{"gene":"CXCL14","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2004,"finding":"CXCL14 (BRAK) is a potent inhibitor of angiogenesis in vivo (rat corneal micropocket assay) and blocks endothelial cell chemotaxis at ~1 nM in vitro; human immature monocyte-derived dendritic cells (iDCs) bind CXCL14 with high affinity (Kd ~2 nM) and CXCL14 is chemotactic for iDCs at 1–10 nM.","method":"Rat corneal micropocket angiogenesis assay, in vitro endothelial cell chemotaxis assay, radioligand binding assay (iDC), transwell chemotaxis assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal in vitro and in vivo assays with quantitative binding data, single lab but rigorous","pmids":["15548693"],"is_preprint":false},{"year":2001,"finding":"CXCL14 (BRAK) is a selective chemoattractant for monocytes (not other blood leukocytes, monocyte-derived DCs, or macrophages); the chemotactic response is pertussis toxin-sensitive (Gi-coupled) and is enhanced by cAMP-elevating agents (PGE2, forskolin), indicating receptor coupling to a Gi protein.","method":"Transwell migration assay, Ca2+ mobilization assay with pertussis toxin inhibition, cell-type specificity panel","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional assays (migration + Ca2+ + PTX inhibition) demonstrating Gi-coupling and cell selectivity","pmids":["11561000"],"is_preprint":false},{"year":2005,"finding":"CXCL14 attracts dendritic cells in vitro and promotes their infiltration into tumors in vivo; CXCL14 upregulates DC maturation markers, enhances allogeneic T cell proliferation in MLR, and activates NF-κB in DCs.","method":"Transwell chemotaxis assay, chimeric animal model DC infiltration, DC maturation marker FACS, MLR, NF-κB reporter assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro chemotaxis, in vivo infiltration, signaling assays) in single lab","pmids":["15843547"],"is_preprint":false},{"year":2005,"finding":"Cutaneous CXCL14 produced constitutively in healthy epidermis attracts CD14+ DC precursors (from CD34+ progenitors or blood), directs their suprabasal positioning in epidermal equivalents, promotes their survival, and drives their differentiation into Langerhans cell-like cells with antigen-presentation function.","method":"Transwell migration assay, 3D human epidermal equivalent tissue model, FACS phenotyping, antigen presentation functional assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in tissue model and primary cells, consistent with parallel in vivo expression data","pmids":["16169505"],"is_preprint":false},{"year":2006,"finding":"CXCL14 stimulates migration of activated human NK cells and an NK leukemia cell line (NKL); this chemotactic effect is blocked by anti-CXCL14 antisera or pertussis toxin, indicating Gi-coupled receptor signaling, but CXCL14 does not affect NK cell proliferation or cytotoxic activity.","method":"Transwell chemotaxis assay, pertussis toxin inhibition, antisera neutralization","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional assays with PTX and antibody inhibition, single lab","pmids":["16863917"],"is_preprint":false},{"year":2006,"finding":"CXCL14 protein stability in cancer cell lines is regulated by the 26S proteasome via polyubiquitylation; a unique five-amino-acid insertion (41VSRYR45) not found in other CXC chemokines mediates proteasomal targeting, as shown by NMR structure determination and deletion/substitution mutagenesis.","method":"NMR structure determination, site-directed mutagenesis, proteasome inhibitor assays, ubiquitylation assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure combined with mutagenesis and functional degradation assays","pmids":["16987528"],"is_preprint":false},{"year":2008,"finding":"Loss of RhoBTB2 (DBC2) in primary human epithelial cells by RNA interference leads to downregulation of CXCL14 mRNA and protein secretion; reintroduction of RhoBTB2 into HNSCC cell lines lacking CXCL14 restores CXCL14 secretion, placing RhoBTB2 upstream of CXCL14 expression.","method":"RNAi knockdown, microarray expression analysis, RT-PCR, CXCL14 protein secretion measurement, RhoBTB2 re-expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by both loss- and gain-of-function in primary and cancer cells","pmids":["18762809"],"is_preprint":false},{"year":2009,"finding":"CXCL14 upregulation by reactive oxygen species via the AP-1 signaling pathway promotes breast cancer cell motility by elevating cytosolic Ca2+ through binding to the inositol 1,4,5-trisphosphate receptor (IP3R) on the endoplasmic reticulum; decoy-mediated abrogation of CXCL14 suppresses motility and invasion.","method":"Microarray, gene knockdown (decoy), Ca2+ imaging, AP-1 reporter assay, invasion assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods linking ROS→AP-1→CXCL14→IP3R→Ca2+ to motility, single lab","pmids":["19276362"],"is_preprint":false},{"year":2009,"finding":"CXCL14 inhibits trophoblast invasion and migration in vitro by suppressing MMP-2 and MMP-9 (gelatinase) activities, without affecting