{"gene":"CAPZA1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2017,"finding":"CAPZA1, the α1 subunit of the CapZ capping protein complex, binds actin filaments (co-immunoprecipitation) and regulates F-actin cytoskeleton remodeling; loss-of-function (knockdown) promotes migration/invasion of HCC cells while gain-of-function (overexpression) inhibits these processes, establishing a direct role for CAPZA1 in controlling actin-dependent EMT.","method":"Immunoprecipitation (CAPZA1–actin interaction), siRNA knockdown and overexpression with Transwell migration/invasion assays, orthotopic xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus loss- and gain-of-function in vitro and in vivo, single lab","pmids":["28093067"],"is_preprint":false},{"year":2019,"finding":"PIP2 binds directly to CAPZA1, causing its release from the barbed end of F-actin. Hypoxia elevates intracellular PIP2 levels via the HIF-1α/RhoA/ROCK1 pathway, thereby uncapping F-actin and driving actin cytoskeleton remodeling and EMT in HCC cells.","method":"Co-immunoprecipitation of CAPZA1 with PIP2, pharmacological/genetic manipulation of HIF-1α, RhoA, and ROCK1, in vitro migration/invasion assays, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for PIP2–CAPZA1 binding plus pathway dissection, single lab, multiple orthogonal approaches","pmids":["30742939"],"is_preprint":false},{"year":2018,"finding":"CAPZA1 localizes to the nucleus and binds LRP1 intracellular domain (LRP1-ICD), preventing LRP1-ICD from binding the LAMP1 proximal promoter; this inhibits LAMP1 expression, blocks autolysosome formation, and impairs autophagic degradation of H. pylori CagA.","method":"Co-immunoprecipitation of nuclear CAPZA1 with LRP1-ICD, ChIP assay for LRP1-ICD on LAMP1 promoter, CAPZA1 overexpression with autolysosome formation readout, qPCR/Western blot","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus functional autolysosome assay, single lab","pmids":["30176157"],"is_preprint":false},{"year":2019,"finding":"CAPZA1 overexpression, following CagA accumulation due to impaired autophagy, enhances β-catenin nuclear accumulation and upregulates ESRP1-mediated alternative splicing of CD44 to generate CD44v9, driving cancer stem-like cell formation. Oxidative stress increases CAPZA1 expression through enhanced histone H3 acetylation at the CAPZA1 promoter.","method":"Western blot/immunofluorescence for β-catenin and CD44v9, ChIP for H3 acetylation at CAPZA1 promoter, CAPZA1 overexpression in AGS cells, H. pylori infection model","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional overexpression experiments plus cell signaling readouts, single lab","pmids":["31146068"],"is_preprint":false},{"year":2021,"finding":"The E3 ubiquitin ligase UBR5 physically interacts with CAPZA1 (identified by co-immunoprecipitation combined with mass spectrometry) and promotes its proteasomal degradation via the ubiquitin-proteasome system, thereby reducing CAPZA1 levels, inducing F-actin accumulation, and enhancing pancreatic cancer cell migration and invasion.","method":"Co-immunoprecipitation combined with mass spectrometry, UBR5 overexpression/knockdown, Western blot for CAPZA1 protein levels, proteasome inhibitor rescue, Transwell migration/invasion, in vivo liver metastasis model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification plus functional loss- and gain-of-function in vitro and in vivo, single lab","pmids":["33777788"],"is_preprint":false},{"year":2022,"finding":"FAM21C interacts with CAPZA1 via its CP-interacting (CPI) domain and inhibits the F-actin capping capacity of CAPZA1, promoting actin cytoskeleton remodeling, HCC cell invasion and migration; mutation of the CPI domain on FAM21C abolishes this effect.","method":"Co-immunoprecipitation of FAM21C with CAPZA1, CPI-domain mutagenesis, F-actin capping assay, Transwell migration/invasion, in vivo xenograft","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain mutagenesis plus functional actin-capping readout, single lab","pmids":["35096613"],"is_preprint":false},{"year":2021,"finding":"miR-875-5p binds the 3'UTR of CAPZA1 mRNA (including the region containing SNP rs373245753) and downregulates CAPZA1 expression; a mRNA affinity pull-down assay confirmed that the SNP rs373245753 disrupts miR-875-5p binding to CAPZA1, reducing its suppressive effect.","method":"Dual-luciferase reporter assay (implied from context), mRNA affinity pull-down assay, miR-875-5p overexpression with CAPZA1 Western blot, Transwell assays","journal":"PeerJ","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mRNA pull-down only for binding confirmation, limited mechanistic follow-up","pmids":["33505778"],"is_preprint":false},{"year":2025,"finding":"TGF-β suppresses CAPZA1 expression by reducing levels of the transcription factor GATA3, which positively regulates CAPZA1 transcription; ChIP assay confirmed GATA3 binding to the CAPZA1 promoter. Reduced CAPZA1 promotes invadopodia formation (co-localization of F-actin with cortactin, gelatin degradation assay) and enhances HCC invasiveness.","method":"ChIP assay (GATA3 at CAPZA1 promoter), GATA3 plasmid transfection and siRNA knockdown, FITC-gelatin degradation assay, immunofluorescence for invadopodia markers, TGF-β inhibitor (SB431542) in nude mice","journal":"The American journal of the medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus