{"gene":"BPIFB1","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2013,"finding":"BPIFB1 (LPLUNC1) suppresses NPC cell proliferation by inhibiting the JAK2/STAT3 signaling pathway downstream of IL-6, reducing cyclin D1 and Bcl-2 expression and increasing Bax and p21 expression.","method":"LPLUNC1 overexpression in NPC cells with western blotting for pathway components; in vivo tumor implantation model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — clean overexpression with defined pathway readouts, in vitro and in vivo, replicated across multiple assays","pmids":["23708661"],"is_preprint":false},{"year":2013,"finding":"BPIFB1 (LPLUNC1) inhibits NPC cell growth by downregulating the MAPK signaling pathway (suppressing MEK1, phospho-ERK1/2, phospho-JNK1/2, c-Myc, c-Jun, and AP-1 transcriptional activity) and the cyclin D1/E2F pathway (reducing cyclin D1, CDK4, and phospho-Rb).","method":"Stable LPLUNC1 overexpression in NPC cells, cDNA microarray, western blotting, cell cycle analysis, in vivo tumor formation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (microarray, western blot, in vivo) with defined pathway placement","pmids":["23650533"],"is_preprint":false},{"year":2017,"finding":"BPIFB1 inhibits NPC cell migration and invasion by interacting with vitronectin (VTN) and vimentin (VIM); BPIFB1 reduces VTN expression and disrupts the VTN-integrin αV complex, thereby inhibiting the FAK/Src/ERK signaling pathway and suppressing epithelial-mesenchymal transition.","method":"Co-immunoprecipitation coupled with mass spectrometry to identify binding partners, western blotting, immunofluorescence, immunohistochemistry, in vitro migration/invasion assays, in vivo lung metastasis model","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP/MS to identify interactors, multiple functional assays in vitro and in vivo, defined pathway readout","pmids":["29123267"],"is_preprint":false},{"year":2018,"finding":"BPIFB1 sensitizes NPC cells to ionizing radiation by inhibiting VTN-mediated radioresistance; VTN promotes G2/M arrest, DNA repair, and activation of ATM-Chk2 and ATR-Chk1 pathways, while BPIFB1 counteracts these effects.","method":"Colony formation and cell survival assays after ionizing radiation, knockdown/overexpression of BPIFB1 and VTN, western blotting for DNA damage pathway components","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — defined mechanistic pathway via VTN interaction, but single lab","pmids":["29568064"],"is_preprint":false},{"year":2019,"finding":"BPIFB1 (LPLUNC1) stabilizes prohibitin 1 (PHB1) by competitively blocking the interaction between PHB1 and the E3 ubiquitin ligase TRIM21, thereby preventing TRIM21-mediated ubiquitination and degradation of PHB1; stabilized PHB1 inhibits NF-κB activity to suppress NPC tumor growth.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, western blotting, NF-κB reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — ubiquitination assay plus Co-IP competitive binding with multiple molecular endpoints","pmids":["30886235"],"is_preprint":false},{"year":2011,"finding":"BPIFB1 (LPLUNC1) attenuates proinflammatory innate immune responses to LPS in a TLR4-dependent manner (but not via TLR2), and is expressed in Paneth cells of the intestine during V. cholerae infection.","method":"In vitro LPS stimulation assays with BPIFB1 treatment, TLR4/TLR2 pathway assessment, immunostaining of duodenal biopsies","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2-3 — TLR4-dependent mechanism established in vitro with dose-dependent responses and receptor specificity shown","pmids":["21900486"],"is_preprint":false},{"year":2013,"finding":"BPIFB1 decreases LPS-induced inflammatory responses in macrophages by reducing expression of CD14, TLR4, and MyD88 and inhibiting downstream signaling via TRAF6 and NF-κB; ERK1/2, p38, and Akt1 phosphorylation are also inhibited by BPIFB1.","method":"ELISA, western blotting, siRNA knockdown of MyD88/TRAF6/NF-κB, kinase inhibitor experiments in RAW264.7 cells treated with BPIFB1 and LPS","journal":"Xi bao yu fen zi mian yi xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2-3 — siRNA and inhibitor validation of pathway components in one lab","pmids":["23746244"],"is_preprint":false},{"year":2010,"finding":"BPIFB1 (LPLUNC1) is a secreted glycoprotein produced by goblet cells and submucosal/minor glands of the respiratory and upper aerodigestive tracts; it is present in bronchoalveolar lavage fluid as two glycosylated isoforms.","method":"Affinity-purified antibody immunolocalization in human tissues, western blotting of BAL and cell culture secretions, primary human airway epithelial cell cultures","journal":"Histochemistry and cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct protein localization by immunohistochemistry and western blot, glycosylation characterization in multiple tissue types","pmids":["20237794"],"is_preprint":false},{"year":2021,"finding":"BPIFB1 inhibits vasculogenic mimicry in NPC by decreasing GLUT1 transcription via downregulation of the JNK/AP-1 signaling pathway; reduced GLUT1 lowers glycolysis, decreasing acetyl-CoA and thus H3K27 acetylation at promoters of vasculogenic mimicry genes (VEGFA, VE-cadherin, MMP2).","method":"BPIFB1 overexpression/knockdown, luciferase reporter assays, ChIP for H3K27ac, western blotting, metabolic assays in NPC cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP and reporter assays provide direct mechanistic evidence linking BPIFB1 to histone acetylation via metabolic reprogramming","pmids":["34725462"],"is_preprint":false},{"year":2022,"finding":"BPIFB1 (LPLUNC1) reduces glycolysis in NPC cells through the PHB1-p53/c-Myc axis; BPIFB1 overexpression promotes phosphorylated PHB1 nuclear translocation via 14-3-3σ, increases p53 expression, and decreases c-Myc expression, leading to decreased glycolysis and increased oxidative phosphorylation.","method":"BPIFB1 and PHB1 overexpression, western blotting, subcellular fractionation, glycolysis and OXPHOS assays in NPC cells","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — defined mechanistic axis with multiple molecular endpoints from single lab","pmids":["36382614"],"is_preprint":false},{"year":2017,"finding":"Bpifb1 is a trans regulator of airway MUC5B protein levels; Bpifb1 knockout mice exhibit higher MUC5B expression, and Bpifb1 mRNA and protein are upregulated in parallel to MUC5B after allergen challenge.","method":"Quantitative trait locus (QTL) mapping in Collaborative Cross mice, Bpifb1 knockout mouse model, allergen challenge (house dust mite), protein and mRNA expression analysis","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via KO mice with defined phenotype (elevated MUC5B), replicated with allergen model","pmids":["28851744"],"is_preprint":false},{"year":2023,"finding":"BPIFB1 is required for effective mucociliary clearance in vivo; loss of BPIFB1 alters biophysical and biochemical properties of mucus without affecting ion transport or ciliary beat frequency, and BPIFB1 colocalizes with MUC5B in secretory granules and the secreted mucus protein network.","method":"Bpifb1 knockout mice, in vivo MCC measurement, in vitro airway epithelial cultures, immunofluorescence colocalization, mucus biophysical characterization","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined functional phenotype and direct colocalization, multiple orthogonal methods","pmids":["37847709"],"is_preprint":false},{"year":2022,"finding":"BPIFB1 acts as a downstream effector of circadian protein PER2 in alveolar type 2 (ATII) cells; light-elicited amplitude enhancement of ATII-specific PER2 upregulates BPIFB1, which mediates lung protection during bacterial (P. aeruginosa) acute lung injury.","method":"Cell-type-specific Per2 knockout mice (ATII, endothelial, myeloid), intense light therapy protocol, genome-wide mRNA array, nobiletin (PER2 enhancer) treatment, P. aeruginosa ALI model","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via cell-type-specific KO with survival phenotype; BPIFB1 identified as downstream target by array but direct mechanism between PER2 and BPIFB1 not fully defined","pmids":["35272486"],"is_preprint":false},{"year":2024,"finding":"BPIFB1 suppresses PD-L1 expression in NPC cells by repressing STAT1 transcription; BPIFB1 overexpression inhibits CD8+ T-cell apoptosis and enhances CD8+ T-cell activity. EBV-encoded miR-BART4 directly targets and inhibits BPIFB1, placing BPIFB1 in an EBV-miR-BART4/BPIFB1/STAT1/PD-L1 immune escape pathway.","method":"Luciferase reporter assay, ChIP, flow cytometry for CD8+ T cells, western blotting, qRT-PCR, overexpression in NPC cells","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase reporter provide direct mechanistic evidence; single lab","pmids":["38467887"],"is_preprint":false},{"year":2013,"finding":"Autoantibodies to BPIFB1 are associated with interstitial lung disease (ILD) in APS1 patients (100% of APS1-ILD subjects) and in non-APS1 ILD; thymic tolerance defects (Aire deficiency) drive autoantibody production targeting lung-specific BPIFB1, and immunoreactivity against BPIFB1 independent of Aire also leads to ILD.","method":"Autoantibody screening in APS1 cohorts, Aire−/− mouse model, immunization experiments, clinical cohort studies","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — causal role of anti-BPIFB1 autoimmunity demonstrated in animal model with Aire−/− mice and immunization; mechanism of BPIFB1 protein function not directly tested","pmids":["24107778"],"is_preprint":false},{"year":2023,"finding":"BPIFB1 promotes metastasis of hormone receptor-positive breast cancer by stimulating M2-like polarization of macrophages, as demonstrated in tumor cell/THP-1 macrophage co-culture experiments and animal models.","method":"BC tumor cells/THP-1 co-culture system, qPCR for M2 markers, Transwell migration/invasion assay, animal experiments","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 — functional phenotype shown but molecular mechanism linking BPIFB1 to macrophage polarization not defined","pmids":["37702269"],"is_preprint":false}],"current_model":"BPIFB1 is a secreted glycoprotein produced by goblet cells and glands of the upper airway that functions as an innate immune modulator and tumor suppressor: it attenuates LPS/TLR4-driven NF-κB and MAPK inflammatory signaling, stabilizes PHB1 by blocking TRIM21-mediated ubiquitination, suppresses JAK2/STAT3 and FAK/Src/ERK pathways by interacting with VTN and VIM, regulates airway MUC5B levels and mucociliary clearance as an integral component of the mucus protein network, and inhibits tumor glycolysis and vasculogenic mimicry via the PHB1-p53/c-Myc axis and JNK/AP-1/GLUT1/H3K27ac cascade."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing where BPIFB1 protein is expressed and secreted resolved the question of which airway cell types produce this innate defense molecule and in what form it reaches the airway surface.","evidence":"Immunohistochemistry with affinity-purified antibodies and western blotting of BAL fluid and primary airway epithelial cultures identified goblet cells and submucosal glands as sources and two glycosylated secreted isoforms","pmids":["20237794"],"confidence":"High","gaps":["Post-translational modification sites not mapped","Receptor or binding partner on target cells not identified","Regulation of secretion not characterized"]},{"year":2011,"claim":"Demonstrating that BPIFB1 attenuates LPS-induced inflammation via TLR4 but not TLR2 established its receptor specificity as an innate immune modulator, answering how a secreted BPIF family member interfaces with pattern-recognition signaling.","evidence":"In vitro LPS stimulation assays with BPIFB1 treatment showing TLR4-dependent attenuation; immunostaining of duodenal biopsies during V. cholerae infection","pmids":["21900486"],"confidence":"Medium","gaps":["Direct binding to LPS or TLR4 not demonstrated","Mechanism of CD14/TLR4 downregulation unknown","In vivo functional relevance in airway infection not tested at this stage"]},{"year":2013,"claim":"Multiple studies established BPIFB1 as a tumor suppressor in nasopharyngeal carcinoma by showing it inhibits two major oncogenic pathways—JAK2/STAT3 and MAPK/ERK—and their downstream cell cycle effectors, resolving the question of whether this innate immune protein has anti-proliferative activity.","evidence":"Stable overexpression in NPC cell lines with western blotting, microarray, cell cycle analysis, and in vivo tumor implantation models","pmids":["23708661","23650533"],"confidence":"High","gaps":["Direct molecular target mediating pathway suppression not identified","Relevance beyond NPC not established","Whether endogenous BPIFB1 levels are tumor-suppressive in patients unclear"]},{"year":2013,"claim":"Dissection of BPIFB1's anti-inflammatory mechanism in macrophages revealed it reduces CD14, TLR4, MyD88, TRAF6, and NF-κB signaling along with ERK1/2, p38, and Akt phosphorylation, providing a detailed pathway map of its LPS-dampening activity.","evidence":"siRNA knockdown of pathway components and kinase inhibitors in RAW264.7 