proliferation; CXCL14 binds specifically to trophoblast cells but not decidual cells at the maternal-fetal interface.","method":"Villous explant Matrigel invasion assay, transwell invasion/migration assay, gelatinase zymography, cell-specific binding assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with mechanism (gelatinase suppression) and cell-type-specific binding, single lab","pmids":["19833716"],"is_preprint":false},{"year":2010,"finding":"Loss of CXCL14 expression in prostate cancer cells is caused by CpG island hypermethylation of the CXCL14 promoter; demethylation with 5-aza-2'-deoxycytidine restores CXCL14 mRNA/protein and produces functionally active DC chemoattractant in conditioned medium, confirmed by affinity chromatography depletion.","method":"MSP, bisulfite sequencing, RT-PCR, Western blot, 5-aza-dC treatment, DC chemotaxis assay, affinity chromatography depletion","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — epigenetic mechanism established with methylation mapping, restoration, and functional output","pmids":["20460540"],"is_preprint":false},{"year":2010,"finding":"CXCL14 expression in HNSCC cells is suppressed by ROS (H2O2, hydroxyl radical) via the EGFR/MEK/ERK pathway, as shown by attenuation with NAC, EGFR inhibitors, and MEK inhibitors.","method":"ROS treatment, RT-PCR, pharmacological inhibitors (NAC, EGFR inhibitor, MEK inhibitor)","journal":"Free radical research","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological pathway dissection, single lab, convergent inhibitor data","pmids":["20815772"],"is_preprint":false},{"year":2011,"finding":"In the adult mouse dentate gyrus, CXCL14 is expressed by GABAergic interneurons and inhibits GABAergic synaptic transmission (both tonic and phasic GABA) to nestin-EGFP+ neural stem/progenitor cells; CXCL14 also raises [Ca2+]i in cultured neural stem cells, indicating they express the CXCL14 receptor. CXCL12 has the opposite effect on GABA transmission at the same synapses.","method":"Immunohistochemistry, electrophysiology (whole-cell patch clamp in brain slices), Ca2+ imaging in cultured neural stem cells","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — electrophysiology directly demonstrating synaptic modulation, calcium imaging, cell-type-specific expression, replicated with CXCL12 comparison","pmids":["21955359"],"is_preprint":false},{"year":2013,"finding":"CXCL14 specifically binds CXCR4 with high affinity and inhibits CXCL12-mediated chemotaxis of human leukemia-derived cell lines and CD34+ hematopoietic progenitor cells; the mechanism involves CXCR4 internalization/inactivation rather than direct competition with CXCL12 for the binding site.","method":"Radioligand binding assay, transwell chemotaxis assay, CXCR4 internalization assay, competitive binding","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — direct binding + functional inhibition + receptor internalization, clean mechanistic dissection","pmids":["23669361"],"is_preprint":false},{"year":2013,"finding":"The C-terminal 51–77 amino acid residues of CXCL14 are responsible for CXCR4 binding; a disulfide dimer peptide of CXCL14(51-77) binds CXCR4 with affinity comparable to full-length CXCL14, induces CXCR4 internalization, and inhibits CXCL12-mediated signaling.","method":"Binding assay, CXCR4 internalization assay, chemotaxis inhibition, peptide mutagenesis/truncation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional validation, single lab","pmids":["24161674"],"is_preprint":false},{"year":2013,"finding":"CXCL14 restores CXCL14 expression suppressed by HPV E7 through epigenetic (DNA hypermethylation) mechanisms; restoration of Cxcl14 in HPV+ mouse oropharyngeal cancer clears tumors in immunocompetent but not Rag1-deficient mice, and increases NK, CD4+, and CD8+ T cell infiltration into tumor-draining lymph nodes via chemotaxis.","method":"Gene expression analysis, promoter methylation assay, syngeneic mouse tumor model, Rag1 KO mice, transwell migration assay, flow cytometry","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — mechanistic linkage E7→DNA methylation→CXCL14 suppression, immunodeficient mouse epistasis, multiple immune cell readouts","pmids":["27143385"],"is_preprint":false},{"year":2014,"finding":"CXCL14 does not directly modulate CXCR4 signaling: in CXCR4-transfected HEK293 and Jurkat T cells, CXCL14 had no effect on CXCL12-induced CXCR4 phosphorylation, G protein-mediated Ca2+ mobilization, ERK1/2 phosphorylation, dynamic mass redistribution, or CXCR4 internalization, suggesting CXCL14–CXCL12 pathway interactions require an unidentified CXCL14 receptor.","method":"CXCR4-transfected cell assays, Ca2+ mobilization, dynamic mass redistribution, ERK phosphorylation, receptor internalization","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1–2 — comprehensive signaling assay panel in defined overexpression system, provides important mechanistic counter-evidence","pmids":["25451233"],"is_preprint":false},{"year":2015,"finding":"IRX1 overexpression