Single lab pseudovirus system","In vivo relevance of the ASGR1/DC-SIGN/TMEM106B combination not tested","Mechanism of endosomal routing unresolved"]},{"year":2026,"claim":"Pharmacological targeting via the polyketide enterocin showed that direct ASGR1 binding and degradation activates the AMPK-LXRα cholesterol efflux program, validating ASGR1 as a druggable lipid-lowering target.","evidence":"Direct enterocin-ASGR1 binding, proteasomal vs lysosomal inhibitor experiments, AMPK/LXRα/ABCA1-G8 assays, ASGR1-KO and HFD mouse models","pmids":["41580117"],"confidence":"Medium","gaps":["Enterocin specificity for ASGR1 versus off-targets not fully excluded","Proteasomal degradation route differs from canonical lysosomal turnover and is unexplained"]},{"year":null,"claim":"The molecular link between glycoprotein endocytosis at the plasma membrane and the intracellular signaling cascade (lysosomal amino acid sensing, AMPK, INSIG1, NF-κB/ATF5) remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the ASGR1 receptor-ligand or signaling interface","The complete repertoire of physiological glycoprotein cargoes is undefined","How a single endocytic receptor coordinates lipid, immune, and antiviral outputs mechanistically is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,4,5]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]}],"complexes":[],"partners":["GP73","ATF5","PON2","KREMEN1","DC-SIGN","TMEM106B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07306","full_name":"Asialoglycoprotein receptor 1","aliases":["C-type lectin domain family 4 member H1","Hepatic lectin H1","HL-1"],"length_aa":291,"mass_kda":33.2,"function":"Transmembrane protein predominantly expressed on hepatocytes that plays a key role in endocytosis of plasma glycoproteins that lack terminal sialic acid residues. Specifically recognizes terminal galactose and N-acetylgalactosamine residues, facilitating the clearance of desialylated glycoproteins from circulation. Plays thereby a role in a variety of physiological processes, such as removal of desialylated platelets, elimination of activated lymphocytes and maintenance of serum glycoprotein homeostasis (PubMed:25485912). Plays a role in the removal of desialylated platelets by activating a feedback loop regulating thrombopoietin (TPO) expression via the JAK2-STAT3 signaling pathway (PubMed:25485912). Contributes also to recognition and elimination of activated lymphocytes by hepatocytes that can act as cytotoxic effectors (PubMed:21656538). May also play a physiological role in the regulatory network of lipid homeostasis (By similarity). Upon ligand binding, the receptor-ligand complex is internalized and trafficked to a sorting organelle, where dissociation occurs. The receptor is then recycled back to the cell surface (Microbial infection) Plays an essential role in ACE2-independent SARS-CoV-2 entry by acting as alternate receptor","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P07306/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASGR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ASGR1","total_profiled":1310},"omim":[{"mim_id":"606920","title":"CERAMIDE SYNTHASE 2; CERS2","url":"https://www.omim.org/entry/606920"},{"mim_id":"606783","title":"C-TYPE LECTIN DOMAIN FAMILY 1, MEMBER B; CLEC1B","url":"https://www.omim.org/entry/606783"},{"mim_id":"191740","title":"UDP-GLYCOSYLTRANSFERASE 1 FAMILY, POLYPEPTIDE A1; UGT1A1","url":"https://www.omim.org/entry/191740"},{"mim_id":"108361","title":"ASIALOGLYCOPROTEIN RECEPTOR 2; ASGR2","url":"https://www.omim.org/entry/108361"},{"mim_id":"108360","title":"ASIALOGLYCOPROTEIN RECEPTOR 1; ASGR1","url":"https://www.omim.org/entry/108360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":1142.4}],"url":"https://www.proteinatlas.org/search/ASGR1"},"hgnc":{"alias_symbol":["CLEC4H1"],"prev_symbol":[]},"alphafold":{"accession":"P07306","domains":[{"cath_id":"3.10.100.10","chopping":"166-279","consensus_level":"high","plddt":98.0481,"start":166,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07306","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07306-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07306-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASGR1","jax_strain_url":"https://www.jax.org/strain/search?query=ASGR1"},"sequence":{"accession":"P07306","fasta_url":"https://rest.uniprot.org/uniprotkb/P07306.