macrophages treated with BPIFB1 and LPS","pmids":["23746244"],"confidence":"Medium","gaps":["Whether BPIFB1 acts extracellularly (e.g., sequestering LPS) or intracellularly not resolved","Single laboratory finding","Direct physical interaction with any pathway component not shown"]},{"year":2013,"claim":"Discovery that anti-BPIFB1 autoantibodies are present in 100% of APS1-ILD patients and that Aire deficiency drives autoimmunity against this lung-restricted antigen established BPIFB1 as a clinically relevant autoantigen in interstitial lung disease.","evidence":"Autoantibody screening in APS1 cohorts, Aire−/− mouse model, immunization experiments inducing ILD","pmids":["24107778"],"confidence":"Medium","gaps":["Whether autoantibodies are pathogenic or merely biomarkers not fully resolved in humans","Mechanism by which loss of BPIFB1 function causes ILD pathology unknown","Prevalence in non-APS1 ILD incompletely defined"]},{"year":2017,"claim":"Identification of VTN and VIM as direct BPIFB1 binding partners answered the long-standing question of which molecular interactors mediate BPIFB1's anti-tumor effects, linking it to FAK/Src/ERK suppression and EMT inhibition.","evidence":"Co-immunoprecipitation coupled with mass spectrometry, immunofluorescence colocalization, in vitro migration/invasion assays, and in vivo lung metastasis model","pmids":["29123267"],"confidence":"High","gaps":["Binding domains on BPIFB1 for VTN/VIM not mapped","Whether this interaction occurs in normal airway physiology unknown","Structural basis of competitive disruption of VTN–integrin αV not defined"]},{"year":2017,"claim":"Genetic evidence from Bpifb1 knockout mice established that BPIFB1 is a trans regulator of MUC5B protein levels, connecting a BPIF family member to mucin homeostasis for the first time.","evidence":"QTL mapping in Collaborative Cross mice, Bpifb1 KO model showing elevated MUC5B, allergen challenge experiments","pmids":["28851744"],"confidence":"High","gaps":["Mechanism by which BPIFB1 regulates MUC5B expression or stability not defined","Whether the effect is transcriptional or post-translational unclear","Human genetic evidence for this regulatory axis lacking"]},{"year":2019,"claim":"Discovery that BPIFB1 stabilizes PHB1 by competitively blocking TRIM21-mediated ubiquitination provided a direct biochemical mechanism for tumor suppression, resolving how BPIFB1 controls NF-κB activity at the post-translational level.","evidence":"Co-immunoprecipitation, in vivo ubiquitination assays, competitive binding experiments, NF-κB reporter assays in NPC cells","pmids":["30886235"],"confidence":"High","gaps":["Binding interface between BPIFB1, PHB1, and TRIM21 not structurally resolved","Physiological relevance in non-tumor airway cells not tested","Whether other E3 ligases also regulate PHB1 in this context unknown"]},{"year":2021,"claim":"Linking BPIFB1 to vasculogenic mimicry via JNK/AP-1-driven GLUT1 transcription and H3K27ac-mediated epigenetic reprogramming revealed a metabolic–epigenetic tumor suppressive axis, answering how BPIFB1 controls tumor angiogenesis.","evidence":"BPIFB1 overexpression/knockdown, ChIP for H3K27ac at VEGFA/VE-cadherin/MMP2 promoters, luciferase reporters, metabolic flux assays in NPC cells","pmids":["34725462"],"confidence":"High","gaps":["Whether acetyl-CoA reduction is sufficient to explain H3K27ac changes not independently confirmed","Role of other histone marks not examined","In vivo validation of vasculogenic mimicry suppression limited"]},{"year":2022,"claim":"Positioning BPIFB1 as a circadian-regulated downstream effector of PER2 in alveolar type 2 cells expanded its functional context beyond innate defense to circadian lung protection during bacterial injury.","evidence":"Cell-type-specific Per2 KO mice, intense light therapy, genome-wide mRNA array, nobiletin treatment, P. aeruginosa acute lung injury model","pmids":["35272486"],"confidence":"Medium","gaps":["Direct transcriptional regulation of BPIFB1 by PER2 not demonstrated (e.g., no PER2 ChIP at BPIFB1 locus)","Mechanism by which BPIFB1 mediates lung protection in this model undefined","Single study without independent replication"]},{"year":2022,"claim":"Demonstrating that BPIFB1 reprograms NPC metabolism from glycolysis to oxidative phosphorylation through the PHB1-p53/c-Myc axis provided a unified metabolic mechanism linking the previously identified PHB1-stabilizing activity to tumor suppression.","evidence":"BPIFB1 and PHB1 overexpression, subcellular fractionation showing phospho-PHB1 nuclear translocation via 14-3-3σ, glycolysis/OXPHOS assays","pmids":["36382614"],"confidence":"Medium","gaps":["Direct kinase phosphorylating PHB1 in this context not identified","Whether metabolic switch occurs in non-NPC tumor types untested","Single laboratory study"]},{"year":2023,"claim":"Knockout studies proved BPIFB1 is required for effective mucociliary clearance and colocalizes with MUC5B in secretory granules and the mucus gel, establishing its structural role in airway mucus beyond regulation of MUC5B levels.","evidence":"Bpifb1 KO mice with in vivo mucociliary clearance measurement, in vitro airway cultures, immunofluorescence colocalization, mucus biophysical assays","pmids":["37847709"],"confidence":"High","gaps":["Molecular basis of how BPIFB1 alters mucus biophysical properties not defined","Whether BPIFB1 directly cross-links mucin polymers or acts indirectly unknown","Human airway relevance of KO phenotype not confirmed"]},{"year":2024,"claim":"Discovery that BPIFB1 suppresses PD-L1 via STAT1 repression and is targeted by EBV-encoded miR-BART4 linked its tumor-suppressive function to immune evasion in EBV-driven NPC, answering how EBV neutralizes BPIFB1.","evidence":"Luciferase reporter assays, ChIP, flow cytometry for CD8+ T-cell apoptosis and activation, overexpression in NPC cells","pmids":["38467887"],"confidence":"Medium","gaps":["In vivo immune evasion phenotype driven by miR-BART4/BPIFB1 axis not demonstrated","Direct binding of BPIFB1 to STAT1 promoter elements not shown","Whether anti-PD-L1 axis operates outside EBV-positive NPC unclear"]},{"year":null,"claim":"The molecular mechanism by which BPIFB1 integrates into the mucus gel to regulate its biophysical properties, the structural basis of its interactions with PHB1/VTN/VIM, and whether its tumor-suppressive functions have physiological relevance beyond NPC remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of BPIFB1 or its complexes","Direct LPS-binding activity not demonstrated biochemically","Whether