orthogonal functional assays (invadopodia, in vivo), single lab","pmids":["40796418"],"is_preprint":false},{"year":2026,"finding":"The selective autophagy receptor NDP52 physically interacts with CAPZA1 via its ZF2 domain and promotes autophagic degradation of CAPZA1 (an F-actin capping protein); NDP52 loss leads to CAPZA1 accumulation, accompanied by aberrant ROS accumulation and activation of p53/Rb cell cycle arrest and NF-κB-mediated SASP signaling, driving nucleus pulposus cell senescence. CAPZA1 knockdown rescues the senescent phenotype caused by NDP52 deficiency.","method":"IP-MS (proteomic identification of CAPZA1 as NDP52 substrate), co-immunoprecipitation, NDP52 ZF2-domain deletion mutant, NDP52 KO mice, CAPZA1 knockdown rescue experiments, Western blot, ROS assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus domain-deletion mutant plus rescue experiments plus in vivo KO, single lab","pmids":["42061478"],"is_preprint":false},{"year":2026,"finding":"CAPZA1 loss-of-function (CRISPR-Cas9 KO in mouse spermatids and in vivo AAV-CRISPR delivery) impairs sperm progressive motility and causes disorganized flagellar ultrastructure (asymmetric fibrous sheath, partial dynein arm loss). KO-CAPZA1 cells show decreased p300/CBP, SLC7A11, and H3K27ac expression, disrupted thiol/disulfide homeostasis, and mislocalization of cytoskeletal proteins DNAH9 and FSCN1, identifying a role for CAPZA1 in flagellar architecture and redox regulation.","method":"CRISPR-Cas9 KO in mouse spermatids and in vivo (AAV delivery), transmission electron microscopy, computer-assisted semen analysis, Western blot, ELISA for cystine, thiol quantification (DTNB), immunofluorescence for DNAH9/FSCN1","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple orthogonal phenotypic readouts (TEM, CASA, biochemical), single lab","pmids":["41858859"],"is_preprint":false},{"year":2026,"finding":"CAPZA1 mRNA stability is regulated in a SNP-dependent manner: the CAPZA1[T] variant (rs373245753) binds RNA-binding proteins hnRNP K and PTBP1, enhancing mRNA stability and tumor-suppressive function, whereas the CAPZA1[G] variant preferentially binds UPF1, leading to accelerated mRNA decay and loss of tumor suppression in ESCC cells.","method":"Biotin-RNA pulldown assay coupled with mass spectrometry, RNA immunoprecipitation (RIP), mRNA decay assay, CAPZA1[T] and CAPZA1[G] stable cell lines, Transwell migration/invasion, subcutaneous xenograft","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown/MS plus RIP plus mRNA decay assay plus in vivo, single lab, multiple orthogonal methods","pmids":["41787560"],"is_preprint":false},{"year":2025,"finding":"Short-chain fatty acids (propionate, butyrate) induce CAPZA1 overexpression via histone deacetylase (HDAC) inhibition, increasing histone acetylation at the CAPZA1 promoter. This CAPZA1 overexpression impairs autophagic degradation of H. pylori CagA, enabling CagA accumulation and CD44v9-positive cancer stem-like cell generation.","method":"Western blot and immunofluorescence in H. pylori-infected cells treated with SCFAs, HDAC inhibition experiments, gastric organoid models, H. pylori mouse infection models, measurement of SCFA levels and microbiota in patient gastric juice","journal":"Gastro hep advances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional cell/organoid model without direct biochemical confirmation of HDAC–CAPZA1 promoter link; limited mechanistic depth in abstract","pmids":["41586340"],"is_preprint":false}],"current_model":"CAPZA1 is an F-actin barbed-end capping protein (the α1 subunit of the CapZ complex) whose capping activity is inhibited by PIP2 binding or by interaction with FAM21C's CPI domain; it is targeted for proteasomal degradation by the E3 ligase UBR5 and for selective autophagic degradation by the receptor NDP52, while its transcription is positively regulated by GATA3 (suppressed by TGF-β) and its mRNA stability is controlled by hnRNP K/PTBP1 versus UPF1 in an SNP-dependent manner; in addition to its canonical cytoskeletal role, nuclear CAPZA1 binds LRP1-ICD to suppress LAMP1 transcription and block autolysosome formation, thereby modulating autophagic degradation of oncoproteins such as H. pylori CagA."},"narrative":{"mechanistic_narrative":"CAPZA1 is the α1 subunit of the heterodimeric CapZ complex that binds the barbed ends of actin filaments and caps them, thereby restraining actin cytoskeleton remodeling and acting as a brake on cancer cell migration, invasion, and epithelial-mesenchymal transition [PMID:28093067]. Its capping activity is switched off by two distinct inputs: direct binding of PIP2 releases CAPZA1 from the F-actin barbed end—an event driven by hypoxia through the HIF-1α/RhoA/ROCK1 axis [PMID:30742939]—and interaction with the CPI domain of FAM21C, which likewise inhibits capping and promotes filament elongation [PMID:35096613]; loss of CAPZA1 capping also licenses invadopodia formation marked by cortactin/F-actin co-localization and gelatin degradation [PMID:40796418]. CAPZA1 abundance is set by multiple layers of control: it is targeted for proteasomal degradation by the E3 ligase UBR5 [PMID:33777788] and for selective autophagic turnover by the receptor NDP52 acting through its ZF2 domain [PMID:42061478], while its transcription is positively driven by GATA3 (which TGF-β suppresses) [PMID:40796418] and