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07306/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07306"}},"corpus_meta":[{"pmid":"34837059","id":"PMC_34837059","title":"Receptome 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AMPK then (1) increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1, and (2) suppresses SREBP1. LXRα upregulates ABCA1 and ABCG5/G8, promoting cholesterol transport to HDL and excretion to bile/faeces. Anti-ASGR1 neutralizing antibody recapitulates this effect and shows synergy with atorvastatin or ezetimibe.\",\n      \"method\": \"Asgr1-knockout mouse model, anti-ASGR1 neutralizing antibody treatment, Western blot, pathway rescue experiments (AMPK inhibition, BRCA1/BARD1 modulation), in vitro and in vivo cholesterol/lipid measurements\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and in vitro methods with genetic KO, antibody treatment, and pathway rescue across a rigorous single study in a high-impact journal\",\n      \"pmids\": [\"35922515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASGR1 deficiency reduces VLDL/LDL secretion and increases uptake via decreased expression of MTTP and PCSK9 (SREBP targets), linked to increased INSIG1 that traps SREBPs in the ER and prevents their nuclear translocation. INSIG1 knockdown independently reversed ASGR1-deficient lipid phenotypes, establishing an ASGR1/INSIG1/SREBP axis in lipid homeostasis.\",\n      \"method\": \"Asgr1-knockout mice, INSIG1 overexpression and knockdown in multiple cell/animal models, SREBP nuclear fractionation, apolipoprotein B secretion assay, LDL uptake assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, multiple rescue/knockdown interventions, two orthogonal cellular readouts (secretion + uptake), pathway validated in vivo and in vitro\",\n      \"pmids\": [\"34622799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASGR1 binds the ER-stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73, which then interacts with BIP to activate ER stress, leading to liver injury. Neutralization of GP73 attenuates ASGR1 deficiency-induced liver injury.\",\n      \"method\": \"Co-IP (ASGR1–GP73 interaction), ASGR1 KO and overexpression mouse models (acetaminophen-induced acute and CCl4-induced chronic injury), GP73 neutralizing antibody, Western blot for ER stress markers\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for binding, KO + overexpression genetic models with defined phenotype, antibody rescue experiment, multiple orthogonal methods in single study\",\n      \"pmids\": [\"38459023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASGR1 and KREMEN1 are sufficient for ACE2-independent SARS-CoV-2 entry in vitro and in vivo; they were identified by screening 5054 human membrane proteins for interaction with the SARS-CoV-2 spike (S) protein. SARS-CoV-2 uses distinct ACE2/ASGR1/KREMEN1 (ASK) receptor combinations to enter different cell types.\",\n      \"method\": \"Genomic receptor profiling screen (5054 membrane proteins), S-protein binding assays, pseudovirus and live-virus entry assays in vitro and in vivo, neutralizing antibody blockade in human lung organoids\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large-scale receptor screen plus functional entry assays in multiple cell types and in vivo, with antibody blockade validation\",\n      \"pmids\": [\"34837059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASGR1 deficiency reduces VLDL production by inhibiting MTTP and ANGPTL3/ANGPTL8, increases LPL activity, increases LDL uptake via elevated LDLR, and promotes cholesterol efflux through upregulation of LXRα, ABCA1, ABCG5, and CYP7A1. Conversely, ASGR1 overexpression augments VLDL production and reduces fecal cholesterol. Confirmed in both KO and overexpression mouse models on ApoE background.