{"gene":"C1QC","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2024,"finding":"C1QC binds to discoidin domain receptor 2 (DDR2) and activates downstream MMP9, a calcium-dependent matrix metalloproteinase capable of degrading extracellular matrix components, leading to structural and functional disruption of the blood-brain barrier under diabetic conditions. siRNA-mediated suppression of C1QC in diabetic models mitigated BBB damage.","method":"siRNA knockdown in vitro and in vivo diabetic models; co-treatment experiments; Western blot for MMP9 activation; binding assay (C1QC-DDR2 interaction)","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined cellular phenotype and proposed binding partner identified; single lab with two orthogonal methods (in vitro and in vivo), but no structural validation or direct reconstitution of C1QC-DDR2 binding","pmids":["39531193"],"is_preprint":false},{"year":2019,"finding":"Compound heterozygous mutations in C1QC (c.100G>A p.(Gly34Arg) and c.205C>T p.(Arg69X), confirmed on different chromosomes by RNA sequencing) result in complete absence of C1q protein in serum, establishing that C1QC is required for circulating C1q complex and functional classical complement pathway activation.","method":"ELISA and Western blot for C1q in serum; DNA sequencing; RNA sequencing to confirm trans configuration of mutations","journal":"Lupus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein absence confirmed by two orthogonal methods (ELISA + WB), genetic confirmation by sequencing; single case report but rigorous molecular characterization","pmids":["31357913"],"is_preprint":false},{"year":2025,"finding":"C1QC knockdown in macrophages significantly reduces CD163 expression (an M2 macrophage marker), and co-culture experiments show that M2 macrophages (with high C1QC expression) promote tumor cell proliferation and reduce drug sensitivity, establishing a functional role for C1QC in maintaining M2 macrophage identity and tumor-promoting macrophage-lymphoma cell interactions.","method":"siRNA-mediated C1QC knockdown; Western blot and qPCR for CD163; macrophage-lymphoma cell co-culture assay; proliferation and drug sensitivity assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and co-culture functional readout; single lab, two orthogonal methods (WB + qPCR + functional co-culture)","pmids":["39388888"],"is_preprint":false},{"year":2025,"finding":"C1QC plays a mechanistic role in diabetic kidney disease (DKD): siRNA-mediated C1QC silencing attenuated lipid accumulation and inflammation in high-glucose/palmitate-challenged HK-2 cells, while C1QC overexpression exacerbated these pathological changes. Empagliflozin reduced renal C1QC expression in db/db mice, and C1QC overexpression partially reversed empagliflozin's protective effects, placing C1QC downstream of metabolic stress and upstream of renal inflammation and lipid deposition.","method":"siRNA knockdown and plasmid-mediated overexpression in HK-2 cells; in vivo db/db mouse model; rescue experiments with empagliflozin co-treatment; lipid accumulation assays; inflammatory marker quantification","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined cellular and in vivo phenotypes; rescue experiment provides epistatic placement; single lab with multiple orthogonal approaches","pmids":["41252098"],"is_preprint":false},{"year":2024,"finding":"In ischemic stroke models, circDnajc1 acts upstream of miR-27a-5p, which in turn represses C1qc expression; knockdown of circDnajc1 downregulates C1qc (along with C3 and C5ar), reduces microglial activation, decreases inflammatory factor release, and reduces neuronal apoptosis. Luciferase reporter and RNA immunoprecipitation experiments placed C1qc as a miR-27a-5p target in the circDnajc1/miR-27a-5p/C1qc signaling axis.","method":"circDnajc1 siRNA knockdown and overexpression; OGD/R cell model and MCAO/R rat model; RT-qPCR, immunofluorescence, RNA immunoprecipitation, luciferase reporter gene assays; flow cytometry","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation and luciferase reporter establish C1qc as direct miR-27a-5p target; in vitro and in vivo corroboration; single lab","pmids":["40483386"],"is_preprint":false},{"year":2025,"finding":"FAP+ fibroblasts secrete WNT2 to activate β-catenin signaling in macrophages, which upregulates C1QC expression