modulated by histone acetylation at its promoter [PMID:31146068]. Beyond its cytoskeletal role, nuclear CAPZA1 binds the LRP1 intracellular domain to block LRP1-ICD occupancy of the LAMP1 promoter, suppressing LAMP1 transcription and autolysosome formation and thereby impairing autophagic degradation of the H. pylori oncoprotein CagA, with downstream β-catenin/ESRP1-mediated CD44v9 cancer stem-like cell generation [PMID:30176157, PMID:31146068]. CAPZA1 also supports flagellar ultrastructure and redox homeostasis, as its loss disrupts sperm motility, dynein arm organization, and thiol/disulfide balance [PMID:41858859].","teleology":[{"year":2017,"claim":"Established CAPZA1 as a functional actin-capping protein whose level controls cancer cell motility, defining its core cytoskeletal role rather than mere family membership.","evidence":"CAPZA1–actin co-IP plus knockdown/overexpression with migration/invasion assays and orthotopic xenograft in HCC","pmids":["28093067"],"confidence":"Medium","gaps":["Does not resolve whether the effect requires the CapZ heterodimer (CAPZB partner)","No structural detail of barbed-end engagement"]},{"year":2018,"claim":"Revealed an unexpected nuclear, transcription-modulating function for CAPZA1 distinct from cytoskeletal capping, linking it to autophagy control via LAMP1.","evidence":"Nuclear CAPZA1–LRP1-ICD co-IP, ChIP on LAMP1 promoter, and autolysosome formation readout in gastric cells","pmids":["30176157"],"confidence":"Medium","gaps":["How CAPZA1 partitions between cytoplasm and nucleus is unknown","Whether nuclear CAPZA1 retains actin-capping or is a separate pool"]},{"year":2019,"claim":"Identified a direct lipid switch (PIP2) and its upstream hypoxia pathway that uncaps CAPZA1, explaining how the capping brake is released under tumor microenvironment stress.","evidence":"CAPZA1–PIP2 co-IP plus HIF-1α/RhoA/ROCK1 manipulation and invasion assays in HCC","pmids":["30742939"],"confidence":"Medium","gaps":["PIP2 binding site on CAPZA1 not mapped","Quantitative relationship between PIP2 levels and capping kinetics unresolved"]},{"year":2019,"claim":"Connected CAPZA1 accumulation to oncogenic stem-cell programs downstream of impaired CagA autophagy, and showed oxidative stress raises CAPZA1 via promoter histone acetylation.","evidence":"ChIP for H3 acetylation at CAPZA1 promoter, β-catenin/CD44v9 readouts, CAPZA1 overexpression in AGS cells with H. pylori infection","pmids":["31146068"],"confidence":"Medium","gaps":["Acetyltransferase responsible not identified","Causal chain from CAPZA1 to ESRP1 splicing not fully dissected"]},{"year":2021,"claim":"Defined post-translational control of CAPZA1 abundance by the proteasome, showing UBR5 ubiquitinates CAPZA1 to derepress actin dynamics and metastasis.","evidence":"Co-IP/MS identification of UBR5, proteasome inhibitor rescue, and migration/metastasis assays in pancreatic cancer","pmids":["33777788"],"confidence":"Medium","gaps":["Ubiquitination sites on CAPZA1 not mapped","Whether UBR5 acts on monomeric or complexed CAPZA1 unknown"]},{"year":2021,"claim":"Provided early evidence that a 3'UTR SNP alters CAPZA1 regulation by miR-875-5p, introducing genotype-dependent expression control.","evidence":"mRNA affinity pull-down and miR-875-5p overexpression with CAPZA1 Western blot","pmids":["33505778"],"confidence":"Low","gaps":["Binding confirmed only by pull-down without reciprocal validation","Functional consequence of the SNP for tumor behavior not established here"]},{"year":2022,"claim":"Identified FAM21C as a direct protein inhibitor of CAPZA1 capping via its CPI domain, defining a second mechanism for releasing the capping brake.","evidence":"FAM21C–CAPZA1 co-IP, CPI-domain mutagenesis, and F-actin capping/invasion assays in HCC","pmids":["35096613"],"confidence":"Medium","gaps":["Structural basis of CPI-domain engagement not solved","Interplay between FAM21C and PIP2 regulation untested"]},{"year":2025,"claim":"Placed CAPZA1 transcription under GATA3 control and the TGF-β axis, linking signaling to invadopodia-driven invasion through loss of capping.","evidence":"ChIP for GATA3 at CAPZA1 promoter, GATA3 gain/loss, gelatin-degradation invadopodia assay, and TGF-β inhibitor in mice","pmids":["40796418"],"confidence":"Medium","gaps":["Direct vs indirect GATA3 regulation in different tissues unclear","Quantitative contribution of CAPZA1 to invadopodia versus other regulators"]},{"year":2025,"claim":"Extended epigenetic control of CAPZA1 to microbial metabolites, showing SCFAs raise CAPZA1 via HDAC inhibition to impair CagA clearance.","evidence":"SCFA treatment with HDAC inhibition, gastric organoid and mouse infection models, patient gastric juice microbiota analysis","pmids":["41586340"],"confidence":"Low","gaps":["Direct HDAC–CAPZA1 promoter link not biochemically confirmed","Specific HDAC isoform not identified"]},{"year":2026,"claim":"Identified NDP52-mediated selective autophagy as a turnover route for CAPZA1, with consequences for ROS, cell-cycle arrest, and senescence.","evidence":"IP-MS, ZF2-domain deletion mutant, NDP52 KO mice, and CAPZA1 knockdown rescue in nucleus pulposus cells","pmids":["42061478"],"confidence":"Medium","gaps":["How CAPZA1 is selected for autophagy (ubiquitin or direct) unknown","Relationship to UBR5-proteasome pathway not reconciled"]},{"year":2026,"claim":"Showed a