\",\n      \"method\": \"Asgr1/ApoE double-KO mice, ASGR1-overexpressing ApoE mice, Western diet feeding, VLDL production assay, LPL activity assay, fecal cholesterol measurement, hepatic gene expression analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (KO and overexpression), multiple molecular and functional readouts, in vivo atherosclerosis model\",\n      \"pmids\": [\"39387120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASGR1 deficiency in pigs reduces hepatic de novo cholesterol synthesis by downregulating HMGCR and increases cholesterol clearance by upregulating LDLR, together lowering non-HDL-C. CRISPR/Cas9-generated ASGR1-deficient pigs on atherogenic diet show lower non-HDL-C and less atherosclerotic lesions.\",\n      \"method\": \"CRISPR/Cas9-generated ASGR1-deficient pigs, atherogenic diet feeding, hepatic transcriptome analysis, in vivo cholesterol metabolism tracing\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in a large-animal model with transcriptome and functional metabolic readouts, independent replication of lipid-lowering phenotype\",\n      \"pmids\": [\"34762653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ASGR1 on porcine liver sinusoidal endothelial cells mediates binding and phagocytosis of human platelets. siRNA knockdown of ASGR1 reduced its protein by ~20%, correlating with a 21% decrease in human platelet binding. Anti-ASGR1 antibodies and the ASGR1 substrate asialofetuin inhibited platelet binding in a dose-dependent manner.\",\n      \"method\": \"siRNA knockdown, anti-ASGR1 inhibition assay, substrate competition with asialofetuin, flow cytometry, quantitative PCR, immunoblot, confocal microscopy\",\n      \"journal\": \"Xenotransplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus antibody/substrate competition in primary cells, single lab, two orthogonal inhibition approaches\",\n      \"pmids\": [\"21848542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ASGR1 promotes monocyte-to-macrophage differentiation by upregulating CD68, F4/80, and CD86. Mechanistically, ASGR1 increases ATF5 expression by promoting phosphorylation of NF-κB and IKBα. ASGR1 physically interacts with ATF5 (demonstrated by co-IP). ASGR1 knockdown in mice suppressed inflammatory monocytes and macrophages in liver and improved survival in LPS-induced sepsis.\",\n      \"method\": \"ASGR1 knockdown/overexpression in THP-1 cells and BMDMs, flow cytometry, RNA-seq, co-IP (ASGR1–ATF5), Western blot (NF-κB and IKBα phosphorylation), ASGR1-knockdown mouse LPS sepsis model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for physical interaction, KD/KO with defined cellular phenotype and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36621538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Paraoxonase-2 (PON2) interacts with ASGR1 and promotes its degradation in a dose-dependent manner, as identified by immunoprecipitation combined with mass spectrometry (IP-MS). PON2-mediated ASGR1 degradation reduced lipid levels in mice.\",\n      \"method\": \"IP-MS (immunoprecipitation + mass spectrometry), dose-dependent co-expression experiments, lipid level measurement in mice\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS for physical interaction with dose-dependent degradation readout and in vivo lipid outcome, single lab\",\n      \"pmids\": [\"39055948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASGR1 (lectin) and DC-SIGN, acting jointly with TMEM106B, allow ACE2-independent entry of SARS-CoV-2 spike mutant E484D. ASGR1 alone or TMEM106B alone was insufficient; the combination directed viral entry to an ACE2-independent, TMEM106B-dependent endosomal pathway that is not inhibited by the neutralizing antibody imdevimab.\",\n      \"method\": \"S protein-pseudotyped particle entry assays, cell lines with single and combinatorial expression of ASGR1/DC-SIGN/TMEM106B, imdevimab neutralization assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pseudovirus entry assay with combinatorial genetic expression, single lab\",\n      \"pmids\": [\"39791910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASGR1 deficiency improved hepatic insulin sensitivity in HFD-fed mice, evidenced by enhanced PI3K-AKT insulin signaling in liver (but not muscle or adipose tissue), reduced hepatic gluconeogenesis and glycogenolysis. ASGR1−/− HepG2 cells showed enhanced insulin signal transduction, and transcriptome analysis showed enrichment in PI3K-AKT signaling.