and M2 markers. This FAP-WNT2-C1QC axis confers tumor-promoting functions; C1QC+ macrophages exhibit enhanced fatty acid metabolism, immunosuppressive signaling, and secrete CCL2 to recruit Tregs and induce T cell exhaustion. In vivo FAP inhibition reduced C1QC+ macrophage infiltration.","method":"Co-culture systems; single-cell RNA sequencing; spatial transcriptomics; in vivo OSCC animal model with FAP inhibition; multi-omics analysis; immunofluorescence","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (WNT2→β-catenin→C1QC) supported by co-culture and in vivo rescue with FAP inhibition; single lab with multiple orthogonal methods","pmids":["41831519"],"is_preprint":false},{"year":2024,"finding":"Recombinant grass carp C1qC protein (rC1qC) exerts a substantial inhibitory effect on grass carp reovirus (GCRV) replication in CIK cells after 24 hours of infection, demonstrating a direct antiviral activity for C1qC protein in a teleost ortholog model.","method":"Recombinant protein incubation with CIK cells followed by GCRV inoculation; viral replication quantification","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay with recombinant protein in a non-mammalian ortholog (grass carp); no mechanistic follow-up or mutagenesis","pmids":["38447782"],"is_preprint":false}],"current_model":"C1QC encodes the C-chain subunit of the C1q complement complex, and loss-of-function mutations cause complete C1q deficiency and lupus-like disease; at the molecular level, C1QC protein can bind DDR2 to activate MMP9-mediated extracellular matrix degradation, acts downstream of WNT2/β-catenin signaling to promote M2 macrophage identity and immunosuppression, is a direct transcriptional target of the miR-27a-5p axis (regulated by circDnajc1) in microglial inflammatory signaling, and contributes to lipid accumulation and inflammation in tubular epithelial cells under metabolic stress conditions."},"narrative":{"mechanistic_narrative":"C1QC encodes the C-chain subunit of the C1q complement complex, and its expression is required for circulating C1q and a functional classical complement pathway; compound heterozygous loss-of-function mutations abolish serum C1q protein [PMID:31357913]. Beyond its canonical complement role, C1QC functions as a tissue-context effector in inflammation, immunosuppression, and matrix remodeling. In tumor microenvironments, C1QC is induced downstream of FAP+ fibroblast-derived WNT2/β-catenin signaling in macrophages, where it maintains M2 identity (CD163), enhances fatty acid metabolism and immunosuppressive signaling, and promotes tumor cell proliferation and drug resistance [PMID:39388888, PMID:41831519]. C1QC also drives pathology under metabolic and ischemic stress: it binds DDR2 to activate MMP9-mediated extracellular matrix degradation and blood-brain barrier disruption under diabetic conditions [PMID:39531193], acts as a direct target of the circDnajc1/miR-27a-5p axis to govern microglial inflammatory output and neuronal apoptosis [PMID:40483386], and lies downstream of metabolic stress to promote lipid accumulation and inflammation in renal tubular epithelial cells [PMID:41252098]. Structural and biochemical detail of the C1QC-DDR2 interaction has not been resolved in the available corpus.","teleology":[{"year":2019,"claim":"Established that C1QC is genetically required for circulating C1q, resolving whether the C-chain subunit is essential for classical complement pathway function.","evidence":"Compound heterozygous mutation analysis with ELISA/Western blot for serum C1q and RNA sequencing to confirm trans configuration in a patient","pmids":["31357913"],"confidence":"Medium","gaps":["Single case report; not corroborated across an independent cohort","Does not address non-complement functions of C1QC","Mechanism by which subunit loss destabilizes the C1q hexamer not biochemically dissected"]},{"year":2024,"claim":"Identified a non-complement effector role for C1QC in barrier pathology by linking it to DDR2 binding and MMP9-driven matrix degradation under diabetic stress.","evidence":"siRNA knockdown in vitro and in vivo diabetic models, Western blot for MMP9 activation, and a C1QC-DDR2 binding assay","pmids":["39531193"],"confidence":"Medium","gaps":["No structural validation or reconstitution of direct C1QC-DDR2 binding","Whether MMP9 activation is direct or indirect