coding-region/3'UTR SNP rewires CAPZA1 mRNA stability via competing RNA-binding proteins, explaining genotype-dependent tumor-suppressor activity.","evidence":"Biotin-RNA pulldown/MS, RIP, mRNA decay assays, and allele-specific stable lines with xenografts in ESCC","pmids":["41787560"],"confidence":"Medium","gaps":["Whether hnRNP K/PTBP1 and UPF1 compete directly is not shown","Population frequency/clinical relevance of alleles not addressed"]},{"year":2026,"claim":"Demonstrated a physiological requirement for CAPZA1 in flagellar architecture and redox balance, broadening its role beyond cancer cytoskeletal regulation.","evidence":"CRISPR-Cas9 KO in mouse spermatids and AAV in vivo delivery with TEM, CASA, and thiol/disulfide biochemistry","pmids":["41858859"],"confidence":"Medium","gaps":["Mechanism linking CAPZA1 to p300/CBP and SLC7A11 not defined","Whether the phenotype reflects capping or non-capping functions unresolved"]},{"year":null,"claim":"How CAPZA1's multiple regulatory inputs (PIP2, FAM21C, UBR5, NDP52, SNP-dependent RNA control) are coordinated, and the structural basis of its barbed-end capping and partner interactions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CAPZA1 capping or its inhibitor interfaces in the corpus","Hierarchy among proteasomal, autophagic, transcriptional, and RNA-stability control not integrated","CAPZB partner relationship in the heterodimer not directly addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9]}],"complexes":["CapZ (F-actin capping protein)"],"partners":["LRP1","UBR5","FAM21C","NDP52","HNRNP K","PTBP1","UPF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52907","full_name":"F-actin-capping protein subunit alpha-1","aliases":["CapZ alpha-1"],"length_aa":286,"mass_kda":32.9,"function":"F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments. May play a role in the formation of epithelial cell junctions (PubMed:22891260). Forms, with CAPZB, the barbed end of the fast growing ends of actin filaments in the dynactin complex and stabilizes dynactin structure. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P52907/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAPZA1","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":10.0},{"gene":"VPS35","stoichiometry":10.0},{"gene":"DCTN2","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"ACTN4","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CAPZA1","total_profiled":1310},"omim":[{"mim_id":"618327","title":"CAPPING PROTEIN INHIBITING REGULATOR OF ACTIN DYNAMICS; CRACD","url":"https://www.omim.org/entry/618327"},{"mim_id":"617368","title":"SH3 DOMAIN-BINDING PROTEIN 1; SH3BP1","url":"https://www.omim.org/entry/617368"},{"mim_id":"616402","title":"MICROCEPHALY 14, PRIMARY, AUTOSOMAL RECESSIVE; MCPH14","url":"https://www.omim.org/entry/616402"},{"mim_id":"610579","title":"RCSD DOMAIN-CONTAINING PROTEIN 1; RCSD1","url":"https://www.omim.org/entry/610579"},{"mim_id":"609321","title":"SAS6 CENTRIOLAR ASSEMBLY PROTEIN; SASS6","url":"https://www.omim.org/entry/609321"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAPZA1"},"hgnc":{"alias_symbol":["CAPPA1"],"prev_symbol":[]},"alphafold":{"accession":"P52907","domains":[{"cath_id":"3.30.1140.60","chopping":"1-61","consensus_level":"medium","plddt":88.8557,"start":1,"end":61},{"cath_id":"3.30.1140.60","chopping":"62-113","consensus_level":"medium","plddt":96.21,"start":62,"end":113},{"cath_id":"3.90.1150.210","chopping":"116-256","consensus_level":"high","plddt":96.5399,"start":116,"end":256}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52907","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52907-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52907-F1-predicted_aligned_error_v6.png","plddt_mean":93.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAPZA1","jax_strain_url":"https://www.jax.org/strain/search?query=CAPZA1"},"sequence":{"accession":"P52907","fasta_url":"https://rest.uniprot.org/uniprotkb/P52907.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52907/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52907"}},"corpus_meta":[{"pmid":"28093067","id":"PMC_28093067","title":"CAPZA1 modulates EMT by regulating actin cytoskeleton remodelling in hepatocellular carcinoma.","date":"2017","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/28093067","citation_count":58,"is_preprint":false},{"pmid":"30742939","id":"PMC_30742939","title":"Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30742939","citation_count":58,"is_preprint":false},{"pmid":"30176157","id":"PMC_30176157","title":"CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30176157","citation_count":49,"is_preprint":false},{"pmid":"31146068","id":"PMC_31146068","title":"Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori-Infected CAPZA1-Overexpressing Cells.","date":"2019","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/31146068","citation_count":38,"is_preprint":false},{"pmid":"36643863","id":"PMC_36643863","title":"Exosome-Delivered circSTAU2 Inhibits the Progression of Gastric Cancer by Targeting the miR-589/CAPZA1 Axis.","date":"2023","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/36643863","citation_count":31,"is_preprint":false},{"pmid":"33777788","id":"PMC_33777788","title":"E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33777788","citation_count":23,"is_preprint":false},{"pmid":"33505778","id":"PMC_33505778","title":"miR-875-5p exerts tumor-promoting function via down-regulation of CAPZA1 in esophageal squamous cell carcinoma.","date":"2021","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/33505778","citation_count":12,"is_preprint":false},{"pmid":"37198664","id":"PMC_37198664","title":"Polymorphism in autophagy-related genes LRP1 and CAPZA1 may promote gastric mucosal atrophy.","date":"2023","source":"Genes and environment : the official journal of the Japanese Environmental Mutagen Society","url":"https://pubmed.ncbi.nlm.nih.gov/37198664","citation_count":6,"is_preprint":false},{"pmid":"35096613","id":"PMC_35096613","title":"FAM21C Promotes Hepatocellular Carcinoma Invasion and Metastasis by Driving Actin Cytoskeleton Remodeling via Inhibiting Capping Ability of CAPZA1.