\",\n      \"method\": \"ASGR1-KO mice fed HFD, ASGR1−/− HepG2 cells, insulin tolerance tests, insulin signaling pathway assays (phospho-AKT), transcriptome analysis, glucose/glycogen metabolism assays\",\n      \"journal\": \"Diabetes & metabolism journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo and in vitro with multiple metabolic readouts and transcriptome support, single lab\",\n      \"pmids\": [\"38310881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASGR1 deficiency in ALI exacerbates liver injury via the NOXs-ROS-PANoptosis-like axis: ASGR1 KO hepatocytes show elevated ROS and reduced mitochondrial membrane potential under LPS/D-Gal challenge, activating apoptosis (BAX/BCL-2, cleaved caspase-8) and necroptosis (p-RIPK1, p-RIPK3, p-MLKL). Inhibiting NOXs or scavenging ROS reversed these effects.\",\n      \"method\": \"ASGR1-KO mice (LPS/D-Gal ALI model), primary hepatocyte KO/overexpression, cell death inhibitors, ROS inhibitor NAC and NOXs inhibitor DPI, electron microscopy, proteomics, Western blot\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with pharmacological rescue in vivo and in vitro, proteomic pathway analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41443470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The natural polyketide enterocin directly binds ASGR1 and promotes its proteasomal (not lysosomal) degradation, leading to AMPKα activation and LXRα-mediated upregulation of cholesterol efflux transporters (ABCA1/G1/G5/G8) in liver cells and in HFD-fed mice.\",\n      \"method\": \"Direct binding assay (enterocin–ASGR1), proteasomal vs. lysosomal inhibitor experiments, AMPKα/LXRα/ABCA1/G1/G5/G8 protein/RNA assays, ASGR1 KO and HFD mouse models\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus mechanistic pathway with KO rescue, single lab, in vitro and in vivo\",\n      \"pmids\": [\"41580117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The mouse ASGR1 gene comprises eight coding exons; a minimal 600 bp proximal upstream region exhibits hepatic-specific promoter activity in HepG2 cells, establishing the basis for liver-restricted expression of this receptor.\",\n      \"method\": \"Gene sequencing, exon mapping, promoter-reporter assay in HepG2 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single reporter assay in cell line, single lab, limited functional follow-up\",\n      \"pmids\": [\"10675034\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASGR1 is a liver-expressed endocytic C-type lectin that internalizes and targets asialoglycoproteins (including glycoprotein hormones, lipoproteins, and viral particles) for lysosomal degradation; loss of ASGR1 blocks this pathway, depletes lysosomal amino acids, inhibits mTORC1 and activates AMPK, which in turn stabilizes LXRα (via reduced BRCA1/BARD1 ubiquitin ligase activity) to upregulate ABCA1/ABCG5/G8-mediated cholesterol excretion and suppresses SREBP1-driven lipogenesis; ASGR1 also directly binds and targets the ER-stress mediator GP73 for lysosomal degradation, and physically interacts with ATF5 to modulate NF-κB-dependent monocyte-to-macrophage differentiation; additionally, ASGR1 serves as an alternative entry receptor for SARS-CoV-2 (spike S protein binding) in an ACE2-independent manner, and on liver sinusoidal endothelial cells mediates phagocytosis of desialylated platelets.