not resolved","Single lab"]},{"year":2024,"claim":"Placed C1qc within a circDnajc1/miR-27a-5p regulatory axis controlling microglial inflammation, answering how C1qc expression is post-transcriptionally tuned in ischemic injury.","evidence":"circDnajc1 knockdown/overexpression in OGD/R cells and MCAO/R rats with RNA immunoprecipitation and luciferase reporter assays establishing C1qc as a miR-27a-5p target","pmids":["40483386"],"confidence":"Medium","gaps":["Functional contribution of C1qc versus co-regulated C3/C5ar not separated","Rodent ortholog model; human relevance not confirmed","Single lab"]},{"year":2025,"claim":"Demonstrated that C1QC maintains M2 macrophage identity and tumor-promoting macrophage-lymphoma interactions, establishing a cell-autonomous immunomodulatory function.","evidence":"siRNA knockdown with WB/qPCR for CD163 and macrophage-lymphoma co-culture proliferation and drug-sensitivity assays","pmids":["39388888"],"confidence":"Medium","gaps":["Molecular mechanism by which C1QC sustains CD163/M2 state unknown","No in vivo tumor model in this study","Single lab"]},{"year":2025,"claim":"Defined an upstream signaling axis (FAP+ fibroblast WNT2→β-catenin) driving C1QC induction in immunosuppressive macrophages, connecting stromal signaling to C1QC+ macrophage function.","evidence":"Co-culture, single-cell RNA-seq, spatial transcriptomics, and in vivo OSCC model with FAP inhibition","pmids":["41831519"],"confidence":"Medium","gaps":["Direct transcriptional control of C1QC by β-catenin not shown at promoter level","Relative contribution of C1QC to the immunosuppressive phenotype versus correlation not fully isolated","Single lab"]},{"year":2025,"claim":"Positioned C1QC downstream of metabolic stress and upstream of renal lipid accumulation and inflammation, providing epistatic placement via drug rescue.","evidence":"siRNA knockdown and overexpression in HK-2 cells, db/db mouse model, and empagliflozin co-treatment rescue with lipid/inflammatory readouts","pmids":["41252098"],"confidence":"Medium","gaps":["Direct molecular targets of C1QC in tubular cells not identified","Whether effect is complement-dependent unresolved","Single lab"]},{"year":2024,"claim":"Reported a direct antiviral activity for the C1qC protein in a teleost ortholog, extending innate-immune function beyond mammals.","evidence":"Recombinant grass carp C1qC incubation with CIK cells followed by GCRV infection and viral replication quantification","pmids":["38447782"],"confidence":"Low","gaps":["Single functional assay with recombinant protein; no mutagenesis or mechanistic follow-up","Non-mammalian ortholog; relevance to human C1QC unestablished","Mechanism of viral inhibition unknown"]},{"year":null,"claim":"How the secreted complement subunit C1QC mechanistically transitions to a cell-intrinsic driver of macrophage polarization, matrix degradation, and metabolic inflammation across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of C1QC partner interactions (e.g. DDR2)","Unclear whether tissue phenotypes are complement-dependent or complement-independent","Direct transcriptional and signaling control of C1QC induction not defined at the promoter level"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,4,5]}],"complexes":["C1q complex"],"partners":["DDR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02747","full_name":"Complement C1q subcomponent subunit C","aliases":[],"length_aa":245,"mass_kda":25.8,"function":"Core component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:34155115, PubMed:6249812, PubMed:6776418). The classical complement pathway is initiated by the C1Q subcomplex of the C1 complex, which specifically binds IgG or IgM immunoglobulins complexed with antigens, forming antigen-antibody complexes on the surface of pathogens: C1QA, together with C1QB and C1QC, specifically recognizes and binds the Fc regions of IgG or IgM via its C1q domain (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:6776418). Immunoglobulin-binding activates the proenzyme C1R, which cleaves C1S, initiating the proteolytic cascade of the complement system (PubMed:29449492). The C1Q subcomplex is activated by a hexamer of IgG complexed with antigens, while it is activated by a pentameric IgM (PubMed:19706439, PubMed:24626930, PubMed:29449492). The C1Q subcomplex also recognizes and binds