driven by promoter hypomethylation upregulates CXCL14/NF-κB signaling to promote osteosarcoma cell migration, invasion, anoikis resistance, and lung metastasis in murine models; IRX1 modulation epistasis places IRX1 upstream of CXCL14 in this pathway.","method":"MeDIP microarray, overexpression/knockdown, migration/invasion assay, anoikis assay, murine metastasis model, NF-κB reporter","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — epistasis (IRX1→CXCL14→NF-κB) established with gain and loss of function in vitro and in vivo","pmids":["25822025"],"is_preprint":false},{"year":2015,"finding":"In CXCL14 transgenic mice, NK cell activity (depleted with anti-asialo-GM1 antibody) is required for CXCL14-mediated suppression of tumor growth and metastasis, demonstrating that CXCL14 acts through NK cells to suppress tumors in vivo.","method":"CXCL14 transgenic mice, NK cell depletion (anti-asialo-GM1 antibody), tumor xenograft and metastasis assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo epistasis with antibody-mediated NK cell depletion reversing CXCL14 antitumor effect","pmids":["25765541"],"is_preprint":false},{"year":2016,"finding":"HPV oncoprotein E7 induces CXCL14 promoter DNA hypermethylation, suppressing CXCL14 expression in HPV-positive head/neck and cervical cancers; this mechanism is E7-dependent and leads to reduced antitumor immune surveillance.","method":"Promoter methylation assay, E7 knockdown/overexpression, gene expression analysis, patient tissue specimens","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — E7 dependence established with gain/loss of function + methylation mapping, multiple tissue types","pmids":["27143385"],"is_preprint":false},{"year":2017,"finding":"CXCL14 acts as a positive allosteric modulator of CXCR4: it binds CXCR4 with high affinity and induces cell-surface CXCR4 redistribution, but does not itself trigger chemotaxis, Ca2+ mobilization, ERK1/2, or Rac1 signaling in CXCR4+ cells; it synergizes with subactive concentrations of CXCL12 to produce supramaximal chemotaxis and enhances HIV-1 infection by >3-fold.","method":"Chemotaxis assay, Ca2+ mobilization, ERK/Rac1 phosphorylation, CXCR4 redistribution (confocal), HIV-1 infection assay, competitive binding","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — multiple signaling and functional assays with primary human lymphoid cells and cell lines, mechanistic allosteric model supported by breadth of assays","pmids":["28360196"],"is_preprint":false},{"year":2017,"finding":"CXCL14 upregulates STAR expression and progesterone synthesis in human luteinized granulosa (hGL) cells via CREB phosphorylation downstream of p38 and JNK pathways; p38 and JNK inhibitors attenuate CXCL14-induced STAR expression and progesterone production.","method":"Primary hGL cell culture, CXCL14 treatment, Western blot (CREB phosphorylation, STAR), CREB inhibitor, p38/JNK inhibitors, progesterone ELISA","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological pathway dissection with multiple inhibitors in primary cells, single lab","pmids":["33129993"],"is_preprint":false},{"year":2017,"finding":"HIF-1α directly binds the CXCL14 promoter and drives hypoxia/ischemia-dependent CXCL14 expression in the brain; CXCL14 promotes adhesion, migration, and homing of circulating CD11c+ iDCs to ischemic tissue via upregulation of PrPC, PECAM-1, and MMPs; accumulated iDCs then secrete IL-2 to promote Treg differentiation and reduce infarct volume.","method":"ChIP assay (HIF-1α on CXCL14 promoter), flow cytometry, migration/adhesion assays, CXCL14 depletion/supplementation in stroke mouse model, Treg differentiation assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional in vivo rescue experiments, single lab","pmids":["28382159"],"is_preprint":false},{"year":2017,"finding":"Cxcl14 depletion in myoblasts promotes cell cycle withdrawal in an ERK1/2-dependent manner, accelerating myogenic differentiation in vitro; in vivo, Cxcl14 knockout mice show accelerated muscle regeneration after injury, with reduced cell proliferation, and impaired regeneration in aged mice is fully restored by Cxcl14 depletion.","method":"siRNA knockdown, ERK1/2 inhibition, differentiation assays, BrdU incorporation, murine muscle injury/regeneration model","journal":"NPJ Regenerative medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanism (ERK1/2) corroborated by in vivo KO phenotype, single lab","pmids":["28775895"],"is_preprint":false},{"year":2019,"finding":"Fibroblast-derived CXCL14 stimulates breast cancer epithelial-to-mesenchymal transition (EMT), migration, invasion, and lung colonization; the atypical chemokine receptor ACKR2 mediates these CXCL14-stimulated responses, and downregulation of ACKR2 or CXCL14-induced NOS1 attenuates pro-EMT and migratory effects.","method":"Co-culture with CXCL14-overexpressing fibroblasts, ACKR2 loss-of-function (siRNA/shRNA), invasion/migration assays, xenograft and tail-vein metastasis models, NOS1 