BPIFB1 tumor-suppressive pathways operate in normal airway epithelium unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4,8,9,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,6,13,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2,8,9,13]}],"complexes":[],"partners":["VTN","VIM","PHB1","TRIM21"],"other_free_text":[]},"mechanistic_narrative":"BPIFB1 is a secreted glycoprotein of the upper airway innate immune system that functions as a modulator of inflammatory signaling, mucus homeostasis, and tumor suppression. Produced by goblet cells and submucosal glands, BPIFB1 is secreted into airway surface liquid where it integrates into the MUC5B-containing mucus network and is required for effective mucociliary clearance; loss of BPIFB1 elevates MUC5B levels and alters mucus biophysical properties without affecting ion transport or ciliary beat frequency [PMID:20237794, PMID:28851744, PMID:37847709]. BPIFB1 attenuates LPS-induced inflammation through TLR4-dependent suppression of MyD88/TRAF6/NF-κB and MAPK signaling, and in nasopharyngeal carcinoma it acts as a tumor suppressor by inhibiting JAK2/STAT3, FAK/Src/ERK, and JNK/AP-1 pathways through interactions with VTN, VIM, and PHB1—stabilizing PHB1 by competitively blocking TRIM21-mediated ubiquitination—and by reprogramming tumor metabolism via the PHB1-p53/c-Myc glycolytic axis and GLUT1-dependent H3K27 acetylation of vasculogenic mimicry genes [PMID:21900486, PMID:23708661, PMID:29123267, PMID:30886235, PMID:34725462, PMID:36382614]. Autoantibodies against BPIFB1 are associated with interstitial lung disease in autoimmune polyendocrinopathy syndrome type 1 (APS1), where Aire deficiency drives loss of thymic tolerance to this lung-restricted antigen [PMID:24107778]."},"prefetch_data":{"uniprot":{"accession":"Q8TDL5","full_name":"BPI fold-containing family B member 1","aliases":["Long palate, lung and nasal epithelium carcinoma-associated protein 1","von Ebner minor salivary gland protein","VEMSGP"],"length_aa":484,"mass_kda":52.4,"function":"May play a role in innate immunity in mouth, nose and lungs. Binds bacterial lipopolysaccharide (LPS) and modulates the cellular responses to LPS","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8TDL5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BPIFB1","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/BPIFB1","total_profiled":1310},"omim":[{"mim_id":"621168","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY B, MEMBER 1; BPIFB1","url":"https://www.omim.org/entry/621168"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":532.0},{"tissue":"salivary gland","ntpm":255.4},{"tissue":"stomach 1","ntpm":483.0}],"url":"https://www.proteinatlas.org/search/BPIFB1"},"hgnc":{"alias_symbol":["dJ1187J4.1","MGC14597","bA49G10.6","LPLUNC1","VEMSGP"],"prev_symbol":["C20orf114"]},"alphafold":{"accession":"Q8TDL5","domains":[{"cath_id":"3.15.10.10","chopping":"34-219","consensus_level":"medium","plddt":89.4567,"start":34,"end":219},{"cath_id":"3.15.20.10","chopping":"298-444","consensus_level":"medium","plddt":94.5129,"start":298,"end":444}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDL5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDL5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDL5-F1-predicted_aligned_error_v6.png","plddt_mean":87.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BPIFB1","jax_strain_url":"https://www.jax.org/strain/search?query=BPIFB1"},"sequence":{"accession":"Q8TDL5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDL5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDL5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDL5"}},"corpus_meta":[{"pmid":"23708661","id":"PMC_23708661","title":"LPLUNC1 suppresses IL-6-induced nasopharyngeal carcinoma cell proliferation via inhibiting the Stat3 activation.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23708661","citation_count":105,"is_preprint":false},{"pmid":"29123267","id":"PMC_29123267","title":"BPIFB1 (LPLUNC1) inhibits migration and invasion of nasopharyngeal carcinoma by interacting with VTN and VIM.","date":"2017","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29123267","citation_count":79,"is_preprint":false},{"pmid":"24107778","id":"PMC_24107778","title":"BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease.","date":"2013","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24107778","citation_count":78,"is_preprint":false},{"pmid":"29568064","id":"PMC_29568064","title":"BPIFB1 (LPLUNC1) inhibits radioresistance in nasopharyngeal carcinoma by inhibiting VTN expression.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29568064","citation_count":67,"is_preprint":false},{"pmid":"23650533","id":"PMC_23650533","title":"LPLUNC1 inhibits nasopharyngeal carcinoma cell growth via down-regulation of the MAP kinase and cyclin D1/E2F pathways.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23650533","citation_count":49,"is_preprint":false},{"pmid":"30886235","id":"PMC_30886235","title":"LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30886235","citation_count":46,"is_preprint":false},{"pmid":"21900486","id":"PMC_21900486","title":"LPLUNC1 modulates innate immune responses to Vibrio cholerae.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21900486","citation_count":43,"is_preprint":false},{"pmid":"20237794","id":"PMC_20237794","title":"Human LPLUNC1 is a secreted product of goblet cells and minor glands of the respiratory and upper aerodigestive tracts.","date":"2010","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20237794","citation_count":41,"is_preprint":false},{"pmid":"32566588","id":"PMC_32566588","title":"Molecular biology of BPIFB1 and its advances in disease.","date":"2020","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32566588","citation_count":35,"is_preprint":false},{"pmid":"22767025","id":"PMC_22767025","title":"BPIFB1 (LPLUNC1) is upregulated in cystic fibrosis lung disease.","date":"2012","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22767025","citation_count":30,"is_preprint":false},{"pmid":"25979078","id":"PMC_25979078","title":"Elevated sputum BPIFB1 levels in smokers with chronic obstructive pulmonary disease: a longitudinal study.","date":"2015","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25979078","citation_count":29,"is_preprint":false},{"pmid":"29296079","id":"PMC_29296079","title":"Association of innate defense proteins BPIFA1 and BPIFB1 with disease severity in COPD.","date":"2017","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/29296079","citation_count":29,"is_preprint":false},{"pmid":"22986921","id":"PMC_22986921","title":"Differential localisation of BPIFA1 (SPLUNC1) and BPIFB1 (LPLUNC1) in the nasal and oral cavities of mice.","date":"2012","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/22986921","citation_count":29,"is_preprint":false},{"pmid":"25574903","id":"PMC_25574903","title":"Polymorphisms associated with expression of BPIFA1/BPIFB1 and lung disease severity in cystic fibrosis.","date":"2015","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25574903","citation_count":28,"is_preprint":false},{"pmid":"34725462","id":"PMC_34725462","title":"BPIFB1 inhibits vasculogenic mimicry via downregulation of GLUT1-mediated H3K27 acetylation in nasopharyngeal carcinoma.