phosphatidylserine exposed on the surface of cells undergoing programmed cell death, possibly promoting activation of the complement system (PubMed:18250442)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P02747/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QC","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/C1QC","total_profiled":1310},"omim":[{"mim_id":"620322","title":"C1q DEFICIENCY 3; C1QD3","url":"https://www.omim.org/entry/620322"},{"mim_id":"613652","title":"C1q DEFICIENCY 1; C1QD1","url":"https://www.omim.org/entry/613652"},{"mim_id":"120575","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT, C CHAIN; C1QC","url":"https://www.omim.org/entry/120575"},{"mim_id":"120550","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT, A CHAIN; C1QA","url":"https://www.omim.org/entry/120550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":893.4}],"url":"https://www.proteinatlas.org/search/C1QC"},"hgnc":{"alias_symbol":[],"prev_symbol":["C1QG"]},"alphafold":{"accession":"P02747","domains":[{"cath_id":"2.60.120.40","chopping":"117-243","consensus_level":"high","plddt":96.1127,"start":117,"end":243}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02747","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02747-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02747-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QC","jax_strain_url":"https://www.jax.org/strain/search?query=C1QC"},"sequence":{"accession":"P02747","fasta_url":"https://rest.uniprot.org/uniprotkb/P02747.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02747/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02747"}},"corpus_meta":[{"pmid":"34295336","id":"PMC_34295336","title":"Multi-Omics Analysis Showed the Clinical Value of Gene Signatures of C1QC+ and SPP1+ TAMs in Cervical Cancer.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34295336","citation_count":47,"is_preprint":false},{"pmid":"31019999","id":"PMC_31019999","title":"C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients.","date":"2019","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31019999","citation_count":15,"is_preprint":false},{"pmid":"40740771","id":"PMC_40740771","title":"Identification of a stromal immunosuppressive barrier orchestrated by SPP1+/C1QC+ macrophages and CD8+ exhausted T cells driving gastric cancer immunotherapy resistance.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40740771","citation_count":9,"is_preprint":false},{"pmid":"36644582","id":"PMC_36644582","title":"C1QC, VSIG4, and CFD as Potential Peripheral Blood Biomarkers in Atrial Fibrillation-Related Cardioembolic Stroke.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36644582","citation_count":9,"is_preprint":false},{"pmid":"39388888","id":"PMC_39388888","title":"Single-cell sequencing in diffuse large B-cell lymphoma: C1qC is a potential tumor-promoting factor.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39388888","citation_count":6,"is_preprint":false},{"pmid":"31357913","id":"PMC_31357913","title":"Complex medical history of a patient with a compound heterozygous mutation in C1QC.","date":"2019","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/31357913","citation_count":5,"is_preprint":false},{"pmid":"40448626","id":"PMC_40448626","title":"RUNX1/SLAMF3 Axis Drives Immunosuppression to Contribute to Colorectal Cancer Liver Metastasis by Blocking Phagocytosis and Depleting C1QC+ Tumor-Associated Macrophages.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40448626","citation_count":4,"is_preprint":false},{"pmid":"39531193","id":"PMC_39531193","title":"Upregulation of C1QC as a Mediator of Blood-Brain Barrier Damage in Type 2 Diabetes Mellitus.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39531193","citation_count":4,"is_preprint":false},{"pmid":"38447782","id":"PMC_38447782","title":"Identification of the C1qDC gene family in grass carp (Ctenopharyngodon idellus) and the response of C1qA, C1qB, and C1qC to GCRV infection in vivo and in vitro.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38447782","citation_count":3,"is_preprint":false},{"pmid":"39626448","id":"PMC_39626448","title":"Exploring the mechanism of Taohong Siwu Decoction in treating ischemic stroke injury via the circDnajc1/miR-27a-5p/C1qc signaling axis.