inhibition","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — receptor identified by loss-of-function, multiple in vitro and in vivo models, downstream NOS1 mechanistic link","pmids":["30850359"],"is_preprint":false},{"year":2019,"finding":"CXCL14 expression restores MHC class I (MHC-I) expression on HPV-positive head and neck cancer cells downregulated by HPV; MHC-I knockdown abolishes CXCL14-mediated tumor suppression; CD8+ T cell-receptor transgenic experiments show that CXCL14-mediated antitumor CD8+ T cell responses require antigen specificity.","method":"MHC-I knockdown, CD8+ T cell depletion, TCR transgenic mouse model, tumor growth assays in immunocompetent syngeneic mice","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — epistasis with MHC-I KD and TCR transgenic model, mechanistic link to antigen-specific CD8+ T cells","pmids":["31417179"],"is_preprint":false},{"year":2019,"finding":"NMR spectroscopy and computational modeling show that CXCL14 interacts with glycosaminoglycans (GAGs) with distinct binding modes depending on GAG sulfation pattern (heparin, hyaluronic acid, chondroitin sulfate-A/C/D, dermatan sulfate), with specificity beyond simple electrostatic interactions.","method":"NMR spectroscopy, microscale thermophoresis, heparin affinity chromatography, molecular docking, molecular dynamics simulations, free energy calculations","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure combined with multiple biophysical and computational methods","pmids":["31264681"],"is_preprint":false},{"year":2019,"finding":"In the embryonic mouse brain, H2A.Z.2 in neural progenitor cells recruits G9a to the Cxcl14 promoter, promoting H3K9me2 modification to repress Cxcl14 transcription; conditional deletion of H2A.Z.2 in NPCs leads to increased Cxcl14 expression and abnormal accumulation of microglia in the ventricular zone.","method":"Conditional knockout (NPC-specific H2A.Z.2 deletion), ChIP assay (H2A.Z.2, G9a, H3K9me2 at Cxcl14 promoter), immunohistochemistry, flow cytometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP demonstrating epigenetic writer (G9a/H3K9me2) recruited by H2A.Z.2 to Cxcl14 promoter, KO phenotype","pmids":["31712428"],"is_preprint":false},{"year":2020,"finding":"CXCL14 preferentially synergizes with homeostatic chemokine receptor systems (CXCR4/CXCL12, CXCR5/CXCL13, CCR7/CCL19/CCL21) but not efficiently with inflammatory chemokines (CXCR3, CCR5); CXCL14 itself does not activate any known conventional or atypical chemokine receptor in β-arrestin recruitment or chemotaxis assays; CXCL14 binds to 300-19 cells and interferes with CCL19 binding to CCR7, suggesting receptor-surface interactions underlie synergy.","method":"Chemotaxis assay, β-arrestin recruitment assay, Ca2+ flux, competitive binding (CCL19/CCR7)","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — systematic receptor panel with multiple assays across multiple chemokine systems, mechanistic binding interference demonstrated","pmids":["33123134"],"is_preprint":false},{"year":2020,"finding":"NFATc2 binds the CXCL14 promoter region (identified by ChIP-seq) in the spinal dorsal horn after paclitaxel treatment; NFATc2 interaction with p300 increases histone H4 acetylation at the CXCL14 promoter, epigenetically upregulating CXCL14 expression and contributing to mechanical allodynia; NFATc2 and CXCL14 knockdown both attenuate paclitaxel-induced pain.","method":"ChIP-seq, ChIP (NFATc2, p300, H4 acetylation), siRNA knockdown, microarray, behavioral pain testing","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq binding site identification + histone acetylation + functional knockdown in vivo","pmids":["33070779"],"is_preprint":false},{"year":2020,"finding":"Malignant cell-specific (not fibroblast or non-malignant cell) CXCL14 expression reduces oral squamous cell carcinoma tumor growth and increases tumor-infiltrating T lymphocytes in immunocompetent mice; CXCL14 knockdown reduces TILs and increases tumor growth, while overexpression has the opposite effect; both effects are abrogated by T cell depletion.","method":"shRNA knockdown, overexpression, syngeneic immunocompetent murine model, T cell depletion, flow cytometry, scRNA-seq","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 2 — T cell depletion epistasis in vivo establishes T cell requirement for CXCL14 antitumor effect","pmids":["32958684"],"is_preprint":false},{"year":2021,"finding":"CXCL14 directly interacts with CXCR4 on platelets (verified by immunoprecipitation and confocal microscopy) and mediates platelet migration via CXCR4; CXCL14-deficient platelets show reduced thrombus formation under flow that is restored by recombinant CXCL14; CXCR4-deficient murine platelets and human iPSC-derived CXCR4-KO platelets do not respond to CXCL14-mediated migration.","method":"Co-immunoprecipitation, confocal microscopy, flow chamber thrombus assay, CXCL14-KO mouse platelets, CXCR4-KO mouse/iPSC-derived platelets, migration assay","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — direct CXCL14–CXCR4 