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34725462","citation_count":21,"is_preprint":false},{"pmid":"28851744","id":"PMC_28851744","title":"Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1.","date":"2017","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28851744","citation_count":19,"is_preprint":false},{"pmid":"37702269","id":"PMC_37702269","title":"BPIFB1 promotes metastasis of hormone receptor-positive breast cancer via inducing macrophage M2-like polarization.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37702269","citation_count":13,"is_preprint":false},{"pmid":"35272486","id":"PMC_35272486","title":"Intense light-elicited alveolar type 2-specific circadian PER2 protects from bacterial lung injury via BPIFB1.","date":"2022","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35272486","citation_count":11,"is_preprint":false},{"pmid":"36382614","id":"PMC_36382614","title":"LPLUNC1 reduces glycolysis in nasopharyngeal carcinoma cells through the PHB1-p53/c-Myc axis.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36382614","citation_count":9,"is_preprint":false},{"pmid":"31933752","id":"PMC_31933752","title":"Overexpression of BPIFB1 promotes apoptosis and inhibits proliferation via the MEK/ERK signal pathway in nasopharyngeal carcinoma.","date":"2019","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31933752","citation_count":8,"is_preprint":false},{"pmid":"37847709","id":"PMC_37847709","title":"BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance.","date":"2023","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37847709","citation_count":7,"is_preprint":false},{"pmid":"26769076","id":"PMC_26769076","title":"Upregulation of Bpifb1 expression in the parotid glands of non-obese diabetic mice.","date":"2015","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26769076","citation_count":4,"is_preprint":false},{"pmid":"38467887","id":"PMC_38467887","title":"BPIFB1, Serving as a Downstream Effector of EBV-miR-BART4, Blocks Immune Escape of Nasopharyngeal Carcinoma via Inhibiting PD-L1 Expression.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38467887","citation_count":3,"is_preprint":false},{"pmid":"39552876","id":"PMC_39552876","title":"CLCA1 and BPIFB1 are potential novel biomarkers for asthma: an iTRAQ analysis.","date":"2024","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/39552876","citation_count":2,"is_preprint":false},{"pmid":"28748269","id":"PMC_28748269","title":"Presence of BPIFB1 in saliva from non-obese diabetic mice.","date":"2017","source":"Odontology","url":"https://pubmed.ncbi.nlm.nih.gov/28748269","citation_count":1,"is_preprint":false},{"pmid":"23746244","id":"PMC_23746244","title":"[Role of BPIFB1 in regulating inflammatory response of RAW264.7 cells infected by P.aeruginosa].","date":"2013","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23746244","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14768,"output_tokens":4019,"usd":0.052295},"stage2":{"model":"claude-opus-4-6","input_tokens":7472,"output_tokens":3758,"usd":0.196965},"total_usd":0.24926,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"BPIFB1 (LPLUNC1) suppresses NPC cell proliferation by inhibiting the JAK2/STAT3 signaling pathway downstream of IL-6, reducing cyclin D1 and Bcl-2 expression and increasing Bax and p21 expression.\",\n      \"method\": \"LPLUNC1 overexpression in NPC cells with western blotting for pathway components; in vivo tumor implantation model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression with defined pathway readouts, in vitro and in vivo, replicated across multiple assays\",\n      \"pmids\": [\"23708661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BPIFB1 (LPLUNC1) inhibits NPC cell growth by downregulating the MAPK signaling pathway (suppressing MEK1, phospho-ERK1/2, phospho-JNK1/2, c-Myc, c-Jun, and AP-1 transcriptional activity) and the cyclin D1/E2F pathway (reducing cyclin D1, CDK4, and phospho-Rb).\",\n      \"method\": \"Stable LPLUNC1 overexpression in NPC cells, cDNA microarray, western blotting, cell cycle analysis, in vivo tumor formation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (microarray, western blot, in vivo) with defined pathway placement\",\n      \"pmids\": [\"23650533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BPIFB1 inhibits NPC cell migration and invasion by interacting with vitronectin (VTN) and vimentin (VIM); BPIFB1 reduces VTN expression and disrupts the VTN-integrin αV complex, thereby inhibiting the FAK/Src/ERK signaling pathway and suppressing epithelial-mesenchymal transition.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry to identify binding partners, western blotting, immunofluorescence, immunohistochemistry, in vitro migration/invasion assays, in vivo lung metastasis model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP/MS to identify interactors, multiple functional assays in vitro and in vivo, defined pathway readout\",\n      \"pmids\": [\"29123267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BPIFB1 sensitizes NPC cells to ionizing radiation by inhibiting VTN-mediated radioresistance; VTN promotes G2/M arrest, DNA repair, and activation of ATM-Chk2 and ATR-Chk1 pathways, while BPIFB1 counteracts these effects.