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35096613","citation_count":6,"is_preprint":false},{"pmid":"34046366","id":"PMC_34046366","title":"Corrigendum: E3 Ubiquitin Ligase UBR5 Promotes the Metastasis of Pancreatic Cancer via Destabilizing F-Actin Capping Protein CAPZA1.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34046366","citation_count":3,"is_preprint":false},{"pmid":"40796418","id":"PMC_40796418","title":"TGF-β induces a decrease in CAPZA1 expression to promote the invasiveness of hepatocellular carcinoma cells.","date":"2025","source":"The American journal of the medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40796418","citation_count":0,"is_preprint":false},{"pmid":"41858859","id":"PMC_41858859","title":"CAPZA1 deficiency disrupts sperm flagellar structure and motility, potentially involving the p300/SLC7A11 pathway.","date":"2026","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/41858859","citation_count":0,"is_preprint":false},{"pmid":"41787560","id":"PMC_41787560","title":"CAPZA1 Suppressed the Progression of Esophageal Squamous Cell Carcinoma by Binding to hnRNP K and PTPB1 to Influence Its mRNA Stability.","date":"2026","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41787560","citation_count":0,"is_preprint":false},{"pmid":"42061478","id":"PMC_42061478","title":"NDP52-mediated autophagic degradation of CAPZA1 ameliorates intervertebral disc degeneration by suppressing cellular senescence.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42061478","citation_count":0,"is_preprint":false},{"pmid":"41586340","id":"PMC_41586340","title":"Helicobacter pylori Exploit Short-Chain Fatty Acids-Induced CAPZA1 Overexpression to Emerge CD44v9-Positive Stemness.","date":"2025","source":"Gastro hep advances","url":"https://pubmed.ncbi.nlm.nih.gov/41586340","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11120,"output_tokens":3524,"usd":0.04311,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11132,"output_tokens":4091,"usd":0.078967,"stage2_stop_reason":"end_turn"},"total_usd":0.122077,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CAPZA1, the α1 subunit of the CapZ capping protein complex, binds actin filaments (co-immunoprecipitation) and regulates F-actin cytoskeleton remodeling; loss-of-function (knockdown) promotes migration/invasion of HCC cells while gain-of-function (overexpression) inhibits these processes, establishing a direct role for CAPZA1 in controlling actin-dependent EMT.\",\n      \"method\": \"Immunoprecipitation (CAPZA1–actin interaction), siRNA knockdown and overexpression with Transwell migration/invasion assays, orthotopic xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus loss- and gain-of-function in vitro and in vivo, single lab\",\n      \"pmids\": [\"28093067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIP2 binds directly to CAPZA1, causing its release from the barbed end of F-actin. Hypoxia elevates intracellular PIP2 levels via the HIF-1α/RhoA/ROCK1 pathway, thereby uncapping F-actin and driving actin cytoskeleton remodeling and EMT in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation of CAPZA1 with PIP2, pharmacological/genetic manipulation of HIF-1α, RhoA, and ROCK1, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for PIP2–CAPZA1 binding plus pathway dissection, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"30742939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAPZA1 localizes to the nucleus and binds LRP1 intracellular domain (LRP1-ICD), preventing LRP1-ICD from binding the LAMP1 proximal promoter; this inhibits LAMP1 expression, blocks autolysosome formation, and impairs autophagic degradation of H. pylori CagA.\",\n      \"method\": \"Co-immunoprecipitation of nuclear CAPZA1 with LRP1-ICD, ChIP assay for LRP1-ICD on LAMP1 promoter, CAPZA1 overexpression with autolysosome formation readout, qPCR/Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus functional autolysosome assay, single lab\",\n      \"pmids\": [\"30176157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CAPZA1 overexpression, following CagA accumulation due to impaired autophagy, enhances β-catenin nuclear accumulation and upregulates ESRP1-mediated alternative splicing of CD44 to generate CD44v9, driving cancer stem-like cell formation. Oxidative stress increases CAPZA1 expression through enhanced histone H3 acetylation at the CAPZA1 promoter.