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASGR1 is a liver-expressed endocytic C-type lectin that internalizes and targets glycoproteins for lysosomal degradation, and it functions as a master node coupling this clearance pathway to systemic lipid homeostasis [#0]. Loss of ASGR1 blocks glycoprotein endocytosis, depletes lysosomal amino acids, inhibits mTORC1 and activates AMPK, which stabilizes LXRα by reducing its BRCA1/BARD1 ubiquitin ligases and suppresses SREBP1, driving ABCA1/ABCG5-G8-mediated cholesterol efflux to HDL and biliary/fecal excretion [#0]. The lipid-lowering output is reinforced through an INSIG1/SREBP axis that traps SREBPs in the ER and lowers MTTP and PCSK9 to reduce VLDL/LDL secretion while raising LDLR-mediated uptake [#1], and through downregulation of HMGCR de novo cholesterol synthesis, effects confirmed bidirectionally in knockout and overexpression rodent and large-animal models with attenuated atherosclerosis [#4, #5]. Beyond bulk glycoprotein clearance, ASGR1 directly binds the ER-stress mediator GP73 and routes it for lysosomal degradation, limiting GP73-BIP-driven ER stress and liver injury [#2], and it physically interacts with ATF5 to promote NF-κB-dependent monocyte-to-macrophage differentiation [#7]. ASGR1 also serves as an ACE2-independent entry receptor for SARS-CoV-2 spike, identified by membrane-protein interaction screening and acting in combination with KREMEN1 or DC-SIGN/TMEM106B [#3, #9]. Its hepatic abundance is regulated by interacting proteins including PON2, which promotes ASGR1 degradation to lower lipid levels [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing why ASGR1 is liver-restricted defined the cis-regulatory basis for its tissue-specific receptor function.\",\n      \"evidence\": \"Exon mapping and promoter-reporter assays in HepG2 cells\",\n      \"pmids\": [\"10675034\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single reporter assay in one cell line\", \"Trans-acting hepatic factors driving the promoter not identified\", \"No link to functional receptor activity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating ASGR1-mediated platelet phagocytosis extended its role beyond hepatocytes to liver sinusoidal endothelial clearance of desialylated cells.\",\n      \"evidence\": \"siRNA knockdown, anti-ASGR1 and asialofetuin competition, flow cytometry in primary porcine cells\",\n      \"pmids\": [\"21848542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only ~20% knockdown achieved\", \"Single lab and species (porcine)\", \"Downstream fate of phagocytosed platelets not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic knockout in mice and pigs established ASGR1 as a regulator of VLDL/LDL handling and de novo cholesterol synthesis, connecting receptor loss to an INSIG1/SREBP axis and reduced atherosclerosis.\",\n      \"evidence\": \"Asgr1-KO mice with INSIG1 knockdown/overexpression rescue; CRISPR ASGR1-deficient pigs on atherogenic diet with transcriptomics\",\n      \"pmids\": [\"34622799\", \"34762653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ASGR1 endocytosis to INSIG1 induction not fully resolved\", \"Relative contributions of synthesis vs secretion vs uptake not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Receptor profiling identified ASGR1 as an ACE2-independent SARS-CoV-2 entry receptor, revealing a non-canonical viral-tropism function.\",\n      \"evidence\": \"Screen of 5054 membrane proteins, S-protein binding, pseudovirus/live-virus entry in vitro and in vivo with antibody blockade\",\n      \"pmids\": [\"34837059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of spike-ASGR1 binding not defined\", \"Physiological relevance versus ACE2 in vivo not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A single integrated study defined the core ASGR1 lipid-lowering pathway: glycoprotein clearance blockade → lysosomal amino-acid depletion → mTORC1 inhibition/AMPK activation → LXRα stabilization and SREBP1 suppression → cholesterol efflux.\",\n      \"evidence\": \"Asgr1-KO mice, anti-ASGR1 neutralizing antibody, AMPK and BRCA1/BARD1 pathway rescue, in vivo/in vitro lipid measurements\",\n      \"pmids\": [\"35922515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct glycoprotein cargo whose clearance limits lysosomal amino acids not enumerated\", \"Whether BRCA1/BARD1 directly ubiquitinate LXRα versus indirect regulation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying ASGR1-ATF5 binding and NF-κB activation defined a function in innate immune cell differentiation distinct from lipid metabolism.