interaction confirmed by Co-IP + confocal, functional validation with multiple KO models","pmids":["32239134"],"is_preprint":false},{"year":2023,"finding":"Brg1 transcriptionally activates CXCL14 expression in hepatocytes during alcoholic liver disease; Brg1 deficiency reduces CXCL14 and hepatic Ly6G+ neutrophil infiltration; CXCL14 knockdown alleviates and CXCL14 overexpression enhances ALD; pharmacological Brg1 inhibition (PFI-3) or CXCL14 receptor antagonism ameliorates ALD pathogenesis.","method":"RNA-seq, Brg1 KO/overexpression, CXCL14 KO/OE in mice, flow cytometry (neutrophils), PFI-3 pharmacological inhibition, CXCL14 receptor antagonist","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — epistasis (Brg1→CXCL14→neutrophil infiltration) established with multiple genetic and pharmacological tools","pmids":["36722664"],"is_preprint":false},{"year":2023,"finding":"CXCL14 promotes non-small cell lung cancer metastasis via ACKR2; ACKR2 knockdown abolishes CXCL14-induced cancer cell motility; ACKR2 mediates CXCL14-triggered PLCβ3/PKCα/c-Src signaling, leading to NF-κB activation, EMT marker upregulation, and lung metastasis in an orthotopic model.","method":"ACKR2 siRNA knockdown, migration/wound healing assays, luciferase NF-κB reporter, Western blot (PLCβ3, PKCα, c-Src, EMT markers), orthotopic lung cancer model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — receptor knockdown with downstream signaling pathway mapping, single lab","pmids":["37056937"],"is_preprint":false},{"year":2023,"finding":"In chronic myeloid leukemia, restoration of CXCL14 (lost from the BM niche) inhibits CML leukemia-initiating stem cell (LSC) maintenance and sensitizes LSCs to imatinib in vitro; in vivo, CXCL14 dramatically inhibits CML engraftment in patient-derived xenograft (PDX) NSG-SGM3 mice; mechanistically, CXCL14 upregulates inflammatory cytokine signaling but downregulates mTOR signaling and oxidative phosphorylation in CML LSCs.","method":"Long-term culture initiating cell assay, RNA-seq, CXCL14 treatment in vitro, PDX mouse model, pathway analysis (mTOR, oxidative phosphorylation)","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo functional evidence with pathway-level mechanistic data, single lab","pmids":["37018663"],"is_preprint":false},{"year":2024,"finding":"CXCL14 binds to integrin α11β1 on fibroblasts, activating actomyosin contractility and matrix remodeling; CXCL14-stimulated fibroblasts produce TGFβ, which increases osteosarcoma invasion and migration; anti-CXCL14/integrin α11β1 antibodies inhibit fibroblast TGFβ production, enhance CD8+ T cell antitumor immunity, and suppress osteosarcoma lung metastasis.","method":"scRNA-seq, Co-IP/binding assay (CXCL14–integrin α11β1), actomyosin contractility assay, TGFβ ELISA, CD8+ T cell assay, anti-CXCL14/integrin mAb in vivo, metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — direct receptor–ligand interaction with downstream signaling and in vivo antibody epistasis across multiple endpoints","pmids":["38295227"],"is_preprint":false},{"year":2024,"finding":"CXCL14 is a potent and selective activator of the orphan GPCR MRGPRX2 (and mouse ortholog MRGPRB2); activation involves G protein-dependent signaling and β-arrestin recruitment; C-terminal domain sequences of CXCL14 (4–11 amino acids) have similar or greater potency than the full 77-amino acid protein at MRGPRX2, as established by mutagenesis and computational docking.","method":"GPCR panel screening (G protein signaling, β-arrestin recruitment assays), MRGPRX2/B2 antagonist inhibition, truncation/mutagenesis of CXCL14, computational docking","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 — receptor identification with functional assays, mutagenesis defining pharmacophore, and computational validation","pmids":["38184723"],"is_preprint":false},{"year":2024,"finding":"p21+ perinecrotic hepatocytes secrete CXCL14 after severe APAP overdose; CXCL14-neutralizing antibody treatment greatly enhances liver recovery and reduces acute liver failure, while targeting p21+ senescent hepatocytes with senolytics (dasatinib/quercetin) has no effect, establishing CXCL14 secretion (not cellular senescence per se) as the critical pathogenic mechanism.","method":"Single-nuclei RNA-seq, spatial transcriptomics, CXCL14 neutralizing antibody, senolytic treatment, liver injury biochemical markers, mouse APAP overdose model","journal":"Toxicology","confidence":"High","confidence_rationale":"Tier 2 — antibody epistasis in vivo with spatial transcriptomics mechanistic localization, human data supporting relevance","pmids":["38614205"],"is_preprint":false}],"current_model":"CXCL14 is a homeostatic CXC chemokine constitutively expressed in epithelial tissues that functions as a selective chemoattractant for monocytes, immature dendritic cells, and activated NK cells via Gi-coupled receptor signaling; it inhibits angiogenesis by blocking endothelial chemotaxis; it acts as a positive allosteric modulator of CXCR4 (synergizing with CXCL12) and also directly inhibits CXCR4 via receptor internalization, while additionally signaling through ACKR2 (promoting EMT/invasion in some cancers) and MRGPRX2 (a newly identified cognate receptor); its expression is regulated by epigenetic silencing (DNA methylation induced by the HPV oncoprotein E7, and by H2A.Z.2/G9a/H3K9me2 in neural progenitors) and by proteasomal degradation via a unique VSRYR insertion; upstream regulators include RhoBTB2, HIF-1α, NFATc2/p300-mediated histone acetylation, and Brg1; downstream, CXCL14 modulates NF-κB, AP-1/Ca2+/IP3R, p38/JNK/CREB, and ERK1/2 pathways and—through antigen-specific CD8+ T cells recruited via restored MHC-I expression—mediates antitumor immune surveillance."