\",\n      \"method\": \"Western blot/immunofluorescence for β-catenin and CD44v9, ChIP for H3 acetylation at CAPZA1 promoter, CAPZA1 overexpression in AGS cells, H. pylori infection model\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional overexpression experiments plus cell signaling readouts, single lab\",\n      \"pmids\": [\"31146068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The E3 ubiquitin ligase UBR5 physically interacts with CAPZA1 (identified by co-immunoprecipitation combined with mass spectrometry) and promotes its proteasomal degradation via the ubiquitin-proteasome system, thereby reducing CAPZA1 levels, inducing F-actin accumulation, and enhancing pancreatic cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, UBR5 overexpression/knockdown, Western blot for CAPZA1 protein levels, proteasome inhibitor rescue, Transwell migration/invasion, in vivo liver metastasis model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification plus functional loss- and gain-of-function in vitro and in vivo, single lab\",\n      \"pmids\": [\"33777788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM21C interacts with CAPZA1 via its CP-interacting (CPI) domain and inhibits the F-actin capping capacity of CAPZA1, promoting actin cytoskeleton remodeling, HCC cell invasion and migration; mutation of the CPI domain on FAM21C abolishes this effect.\",\n      \"method\": \"Co-immunoprecipitation of FAM21C with CAPZA1, CPI-domain mutagenesis, F-actin capping assay, Transwell migration/invasion, in vivo xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain mutagenesis plus functional actin-capping readout, single lab\",\n      \"pmids\": [\"35096613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-875-5p binds the 3'UTR of CAPZA1 mRNA (including the region containing SNP rs373245753) and downregulates CAPZA1 expression; a mRNA affinity pull-down assay confirmed that the SNP rs373245753 disrupts miR-875-5p binding to CAPZA1, reducing its suppressive effect.\",\n      \"method\": \"Dual-luciferase reporter assay (implied from context), mRNA affinity pull-down assay, miR-875-5p overexpression with CAPZA1 Western blot, Transwell assays\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mRNA pull-down only for binding confirmation, limited mechanistic follow-up\",\n      \"pmids\": [\"33505778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β suppresses CAPZA1 expression by reducing levels of the transcription factor GATA3, which positively regulates CAPZA1 transcription; ChIP assay confirmed GATA3 binding to the CAPZA1 promoter. Reduced CAPZA1 promotes invadopodia formation (co-localization of F-actin with cortactin, gelatin degradation assay) and enhances HCC invasiveness.\",\n      \"method\": \"ChIP assay (GATA3 at CAPZA1 promoter), GATA3 plasmid transfection and siRNA knockdown, FITC-gelatin degradation assay, immunofluorescence for invadopodia markers, TGF-β inhibitor (SB431542) in nude mice\",\n      \"journal\": \"The American journal of the medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus orthogonal functional assays (invadopodia, in vivo), single lab\",\n      \"pmids\": [\"40796418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The selective autophagy receptor NDP52 physically interacts with CAPZA1 via its ZF2 domain and promotes autophagic degradation of CAPZA1 (an F-actin capping protein); NDP52 loss leads to CAPZA1 accumulation, accompanied by aberrant ROS accumulation and activation of p53/Rb cell cycle arrest and NF-κB-mediated SASP signaling, driving nucleus pulposus cell senescence. CAPZA1 knockdown rescues the senescent phenotype caused by NDP52 deficiency.\",\n      \"method\": \"IP-MS (proteomic identification of CAPZA1 as NDP52 substrate), co-immunoprecipitation, NDP52 ZF2-domain deletion mutant, NDP52 KO mice, CAPZA1 knockdown rescue experiments, Western blot, ROS assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus domain-deletion mutant plus rescue experiments plus in vivo KO, single lab\",\n      \"pmids\": [\"42061478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAPZA1 loss-of-function (CRISPR-Cas9 KO in mouse spermatids and in vivo AAV-CRISPR delivery) impairs sperm progressive motility and causes disorganized flagellar ultrastructure (asymmetric fibrous sheath, partial dynein arm loss). KO-CAPZA1 cells show decreased p300/CBP, SLC7A11, and H3K27ac expression, disrupted thiol/disulfide homeostasis, and mislocalization of cytoskeletal proteins DNAH9 and FSCN1, identifying a role for CAPZA1 in flagellar architecture and redox regulation.\",\n      \"method\": \"CRISPR-Cas9 KO in mouse spermatids and in vivo (AAV delivery), transmission electron microscopy, computer-assisted semen analysis, Western blot, ELISA for cystine, thiol quantification (DTNB), immunofluorescence for DNAH9/FSCN1\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple orthogonal phenotypic readouts (TEM, CASA, biochemical), single lab\",\n      \"pmids\": [\"41858859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAPZA1 mRNA stability is regulated in a SNP-dependent manner: the CAPZA1[T] variant (rs373245753) binds RNA-binding proteins hnRNP K and PTBP1, enhancing mRNA stability and tumor-suppressive function, whereas the CAPZA1[G] variant preferentially binds UPF1, leading to accelerated mRNA decay and loss of tumor suppression in ESCC cells.