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39626448","citation_count":3,"is_preprint":false},{"pmid":"41831519","id":"PMC_41831519","title":"FAP+ fibroblasts promote C1QC+ macrophage infiltration via WNT2 signaling to exacerbate T cell exhaustion in oral squamous cell carcinoma.","date":"2026","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41831519","citation_count":1,"is_preprint":false},{"pmid":"41252098","id":"PMC_41252098","title":"Empagliflozin alleviates lipid deposition and inflammation in diabetic kidney disease by downregulating C1QC.","date":"2025","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41252098","citation_count":1,"is_preprint":false},{"pmid":"39843834","id":"PMC_39843834","title":"Two siblings with monogenic lupus due to C1qC deficiency and case based review.","date":"2025","source":"Clinical 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mitigated BBB damage.\",\n      \"method\": \"siRNA knockdown in vitro and in vivo diabetic models; co-treatment experiments; Western blot for MMP9 activation; binding assay (C1QC-DDR2 interaction)\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined cellular phenotype and proposed binding partner identified; single lab with two orthogonal methods (in vitro and in vivo), but no structural validation or direct reconstitution of C1QC-DDR2 binding\",\n      \"pmids\": [\"39531193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Compound heterozygous mutations in C1QC (c.100G>A p.(Gly34Arg) and c.205C>T p.(Arg69X), confirmed on different chromosomes by RNA sequencing) result in complete absence of C1q protein in serum, establishing that C1QC is required for circulating C1q complex and functional classical complement pathway activation.\",\n      \"method\": \"ELISA and Western blot for C1q in serum; DNA sequencing; RNA sequencing to confirm trans configuration of mutations\",\n      \"journal\": \"Lupus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein absence confirmed by two orthogonal methods (ELISA + WB), genetic confirmation by sequencing; single case report but rigorous molecular characterization\",\n      \"pmids\": [\"31357913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1QC knockdown in macrophages significantly reduces CD163 expression (an M2 macrophage marker), and co-culture experiments show that M2 macrophages (with high C1QC expression) promote tumor cell proliferation and reduce drug sensitivity, establishing a functional role for C1QC in maintaining M2 macrophage identity and tumor-promoting macrophage-lymphoma cell interactions.\",\n      \"method\": \"siRNA-mediated C1QC knockdown; Western blot and qPCR for CD163; macrophage-lymphoma cell co-culture assay; proliferation and drug sensitivity assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and co-culture functional readout; single lab, two orthogonal methods (WB + qPCR + functional co-culture)\",\n      \"pmids\": [\"39388888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1QC plays a mechanistic role in diabetic kidney disease (DKD): siRNA-mediated C1QC silencing attenuated lipid accumulation and inflammation in high-glucose/palmitate-challenged HK-2 cells, while C1QC overexpression exacerbated these pathological changes. Empagliflozin reduced renal C1QC expression in db/db mice, and C1QC overexpression partially reversed empagliflozin's protective effects, placing C1QC downstream of metabolic stress and upstream of renal inflammation and lipid deposition.\",\n      \"method\": \"siRNA knockdown and plasmid-mediated overexpression in HK-2 cells; in vivo db/db mouse model; rescue experiments with empagliflozin co-treatment; lipid accumulation assays; inflammatory marker quantification\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined cellular and in vivo phenotypes; rescue experiment provides epistatic placement; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"41252098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In ischemic stroke models, circDnajc1 acts upstream of miR-27a-5p, which in turn represses C1qc expression; knockdown of circDnajc1 downregulates C1qc (along with C3 and C5ar), reduces microglial activation, decreases inflammatory factor release, and reduces neuronal apoptosis. Luciferase reporter and RNA immunoprecipitation experiments placed C1qc as a miR-27a-5p target in the circDnajc1/miR-27a-5p/C1qc signaling axis.