},"narrative":{"teleology":[{"year":2001,"claim":"The first mechanistic characterization of CXCL14 established it as a selective monocyte chemoattractant signaling through a Gi-coupled receptor, distinguishing it from other CXC chemokines and defining its basic signaling mode.","evidence":"Transwell migration, Ca²⁺ mobilization with pertussis toxin inhibition, cell-type specificity panel","pmids":["11561000"],"confidence":"High","gaps":["Cognate receptor identity unknown","Mechanism of monocyte selectivity undefined","In vivo relevance not tested"]},{"year":2004,"claim":"CXCL14 was shown to be a potent angiogenesis inhibitor and high-affinity ligand for immature dendritic cells, expanding its functional repertoire beyond monocyte chemotaxis to include vascular and DC biology.","evidence":"Rat corneal micropocket assay, radioligand binding (Kd ~2 nM on iDCs), endothelial chemotaxis inhibition","pmids":["15548693"],"confidence":"High","gaps":["Receptor on iDCs and endothelial cells not identified","Anti-angiogenic mechanism of action unknown"]},{"year":2005,"claim":"CXCL14 was established as a constitutive epidermal chemokine that recruits DC precursors, directs their suprabasal positioning, promotes Langerhans cell differentiation, and activates NF-κB in DCs—defining its role in cutaneous immune homeostasis.","evidence":"3D epidermal equivalents, DC maturation/antigen presentation assays, NF-κB reporter, chimeric animal DC infiltration models","pmids":["15843547","16169505"],"confidence":"High","gaps":["DC-expressed CXCL14 receptor still unidentified","Whether CXCL14 is required (not just sufficient) for Langerhans cell homeostasis not tested genetically"]},{"year":2006,"claim":"Two independent advances resolved structural determinants of CXCL14 turnover and extended its chemotactic target cells to NK cells: the NMR structure revealed a unique VSRYR insertion mediating proteasomal degradation, while NK chemotaxis was shown to be Gi-dependent.","evidence":"NMR structure/mutagenesis/ubiquitylation assays; NK transwell migration with PTX and antibody neutralization","pmids":["16987528","16863917"],"confidence":"High","gaps":["E3 ubiquitin ligase targeting VSRYR not identified","NK cell CXCL14 receptor unknown","Whether proteasomal regulation occurs in vivo not shown"]},{"year":2008,"claim":"RhoBTB2 was placed upstream of CXCL14 expression through loss- and gain-of-function experiments, providing the first upstream regulator linking GTPase signaling to CXCL14 transcription.","evidence":"RNAi in primary epithelial cells, RhoBTB2 re-expression in HNSCC lines restoring CXCL14 secretion","pmids":["18762809"],"confidence":"Medium","gaps":["Whether RhoBTB2 acts directly on the CXCL14 promoter or through intermediaries unknown","Not replicated in independent labs"]},{"year":2009,"claim":"Context-dependent CXCL14 signaling was revealed: in breast cancer, ROS/AP-1 induces CXCL14 to elevate cytosolic Ca²⁺ via IP3R promoting motility, while in trophoblasts CXCL14 inhibits invasion by suppressing MMP-2/9—demonstrating cell-type-specific functional outcomes.","evidence":"Ca²⁺ imaging, AP-1 reporter, invasion assays in breast cancer cells; gelatinase zymography and villous explant invasion assays for trophoblasts","pmids":["19276362","19833716"],"confidence":"Medium","gaps":["Receptor mediating trophoblast or breast cancer cell responses not identified","Mechanism of MMP suppression not defined","Single-lab findings for each"]},{"year":2010,"claim":"Epigenetic silencing of CXCL14 by promoter CpG hypermethylation was established in prostate cancer, with demethylation restoring functional DC-chemoattractant activity—providing the first direct link between CXCL14 epigenetic loss and impaired immune recruitment.","evidence":"MSP, bisulfite sequencing, 5-aza-dC restoration, DC chemotaxis with affinity depletion confirmation","pmids":["20460540"],"confidence":"High","gaps":["Methyltransferase(s) responsible not identified at this point","Whether methylation-mediated silencing occurs in vivo in patient tumors not formally tested"]},{"year":2013,"claim":"CXCL14 was identified as a high-affinity CXCR4 binder that inhibits CXCL12-mediated chemotaxis via receptor internalization, with the C-terminal domain (residues 51–77) mapped as the CXCR4-binding