\",\n      \"evidence\": \"Co-IP (ASGR1-ATF5), KD/OE in THP-1 and BMDMs, RNA-seq, ASGR1-knockdown mouse LPS sepsis model\",\n      \"pmids\": [\"36621538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How a hepatic lectin signals to NF-κB/ATF5 mechanistically unclear\", \"Co-IP not reciprocally validated for directness\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ASGR1 was shown to directly clear the ER-stress mediator GP73, linking its endocytic activity to protection from ER-stress-driven liver injury.\",\n      \"evidence\": \"Reciprocal Co-IP, ASGR1 KO/OE in acetaminophen and CCl4 injury models, GP73 neutralizing antibody rescue\",\n      \"pmids\": [\"38459023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan determinant on GP73 recognized by ASGR1 not defined\", \"Quantitative contribution of GP73 clearance to total ASGR1 cargo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Bidirectional genetic manipulation extended the lipid phenotype to ANGPTL3/8, LPL, LDLR and CYP7A1, and identified PON2 as an interactor that degrades ASGR1, while KO improved hepatic insulin sensitivity — broadening ASGR1's metabolic regulatory scope.\",\n      \"evidence\": \"Asgr1/ApoE double-KO and overexpression mice; IP-MS identification of PON2; HFD-fed KO mice and HepG2 insulin signaling assays\",\n      \"pmids\": [\"39387120\", \"39055948\", \"38310881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PON2-driven degradation route (proteasomal vs lysosomal) not defined\", \"Insulin sensitivity mechanism downstream of ASGR1 loss unresolved\", \"Liver-specific PI3K-AKT enhancement mechanism unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ASGR1 deficiency was linked to a NOXs-ROS-PANoptosis-like cell death axis, indicating a hepatoprotective role under acute inflammatory challenge.\",\n      \"evidence\": \"ASGR1-KO mice (LPS/D-Gal), primary hepatocytes, ROS/NOX inhibitors, proteomics, electron microscopy\",\n      \"pmids\": [\"41443470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct molecular link between ASGR1 and NOX/ROS regulation undefined\", \"Apparent conflict with protective roles elsewhere not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ASGR1 was shown to cooperate with DC-SIGN and TMEM106B to route a spike mutant into an ACE2-independent endosomal entry pathway resistant to a neutralizing antibody, refining the combinatorial receptor model.\",\n      \"evidence\": \"Pseudovirus entry assays with single and combinatorial ASGR1/DC-SIGN/TMEM106B expression, imdevimab neutralization\",\n      \"pmids\": [\"39791910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab pseudovirus system\", \"In vivo relevance of the ASGR1/DC-SIGN/TMEM106B combination not tested\", \"Mechanism of endosomal routing unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Pharmacological targeting via the polyketide enterocin showed that direct ASGR1 binding and degradation activates the AMPK-LXRα cholesterol efflux program, validating ASGR1 as a druggable lipid-lowering target.\",\n      \"evidence\": \"Direct enterocin-ASGR1 binding, proteasomal vs lysosomal inhibitor experiments, AMPK/LXRα/ABCA1-G8 assays, ASGR1-KO and HFD mouse models\",\n      \"pmids\": [\"41580117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enterocin specificity for ASGR1 versus off-targets not fully excluded\", \"Proteasomal degradation route differs from canonical lysosomal turnover and is unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular link between glycoprotein endocytosis at the plasma membrane and the intracellular signaling cascade (lysosomal amino acid sensing, AMPK, INSIG1, NF-κB/ATF5) remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the ASGR1 receptor-ligand or signaling interface\", \"The complete repertoire of physiological glycoprotein cargoes is undefined\", \"How a single endocytic receptor coordinates lipid, immune, and antiviral outputs mechanistically is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 4, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GP73\", \"ATF5\", \"PON2\", \"KREMEN1\", \"DC-SIGN\", \"TMEM106B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}