\",\n      \"method\": \"Colony formation and cell survival assays after ionizing radiation, knockdown/overexpression of BPIFB1 and VTN, western blotting for DNA damage pathway components\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined mechanistic pathway via VTN interaction, but single lab\",\n      \"pmids\": [\"29568064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BPIFB1 (LPLUNC1) stabilizes prohibitin 1 (PHB1) by competitively blocking the interaction between PHB1 and the E3 ubiquitin ligase TRIM21, thereby preventing TRIM21-mediated ubiquitination and degradation of PHB1; stabilized PHB1 inhibits NF-κB activity to suppress NPC tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, western blotting, NF-κB reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitination assay plus Co-IP competitive binding with multiple molecular endpoints\",\n      \"pmids\": [\"30886235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BPIFB1 (LPLUNC1) attenuates proinflammatory innate immune responses to LPS in a TLR4-dependent manner (but not via TLR2), and is expressed in Paneth cells of the intestine during V. cholerae infection.\",\n      \"method\": \"In vitro LPS stimulation assays with BPIFB1 treatment, TLR4/TLR2 pathway assessment, immunostaining of duodenal biopsies\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — TLR4-dependent mechanism established in vitro with dose-dependent responses and receptor specificity shown\",\n      \"pmids\": [\"21900486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BPIFB1 decreases LPS-induced inflammatory responses in macrophages by reducing expression of CD14, TLR4, and MyD88 and inhibiting downstream signaling via TRAF6 and NF-κB; ERK1/2, p38, and Akt1 phosphorylation are also inhibited by BPIFB1.\",\n      \"method\": \"ELISA, western blotting, siRNA knockdown of MyD88/TRAF6/NF-κB, kinase inhibitor experiments in RAW264.7 cells treated with BPIFB1 and LPS\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — siRNA and inhibitor validation of pathway components in one lab\",\n      \"pmids\": [\"23746244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BPIFB1 (LPLUNC1) is a secreted glycoprotein produced by goblet cells and submucosal/minor glands of the respiratory and upper aerodigestive tracts; it is present in bronchoalveolar lavage fluid as two glycosylated isoforms.\",\n      \"method\": \"Affinity-purified antibody immunolocalization in human tissues, western blotting of BAL and cell culture secretions, primary human airway epithelial cell cultures\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization by immunohistochemistry and western blot, glycosylation characterization in multiple tissue types\",\n      \"pmids\": [\"20237794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BPIFB1 inhibits vasculogenic mimicry in NPC by decreasing GLUT1 transcription via downregulation of the JNK/AP-1 signaling pathway; reduced GLUT1 lowers glycolysis, decreasing acetyl-CoA and thus H3K27 acetylation at promoters of vasculogenic mimicry genes (VEGFA, VE-cadherin, MMP2).\",\n      \"method\": \"BPIFB1 overexpression/knockdown, luciferase reporter assays, ChIP for H3K27ac, western blotting, metabolic assays in NPC cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP and reporter assays provide direct mechanistic evidence linking BPIFB1 to histone acetylation via metabolic reprogramming\",\n      \"pmids\": [\"34725462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BPIFB1 (LPLUNC1) reduces glycolysis in NPC cells through the PHB1-p53/c-Myc axis; BPIFB1 overexpression promotes phosphorylated PHB1 nuclear translocation via 14-3-3σ, increases p53 expression, and decreases c-Myc expression, leading to decreased glycolysis and increased oxidative phosphorylation.\",\n      \"method\": \"BPIFB1 and PHB1 overexpression, western blotting, subcellular fractionation, glycolysis and OXPHOS assays in NPC cells\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined mechanistic axis with multiple molecular endpoints from single lab\",\n      \"pmids\": [\"36382614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Bpifb1 is a trans regulator of airway MUC5B protein levels; Bpifb1 knockout mice exhibit higher MUC5B expression, and Bpifb1 mRNA and protein are upregulated in parallel to MUC5B after allergen challenge.\",\n      \"method\": \"Quantitative trait locus (QTL) mapping in Collaborative Cross mice, Bpifb1 knockout mouse model, allergen challenge (house dust mite), protein and mRNA expression analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via KO mice with defined phenotype (elevated MUC5B), replicated with allergen model\",\n      \"pmids\": [\"28851744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BPIFB1 is required for effective mucociliary clearance in vivo; loss of BPIFB1 alters biophysical and biochemical properties of mucus without affecting ion transport or ciliary beat frequency, and BPIFB1 colocalizes with MUC5B in secretory granules and the secreted mucus protein network.\",\n      \"method\": \"Bpifb1 knockout mice, in vivo MCC measurement, in vitro airway epithelial cultures, immunofluorescence colocalization, mucus biophysical characterization\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined functional phenotype and direct colocalization, multiple orthogonal methods\",\n      \"pmids\": [\"37847709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BPIFB1 acts as a downstream effector of circadian protein PER2 in alveolar type 2 (ATII) cells; light-elicited amplitude enhancement of ATII-specific PER2 upregulates BPIFB1, which mediates lung protection during bacterial (P. aeruginosa) acute lung injury.\",\n      \"method\": \"Cell-type-specific Per2 knockout mice (ATII, endothelial, myeloid), intense light therapy protocol, genome-wide mRNA array, nobiletin (PER2 enhancer) treatment, P. aeruginosa ALI model\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via cell-type-specific KO with survival phenotype; BPIFB1 identified as downstream target by array but direct mechanism between PER2 and BPIFB1 not fully defined\",\n      \"pmids\": [\"35272486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BPIFB1 suppresses PD-L1 expression in NPC cells by repressing STAT1 transcription; BPIFB1 overexpression inhibits CD8+ T-cell apoptosis and enhances CD8+ T-cell activity. EBV-encoded miR-BART4 directly targets and inhibits BPIFB1, placing BPIFB1 in an EBV-miR-BART4/BPIFB1/STAT1/PD-L1 immune escape pathway.\",\n      \"method\": \"Luciferase reporter assay, ChIP, flow cytometry for CD8+ T cells, western blotting, qRT-PCR, overexpression in NPC cells\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase reporter provide direct mechanistic evidence; single lab\",\n      \"pmids\": [\"38467887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Autoantibodies to BPIFB1 are associated with interstitial lung disease (ILD) in APS1 patients (100% of APS1-ILD subjects) and in non-APS1 ILD; thymic tolerance defects (Aire deficiency) drive autoantibody production targeting lung-specific BPIFB1, and immunoreactivity against BPIFB1 independent of Aire also leads to ILD.