\",\n      \"method\": \"Biotin-RNA pulldown assay coupled with mass spectrometry, RNA immunoprecipitation (RIP), mRNA decay assay, CAPZA1[T] and CAPZA1[G] stable cell lines, Transwell migration/invasion, subcutaneous xenograft\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown/MS plus RIP plus mRNA decay assay plus in vivo, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41787560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Short-chain fatty acids (propionate, butyrate) induce CAPZA1 overexpression via histone deacetylase (HDAC) inhibition, increasing histone acetylation at the CAPZA1 promoter. This CAPZA1 overexpression impairs autophagic degradation of H. pylori CagA, enabling CagA accumulation and CD44v9-positive cancer stem-like cell generation.\",\n      \"method\": \"Western blot and immunofluorescence in H. pylori-infected cells treated with SCFAs, HDAC inhibition experiments, gastric organoid models, H. pylori mouse infection models, measurement of SCFA levels and microbiota in patient gastric juice\",\n      \"journal\": \"Gastro hep advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional cell/organoid model without direct biochemical confirmation of HDAC–CAPZA1 promoter link; limited mechanistic depth in abstract\",\n      \"pmids\": [\"41586340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAPZA1 is an F-actin barbed-end capping protein (the α1 subunit of the CapZ complex) whose capping activity is inhibited by PIP2 binding or by interaction with FAM21C's CPI domain; it is targeted for proteasomal degradation by the E3 ligase UBR5 and for selective autophagic degradation by the receptor NDP52, while its transcription is positively regulated by GATA3 (suppressed by TGF-β) and its mRNA stability is controlled by hnRNP K/PTBP1 versus UPF1 in an SNP-dependent manner; in addition to its canonical cytoskeletal role, nuclear CAPZA1 binds LRP1-ICD to suppress LAMP1 transcription and block autolysosome formation, thereby modulating autophagic degradation of oncoproteins such as H. pylori CagA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAPZA1 is the \\u03b11 subunit of the heterodimeric CapZ complex that binds the barbed ends of actin filaments and caps them, thereby restraining actin cytoskeleton remodeling and acting as a brake on cancer cell migration, invasion, and epithelial-mesenchymal transition [#0]. Its capping activity is switched off by two distinct inputs: direct binding of PIP2 releases CAPZA1 from the F-actin barbed end\\u2014an event driven by hypoxia through the HIF-1\\u03b1/RhoA/ROCK1 axis [#1]\\u2014and interaction with the CPI domain of FAM21C, which likewise inhibits capping and promotes filament elongation [#5]; loss of CAPZA1 capping also licenses invadopodia formation marked by cortactin/F-actin co-localization and gelatin degradation [#7]. CAPZA1 abundance is set by multiple layers of control: it is targeted for proteasomal degradation by the E3 ligase UBR5 [#4] and for selective autophagic turnover by the receptor NDP52 acting through its ZF2 domain [#8], while its transcription is positively driven by GATA3 (which TGF-\\u03b2 suppresses) [#7] and modulated by histone acetylation at its promoter [#3]. Beyond its cytoskeletal role, nuclear CAPZA1 binds the LRP1 intracellular domain to block LRP1-ICD occupancy of the LAMP1 promoter, suppressing LAMP1 transcription and autolysosome formation and thereby impairing autophagic degradation of the H. pylori oncoprotein CagA, with downstream \\u03b2-catenin/ESRP1-mediated CD44v9 cancer stem-like cell generation [#2, #3]. CAPZA1 also supports flagellar ultrastructure and redox homeostasis, as its loss disrupts sperm motility, dynein arm organization, and thiol/disulfide balance [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established CAPZA1 as a functional actin-capping protein whose level controls cancer cell motility, defining its core cytoskeletal role rather than mere family membership.\",\n      \"evidence\": \"CAPZA1\\u2013actin co-IP plus knockdown/overexpression with migration/invasion assays and orthotopic xenograft in HCC\",\n      \"pmids\": [\"28093067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve whether the effect requires the CapZ heterodimer (CAPZB partner)\", \"No structural detail of barbed-end engagement\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an unexpected nuclear, transcription-modulating function for CAPZA1 distinct from cytoskeletal capping, linking it to autophagy control via LAMP1.\",\n      \"evidence\": \"Nuclear CAPZA1\\u2013LRP1-ICD co-IP, ChIP on LAMP1 promoter, and autolysosome formation readout in gastric cells\",\n      \"pmids\": [\"30176157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CAPZA1 partitions between cytoplasm and nucleus is unknown\", \"Whether nuclear CAPZA1 retains actin-capping or is a separate pool\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a direct lipid switch (PIP2) and its upstream hypoxia pathway that uncaps CAPZA1, explaining how the capping brake is released under tumor microenvironment stress.\",\n      \"evidence\": \"CAPZA1\\u2013PIP2 co-IP plus HIF-1\\u03b1/RhoA/ROCK1 manipulation and invasion assays in HCC\",\n      \"pmids\": [\"30742939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PIP2 binding site on CAPZA1 not mapped\", \"Quantitative relationship between PIP2 levels and capping kinetics unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected CAPZA1 accumulation to oncogenic stem-cell programs downstream of impaired CagA autophagy, and showed oxidative stress raises CAPZA1 via promoter histone acetylation.