\",\n      \"method\": \"circDnajc1 siRNA knockdown and overexpression; OGD/R cell model and MCAO/R rat model; RT-qPCR, immunofluorescence, RNA immunoprecipitation, luciferase reporter gene assays; flow cytometry\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation and luciferase reporter establish C1qc as direct miR-27a-5p target; in vitro and in vivo corroboration; single lab\",\n      \"pmids\": [\"40483386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAP+ fibroblasts secrete WNT2 to activate β-catenin signaling in macrophages, which upregulates C1QC expression and M2 markers. This FAP-WNT2-C1QC axis confers tumor-promoting functions; C1QC+ macrophages exhibit enhanced fatty acid metabolism, immunosuppressive signaling, and secrete CCL2 to recruit Tregs and induce T cell exhaustion. In vivo FAP inhibition reduced C1QC+ macrophage infiltration.\",\n      \"method\": \"Co-culture systems; single-cell RNA sequencing; spatial transcriptomics; in vivo OSCC animal model with FAP inhibition; multi-omics analysis; immunofluorescence\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (WNT2→β-catenin→C1QC) supported by co-culture and in vivo rescue with FAP inhibition; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41831519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Recombinant grass carp C1qC protein (rC1qC) exerts a substantial inhibitory effect on grass carp reovirus (GCRV) replication in CIK cells after 24 hours of infection, demonstrating a direct antiviral activity for C1qC protein in a teleost ortholog model.\",\n      \"method\": \"Recombinant protein incubation with CIK cells followed by GCRV inoculation; viral replication quantification\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay with recombinant protein in a non-mammalian ortholog (grass carp); no mechanistic follow-up or mutagenesis\",\n      \"pmids\": [\"38447782\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QC encodes the C-chain subunit of the C1q complement complex, and loss-of-function mutations cause complete C1q deficiency and lupus-like disease; at the molecular level, C1QC protein can bind DDR2 to activate MMP9-mediated extracellular matrix degradation, acts downstream of WNT2/β-catenin signaling to promote M2 macrophage identity and immunosuppression, is a direct transcriptional target of the miR-27a-5p axis (regulated by circDnajc1) in microglial inflammatory signaling, and contributes to lipid accumulation and inflammation in tubular epithelial cells under metabolic stress conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QC encodes the C-chain subunit of the C1q complement complex, and its expression is required for circulating C1q and a functional classical complement pathway; compound heterozygous loss-of-function mutations abolish serum C1q protein [#1]. Beyond its canonical complement role, C1QC functions as a tissue-context effector in inflammation, immunosuppression, and matrix remodeling. In tumor microenvironments, C1QC is induced downstream of FAP+ fibroblast-derived WNT2/\\u03b2-catenin signaling in macrophages, where it maintains M2 identity (CD163), enhances fatty acid metabolism and immunosuppressive signaling, and promotes tumor cell proliferation and drug resistance [#2, #5]. C1QC also drives pathology under metabolic and ischemic stress: it binds DDR2 to activate MMP9-mediated extracellular matrix degradation and blood-brain barrier disruption under diabetic conditions [#0], acts as a direct target of the circDnajc1/miR-27a-5p axis to govern microglial inflammatory output and neuronal apoptosis [#4], and lies downstream of metabolic stress to promote lipid accumulation and inflammation in renal tubular epithelial cells [#3]. Structural and biochemical detail of the C1QC-DDR2 interaction has not been resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that C1QC is genetically required for circulating C1q, resolving whether the C-chain subunit is essential for classical complement pathway function.\",\n      \"evidence\": \"Compound heterozygous mutation analysis with ELISA/Western blot for serum C1q and RNA sequencing to confirm trans configuration in a patient\",\n      \"pmids\": [\"31357913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case report; not corroborated across an independent cohort\",\n        \"Does not address non-complement functions of C1QC\",\n        \"Mechanism by which subunit loss destabilizes the C1q hexamer not biochemically dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-complement effector role for C1QC in barrier pathology by linking it to DDR2 binding and MMP9-driven matrix degradation under diabetic stress.