\",\n      \"method\": \"Autoantibody screening in APS1 cohorts, Aire−/− mouse model, immunization experiments, clinical cohort studies\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — causal role of anti-BPIFB1 autoimmunity demonstrated in animal model with Aire−/− mice and immunization; mechanism of BPIFB1 protein function not directly tested\",\n      \"pmids\": [\"24107778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BPIFB1 promotes metastasis of hormone receptor-positive breast cancer by stimulating M2-like polarization of macrophages, as demonstrated in tumor cell/THP-1 macrophage co-culture experiments and animal models.\",\n      \"method\": \"BC tumor cells/THP-1 co-culture system, qPCR for M2 markers, Transwell migration/invasion assay, animal experiments\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional phenotype shown but molecular mechanism linking BPIFB1 to macrophage polarization not defined\",\n      \"pmids\": [\"37702269\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BPIFB1 is a secreted glycoprotein produced by goblet cells and glands of the upper airway that functions as an innate immune modulator and tumor suppressor: it attenuates LPS/TLR4-driven NF-κB and MAPK inflammatory signaling, stabilizes PHB1 by blocking TRIM21-mediated ubiquitination, suppresses JAK2/STAT3 and FAK/Src/ERK pathways by interacting with VTN and VIM, regulates airway MUC5B levels and mucociliary clearance as an integral component of the mucus protein network, and inhibits tumor glycolysis and vasculogenic mimicry via the PHB1-p53/c-Myc axis and JNK/AP-1/GLUT1/H3K27ac cascade.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BPIFB1 is a secreted glycoprotein of the upper airway innate immune system that functions as a modulator of inflammatory signaling, mucus homeostasis, and tumor suppression. Produced by goblet cells and submucosal glands, BPIFB1 is secreted into airway surface liquid where it integrates into the MUC5B-containing mucus network and is required for effective mucociliary clearance; loss of BPIFB1 elevates MUC5B levels and alters mucus biophysical properties without affecting ion transport or ciliary beat frequency [PMID:20237794, PMID:28851744, PMID:37847709]. BPIFB1 attenuates LPS-induced inflammation through TLR4-dependent suppression of MyD88/TRAF6/NF-κB and MAPK signaling, and in nasopharyngeal carcinoma it acts as a tumor suppressor by inhibiting JAK2/STAT3, FAK/Src/ERK, and JNK/AP-1 pathways through interactions with VTN, VIM, and PHB1—stabilizing PHB1 by competitively blocking TRIM21-mediated ubiquitination—and by reprogramming tumor metabolism via the PHB1-p53/c-Myc glycolytic axis and GLUT1-dependent H3K27 acetylation of vasculogenic mimicry genes [PMID:21900486, PMID:23708661, PMID:29123267, PMID:30886235, PMID:34725462, PMID:36382614]. Autoantibodies against BPIFB1 are associated with interstitial lung disease in autoimmune polyendocrinopathy syndrome type 1 (APS1), where Aire deficiency drives loss of thymic tolerance to this lung-restricted antigen [PMID:24107778].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing where BPIFB1 protein is expressed and secreted resolved the question of which airway cell types produce this innate defense molecule and in what form it reaches the airway surface.\",\n      \"evidence\": \"Immunohistochemistry with affinity-purified antibodies and western blotting of BAL fluid and primary airway epithelial cultures identified goblet cells and submucosal glands as sources and two glycosylated secreted isoforms\",\n      \"pmids\": [\"20237794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational modification sites not mapped\", \"Receptor or binding partner on target cells not identified\", \"Regulation of secretion not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that BPIFB1 attenuates LPS-induced inflammation via TLR4 but not TLR2 established its receptor specificity as an innate immune modulator, answering how a secreted BPIF family member interfaces with pattern-recognition signaling.\",\n      \"evidence\": \"In vitro LPS stimulation assays with BPIFB1 treatment showing TLR4-dependent attenuation; immunostaining of duodenal biopsies during V. cholerae infection\",\n      \"pmids\": [\"21900486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to LPS or TLR4 not demonstrated\", \"Mechanism of CD14/TLR4 downregulation unknown\", \"In vivo functional relevance in airway infection not tested at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Multiple studies established BPIFB1 as a tumor suppressor in nasopharyngeal carcinoma by showing it inhibits two major oncogenic pathways—JAK2/STAT3 and MAPK/ERK—and their downstream cell cycle effectors, resolving the question of whether this innate immune protein has anti-proliferative activity.\",\n      \"evidence\": \"Stable overexpression in NPC cell lines with western blotting, microarray, cell cycle analysis, and in vivo tumor implantation models\",\n      \"pmids\": [\"23708661\", \"23650533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target mediating pathway suppression not identified\", \"Relevance beyond NPC not established\", \"Whether endogenous BPIFB1 levels are tumor-suppressive in patients unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Dissection of BPIFB1's anti-inflammatory mechanism in macrophages revealed it reduces CD14, TLR4, MyD88, TRAF6, and NF-κB signaling along with ERK1/2, p38, and Akt phosphorylation, providing a detailed pathway map of its LPS-dampening activity.\",\n      \"evidence\": \"siRNA knockdown of pathway components and kinase inhibitors in RAW264.7 macrophages treated with BPIFB1 and LPS\",\n      \"pmids\": [\"23746244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BPIFB1 acts extracellularly (e.g., sequestering LPS) or intracellularly not resolved\", \"Single laboratory finding\", \"Direct physical interaction with any pathway component not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that anti-BPIFB1 autoantibodies are present in 100% of APS1-ILD patients and that Aire deficiency drives autoimmunity against this lung-restricted antigen established BPIFB1 as a clinically relevant autoantigen in interstitial lung disease.