\",\n      \"evidence\": \"ChIP for H3 acetylation at CAPZA1 promoter, \\u03b2-catenin/CD44v9 readouts, CAPZA1 overexpression in AGS cells with H. pylori infection\",\n      \"pmids\": [\"31146068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyltransferase responsible not identified\", \"Causal chain from CAPZA1 to ESRP1 splicing not fully dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined post-translational control of CAPZA1 abundance by the proteasome, showing UBR5 ubiquitinates CAPZA1 to derepress actin dynamics and metastasis.\",\n      \"evidence\": \"Co-IP/MS identification of UBR5, proteasome inhibitor rescue, and migration/metastasis assays in pancreatic cancer\",\n      \"pmids\": [\"33777788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on CAPZA1 not mapped\", \"Whether UBR5 acts on monomeric or complexed CAPZA1 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided early evidence that a 3'UTR SNP alters CAPZA1 regulation by miR-875-5p, introducing genotype-dependent expression control.\",\n      \"evidence\": \"mRNA affinity pull-down and miR-875-5p overexpression with CAPZA1 Western blot\",\n      \"pmids\": [\"33505778\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding confirmed only by pull-down without reciprocal validation\", \"Functional consequence of the SNP for tumor behavior not established here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified FAM21C as a direct protein inhibitor of CAPZA1 capping via its CPI domain, defining a second mechanism for releasing the capping brake.\",\n      \"evidence\": \"FAM21C\\u2013CAPZA1 co-IP, CPI-domain mutagenesis, and F-actin capping/invasion assays in HCC\",\n      \"pmids\": [\"35096613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CPI-domain engagement not solved\", \"Interplay between FAM21C and PIP2 regulation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed CAPZA1 transcription under GATA3 control and the TGF-\\u03b2 axis, linking signaling to invadopodia-driven invasion through loss of capping.\",\n      \"evidence\": \"ChIP for GATA3 at CAPZA1 promoter, GATA3 gain/loss, gelatin-degradation invadopodia assay, and TGF-\\u03b2 inhibitor in mice\",\n      \"pmids\": [\"40796418\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect GATA3 regulation in different tissues unclear\", \"Quantitative contribution of CAPZA1 to invadopodia versus other regulators\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended epigenetic control of CAPZA1 to microbial metabolites, showing SCFAs raise CAPZA1 via HDAC inhibition to impair CagA clearance.\",\n      \"evidence\": \"SCFA treatment with HDAC inhibition, gastric organoid and mouse infection models, patient gastric juice microbiota analysis\",\n      \"pmids\": [\"41586340\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct HDAC\\u2013CAPZA1 promoter link not biochemically confirmed\", \"Specific HDAC isoform not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified NDP52-mediated selective autophagy as a turnover route for CAPZA1, with consequences for ROS, cell-cycle arrest, and senescence.\",\n      \"evidence\": \"IP-MS, ZF2-domain deletion mutant, NDP52 KO mice, and CAPZA1 knockdown rescue in nucleus pulposus cells\",\n      \"pmids\": [\"42061478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CAPZA1 is selected for autophagy (ubiquitin or direct) unknown\", \"Relationship to UBR5-proteasome pathway not reconciled\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed a coding-region/3'UTR SNP rewires CAPZA1 mRNA stability via competing RNA-binding proteins, explaining genotype-dependent tumor-suppressor activity.\",\n      \"evidence\": \"Biotin-RNA pulldown/MS, RIP, mRNA decay assays, and allele-specific stable lines with xenografts in ESCC\",\n      \"pmids\": [\"41787560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether hnRNP K/PTBP1 and UPF1 compete directly is not shown\", \"Population frequency/clinical relevance of alleles not addressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a physiological requirement for CAPZA1 in flagellar architecture and redox balance, broadening its role beyond cancer cytoskeletal regulation.\",\n      \"evidence\": \"CRISPR-Cas9 KO in mouse spermatids and AAV in vivo delivery with TEM, CASA, and thiol/disulfide biochemistry\",\n      \"pmids\": [\"41858859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CAPZA1 to p300/CBP and SLC7A11 not defined\", \"Whether the phenotype reflects capping or non-capping functions unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAPZA1's multiple regulatory inputs (PIP2, FAM21C, UBR5, NDP52, SNP-dependent RNA control) are coordinated, and the structural basis of its barbed-end capping and partner interactions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CAPZA1 capping or its inhibitor interfaces in the corpus\", \"Hierarchy among proteasomal, autophagic, transcriptional, and RNA-stability control not integrated\", \"CAPZB partner relationship in the heterodimer not directly addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"CapZ (F-actin capping protein)\"],\n    \"partners\": [\"LRP1\", \"UBR5\", \"FAM21C\", \"NDP52\", \"hnRNP K\", \"PTBP1\", \"UPF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}