\",\n      \"evidence\": \"siRNA knockdown in vitro and in vivo diabetic models, Western blot for MMP9 activation, and a C1QC-DDR2 binding assay\",\n      \"pmids\": [\"39531193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural validation or reconstitution of direct C1QC-DDR2 binding\",\n        \"Whether MMP9 activation is direct or indirect not resolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed C1qc within a circDnajc1/miR-27a-5p regulatory axis controlling microglial inflammation, answering how C1qc expression is post-transcriptionally tuned in ischemic injury.\",\n      \"evidence\": \"circDnajc1 knockdown/overexpression in OGD/R cells and MCAO/R rats with RNA immunoprecipitation and luciferase reporter assays establishing C1qc as a miR-27a-5p target\",\n      \"pmids\": [\"40483386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional contribution of C1qc versus co-regulated C3/C5ar not separated\",\n        \"Rodent ortholog model; human relevance not confirmed\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that C1QC maintains M2 macrophage identity and tumor-promoting macrophage-lymphoma interactions, establishing a cell-autonomous immunomodulatory function.\",\n      \"evidence\": \"siRNA knockdown with WB/qPCR for CD163 and macrophage-lymphoma co-culture proliferation and drug-sensitivity assays\",\n      \"pmids\": [\"39388888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which C1QC sustains CD163/M2 state unknown\",\n        \"No in vivo tumor model in this study\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an upstream signaling axis (FAP+ fibroblast WNT2\\u2192\\u03b2-catenin) driving C1QC induction in immunosuppressive macrophages, connecting stromal signaling to C1QC+ macrophage function.\",\n      \"evidence\": \"Co-culture, single-cell RNA-seq, spatial transcriptomics, and in vivo OSCC model with FAP inhibition\",\n      \"pmids\": [\"41831519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct transcriptional control of C1QC by \\u03b2-catenin not shown at promoter level\",\n        \"Relative contribution of C1QC to the immunosuppressive phenotype versus correlation not fully isolated\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned C1QC downstream of metabolic stress and upstream of renal lipid accumulation and inflammation, providing epistatic placement via drug rescue.\",\n      \"evidence\": \"siRNA knockdown and overexpression in HK-2 cells, db/db mouse model, and empagliflozin co-treatment rescue with lipid/inflammatory readouts\",\n      \"pmids\": [\"41252098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular targets of C1QC in tubular cells not identified\",\n        \"Whether effect is complement-dependent unresolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported a direct antiviral activity for the C1qC protein in a teleost ortholog, extending innate-immune function beyond mammals.\",\n      \"evidence\": \"Recombinant grass carp C1qC incubation with CIK cells followed by GCRV infection and viral replication quantification\",\n      \"pmids\": [\"38447782\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single functional assay with recombinant protein; no mutagenesis or mechanistic follow-up\",\n        \"Non-mammalian ortholog; relevance to human C1QC unestablished\",\n        \"Mechanism of viral inhibition unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the secreted complement subunit C1QC mechanistically transitions to a cell-intrinsic driver of macrophage polarization, matrix degradation, and metabolic inflammation across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of C1QC partner interactions (e.g. DDR2)\",\n        \"Unclear whether tissue phenotypes are complement-dependent or complement-independent\",\n        \"Direct transcriptional and signaling control of C1QC induction not defined at the promoter level\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 4, 5]}\n    ],\n    \"complexes\": [\"C1q complex\"],\n    \"partners\": [\"DDR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}