determinant; however, a contradicting study found no direct CXCR4 modulation in reconstituted systems, leaving the CXCL14–CXCR4 relationship unresolved.","evidence":"Radioligand binding, CXCR4 internalization, truncation/mutagenesis; counter-evidence from CXCR4-transfected HEK293/Jurkat signaling panel (Ca²⁺, ERK, DMR, internalization)","pmids":["23669361","24161674","25451233"],"confidence":"High","gaps":["Discrepancy between endogenous and overexpression systems unresolved","Whether CXCL14 requires a co-receptor or accessory factor for CXCR4 engagement not tested"]},{"year":2015,"claim":"Two studies established CXCL14's antitumor immune mechanism in vivo: IRX1 was placed upstream of CXCL14/NF-κB in osteosarcoma metastasis, while transgenic CXCL14 suppressed tumors through an NK cell–dependent mechanism demonstrated by antibody depletion.","evidence":"IRX1 overexpression/knockdown epistasis with NF-κB reporter and murine metastasis model; CXCL14-transgenic mice with anti-asialo-GM1 NK depletion","pmids":["25822025","25765541"],"confidence":"High","gaps":["Whether NK cells are directly recruited by CXCL14 or activated indirectly not distinguished","IRX1 direct binding to CXCL14 promoter not shown"]},{"year":2016,"claim":"The HPV E7 oncoprotein was shown to induce CXCL14 promoter DNA hypermethylation, mechanistically explaining CXCL14 loss in HPV-positive cancers; restoration of CXCL14 cleared tumors in immunocompetent but not Rag1-knockout mice, proving adaptive immunity is required.","evidence":"E7 gain/loss of function, promoter methylation mapping, syngeneic tumor model, Rag1-KO epistasis, flow cytometry","pmids":["27143385"],"confidence":"High","gaps":["Specific methyltransferase recruited by E7 not identified","Whether E7 acts directly on CXCL14 promoter or through intermediaries not resolved"]},{"year":2017,"claim":"The CXCL14–CXCR4 discrepancy was resolved by showing CXCL14 acts as a positive allosteric modulator of CXCR4: it binds CXCR4, redistributes it on the cell surface, and synergizes with sub-active CXCL12 for supramaximal chemotaxis and enhanced HIV-1 infection, without triggering canonical CXCR4 signaling alone.","evidence":"Chemotaxis synergy, Ca²⁺/ERK/Rac1 negative results for CXCL14 alone, CXCR4 redistribution by confocal, HIV-1 infection assay","pmids":["28360196"],"confidence":"High","gaps":["Structural basis for allosteric modulation not determined","Whether allosteric mechanism applies to all CXCR4-expressing cell types unknown"]},{"year":2017,"claim":"Multiple new biological contexts for CXCL14 were established: HIF-1α directly binds the CXCL14 promoter to drive ischemia-dependent expression and DC homing in stroke; CXCL14 activates p38/JNK/CREB to regulate steroidogenesis; and Cxcl14 depletion accelerates myogenic differentiation through ERK1/2-dependent cell cycle withdrawal.","evidence":"ChIP (HIF-1α at CXCL14 promoter), stroke mouse model; p38/JNK inhibitors in primary granulosa cells; Cxcl14-KO mice muscle regeneration with BrdU incorporation","pmids":["28382159","33129993","28775895"],"confidence":"Medium","gaps":["HIF-1α regulation not validated in non-neural tissues","Receptor mediating p38/JNK signaling in granulosa cells unidentified","ERK1/2 mechanism in myoblasts may be indirect"]},{"year":2019,"claim":"ACKR2 was identified as a functional CXCL14 receptor mediating fibroblast-to-cancer cell paracrine EMT signaling; CXCL14 was shown to restore MHC-I on HPV+ cancer cells and recruit antigen-specific CD8+ T cells; and GAG interactions were structurally characterized, revealing sulfation-dependent specificity.","evidence":"ACKR2 siRNA/shRNA with invasion/metastasis models and NOS1 inhibition; MHC-I knockdown and TCR-transgenic mouse epistasis; NMR/thermophoresis GAG binding characterization","pmids":["30850359","31417179","31264681"],"confidence":"High","gaps":["Whether ACKR2 signals directly or through ligand scavenging affecting other chemokines not fully distinguished","GAG binding functional consequences in vivo untested","How CXCL14 upregulates MHC-I expression is mechanistically undefined"]},{"year":2019,"claim":"Epigenetic repression of Cxcl14 in neural progenitors was shown to depend on H2A.Z.2 recruiting G9a to deposit H3K9me2 at the promoter, with conditional deletion causing microglial accumulation—linking CXCL14 to brain immune homeostasis during development.","evidence":"NPC-specific H2A.Z.2 conditional KO, ChIP for H2A.Z.2/G9a/H3K9me2, immunohistochemistry","pmids":["31712428"],"confidence":"High","gaps":["Whether G9a inhibition alone is sufficient to derepress Cxcl14 not tested pharmacologically","Functional consequences of microglial accumulation on brain development not explored"]},{"year":2020,"claim":"Systematic receptor screening showed CXCL14 does not activate any known conventional or atypical chemokine receptor in β-arrestin or chemotaxis assays but preferentially synergizes with homeostatic chemokine systems (CXCR4/CXCL12, CXCR5/CXCL13, CCR7/CCL19), reinforcing the allosteric modulator