\",\n      \"evidence\": \"Autoantibody screening in APS1 cohorts, Aire−/− mouse model, immunization experiments inducing ILD\",\n      \"pmids\": [\"24107778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autoantibodies are pathogenic or merely biomarkers not fully resolved in humans\", \"Mechanism by which loss of BPIFB1 function causes ILD pathology unknown\", \"Prevalence in non-APS1 ILD incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of VTN and VIM as direct BPIFB1 binding partners answered the long-standing question of which molecular interactors mediate BPIFB1's anti-tumor effects, linking it to FAK/Src/ERK suppression and EMT inhibition.\",\n      \"evidence\": \"Co-immunoprecipitation coupled with mass spectrometry, immunofluorescence colocalization, in vitro migration/invasion assays, and in vivo lung metastasis model\",\n      \"pmids\": [\"29123267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding domains on BPIFB1 for VTN/VIM not mapped\", \"Whether this interaction occurs in normal airway physiology unknown\", \"Structural basis of competitive disruption of VTN–integrin αV not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic evidence from Bpifb1 knockout mice established that BPIFB1 is a trans regulator of MUC5B protein levels, connecting a BPIF family member to mucin homeostasis for the first time.\",\n      \"evidence\": \"QTL mapping in Collaborative Cross mice, Bpifb1 KO model showing elevated MUC5B, allergen challenge experiments\",\n      \"pmids\": [\"28851744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BPIFB1 regulates MUC5B expression or stability not defined\", \"Whether the effect is transcriptional or post-translational unclear\", \"Human genetic evidence for this regulatory axis lacking\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that BPIFB1 stabilizes PHB1 by competitively blocking TRIM21-mediated ubiquitination provided a direct biochemical mechanism for tumor suppression, resolving how BPIFB1 controls NF-κB activity at the post-translational level.\",\n      \"evidence\": \"Co-immunoprecipitation, in vivo ubiquitination assays, competitive binding experiments, NF-κB reporter assays in NPC cells\",\n      \"pmids\": [\"30886235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between BPIFB1, PHB1, and TRIM21 not structurally resolved\", \"Physiological relevance in non-tumor airway cells not tested\", \"Whether other E3 ligases also regulate PHB1 in this context unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking BPIFB1 to vasculogenic mimicry via JNK/AP-1-driven GLUT1 transcription and H3K27ac-mediated epigenetic reprogramming revealed a metabolic–epigenetic tumor suppressive axis, answering how BPIFB1 controls tumor angiogenesis.\",\n      \"evidence\": \"BPIFB1 overexpression/knockdown, ChIP for H3K27ac at VEGFA/VE-cadherin/MMP2 promoters, luciferase reporters, metabolic flux assays in NPC cells\",\n      \"pmids\": [\"34725462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether acetyl-CoA reduction is sufficient to explain H3K27ac changes not independently confirmed\", \"Role of other histone marks not examined\", \"In vivo validation of vasculogenic mimicry suppression limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioning BPIFB1 as a circadian-regulated downstream effector of PER2 in alveolar type 2 cells expanded its functional context beyond innate defense to circadian lung protection during bacterial injury.\",\n      \"evidence\": \"Cell-type-specific Per2 KO mice, intense light therapy, genome-wide mRNA array, nobiletin treatment, P. aeruginosa acute lung injury model\",\n      \"pmids\": [\"35272486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional regulation of BPIFB1 by PER2 not demonstrated (e.g., no PER2 ChIP at BPIFB1 locus)\", \"Mechanism by which BPIFB1 mediates lung protection in this model undefined\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that BPIFB1 reprograms NPC metabolism from glycolysis to oxidative phosphorylation through the PHB1-p53/c-Myc axis provided a unified metabolic mechanism linking the previously identified PHB1-stabilizing activity to tumor suppression.\",\n      \"evidence\": \"BPIFB1 and PHB1 overexpression, subcellular fractionation showing phospho-PHB1 nuclear translocation via 14-3-3σ, glycolysis/OXPHOS assays\",\n      \"pmids\": [\"36382614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase phosphorylating PHB1 in this context not identified\", \"Whether metabolic switch occurs in non-NPC tumor types untested\", \"Single laboratory study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Knockout studies proved BPIFB1 is required for effective mucociliary clearance and colocalizes with MUC5B in secretory granules and the mucus gel, establishing its structural role in airway mucus beyond regulation of MUC5B levels.\",\n      \"evidence\": \"Bpifb1 KO mice with in vivo mucociliary clearance measurement, in vitro airway cultures, immunofluorescence colocalization, mucus biophysical assays\",\n      \"pmids\": [\"37847709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of how BPIFB1 alters mucus biophysical properties not defined\", \"Whether BPIFB1 directly cross-links mucin polymers or acts indirectly unknown\", \"Human airway relevance of KO phenotype not confirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that BPIFB1 suppresses PD-L1 via STAT1 repression and is targeted by EBV-encoded miR-BART4 linked its tumor-suppressive function to immune evasion in EBV-driven NPC, answering how EBV neutralizes BPIFB1.\",\n      \"evidence\": \"Luciferase reporter assays, ChIP, flow cytometry for CD8+ T-cell apoptosis and activation, overexpression in NPC cells\",\n      \"pmids\": [\"38467887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo immune evasion phenotype driven by miR-BART4/BPIFB1 axis not demonstrated\", \"Direct binding of BPIFB1 to STAT1 promoter elements not shown\", \"Whether anti-PD-L1 axis operates outside EBV-positive NPC unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which BPIFB1 integrates into the mucus gel to regulate its biophysical properties, the structural basis of its interactions with PHB1/VTN/VIM, and whether its tumor-suppressive functions have physiological relevance beyond NPC remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of BPIFB1 or its complexes\", \"Direct LPS-binding activity not demonstrated biochemically\", \"Whether BPIFB1 tumor-suppressive pathways operate in normal airway epithelium unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4, 8, 9, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 6, 13, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2, 8, 9, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VTN\", \"VIM\", \"PHB1\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}\n```"}