model; NFATc2/p300 was identified as an epigenetic activator depositing H4 acetylation at the CXCL14 promoter in neuropathic pain; and T cell depletion in oral cancer proved CXCL14 antitumor effects require T cell–mediated immunity.","evidence":"GPCR panel screening, β-arrestin/Ca²⁺/chemotaxis assays, CCL19 competitive binding; ChIP-seq/ChIP for NFATc2/p300/H4Ac; shRNA/OE with T cell depletion in syngeneic model","pmids":["33123134","33070779","32958684"],"confidence":"High","gaps":["Mechanism by which CXCL14 synergizes with CCR7 and CXCR5 systems not defined","Whether NFATc2 regulation is tissue-specific or generalizable unknown"]},{"year":2021,"claim":"Direct CXCL14–CXCR4 interaction on platelets was confirmed by co-immunoprecipitation and functional validation using both CXCL14-KO and CXCR4-KO platelets, establishing a CXCR4-dependent role for CXCL14 in platelet migration and thrombus formation.","evidence":"Co-IP, confocal, flow-chamber thrombus assay, CXCL14-KO mouse platelets, CXCR4-KO mouse and iPSC-derived platelets","pmids":["32239134"],"confidence":"High","gaps":["Whether platelet CXCL14–CXCR4 interaction operates allosterically (as in leukocytes) or through a distinct mechanism not tested","In vivo thrombosis model not performed"]},{"year":2023,"claim":"Downstream signaling through ACKR2 was elaborated: CXCL14 activates PLCβ3/PKCα/c-Src/NF-κB to drive EMT and lung metastasis in NSCLC; Brg1 was identified as a direct transcriptional activator of CXCL14 in hepatocytes driving neutrophil recruitment in alcoholic liver disease; and CXCL14 was shown to inhibit CML leukemia-initiating stem cells by downregulating mTOR and oxidative phosphorylation.","evidence":"ACKR2 knockdown with PLCβ3/PKCα/c-Src/NF-κB signaling in NSCLC orthotopic model; Brg1 KO/OE epistasis with CXCL14 in ALD mouse model; RNA-seq and PDX model for CML","pmids":["37056937","36722664","37018663"],"confidence":"Medium","gaps":["ACKR2 signaling cascade not validated with reconstituted components","Whether Brg1 binds CXCL14 promoter directly not shown by ChIP","CML mTOR suppression mechanism indirect and correlative"]},{"year":2024,"claim":"Two major receptor discoveries emerged: CXCL14 binds integrin α11β1 on fibroblasts to activate actomyosin contractility and TGFβ secretion promoting osteosarcoma invasion; and MRGPRX2 was identified as a bona fide cognate GPCR for CXCL14, activated potently by the C-terminal domain through G protein and β-arrestin pathways. Additionally, CXCL14 secreted by p21+ perinecrotic hepatocytes was shown to be the critical pathogenic mediator in APAP-induced liver failure.","evidence":"Co-IP of CXCL14–integrin α11β1, anti-CXCL14/integrin mAb in vivo metastasis model; GPCR panel screen, MRGPRX2 antagonist, truncation/mutagenesis defining C-terminal pharmacophore; spatial transcriptomics, CXCL14-neutralizing antibody vs senolytics in APAP model","pmids":["38295227","38184723","38614205"],"confidence":"High","gaps":["Whether MRGPRX2 mediates the classical monocyte/DC chemotactic activities attributed to CXCL14 not tested","Integrin α11β1 interaction not validated structurally","APAP liver injury findings require independent replication"]},{"year":null,"claim":"Key unresolved questions include: which receptor(s) mediate CXCL14's chemotactic activity toward monocytes and immature DCs (MRGPRX2, CXCR4, ACKR2, integrin α11β1, or an unidentified receptor); the structural basis for CXCL14's allosteric modulation of CXCR4 and synergy with homeostatic chemokine systems; and how CXCL14 restores MHC-I expression on tumor cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["Cognate receptor for monocyte/iDC chemotaxis remains unresolved despite multiple receptor candidates","No structural model of CXCL14–CXCR4 allosteric complex exists","Mechanism by which CXCL14 upregulates MHC-I is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,3,4,19,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,27]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,3,5,9,36]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3,14,17,24,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,16,19,20,32]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[34]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,26,28]}],"complexes":[],"partners":["CXCR4","ACKR2","MRGPRX2","ITGA11"],"other_free_text":[]},"mechanistic_narrative":"CXCL14 is a homeostatic CXC chemokine constitutively expressed in epithelial and stromal tissues that orchestrates innate and adaptive immune cell recruitment, modulates angiogenesis, and shapes tissue remodeling across developmental and pathological contexts. It functions as a selective chemoattractant for monocytes, immature dendritic cells, NK cells, and neutrophils through pertussis toxin–sensitive Gi-coupled receptor signaling [PMID:11561000, PMID:15548693, PMID:16169505, PMID:16863917], acts as a positive allosteric modulator of CXCR4 that synergizes with CXCL12 for supramaximal chemotaxis without itself activating canonical CXCR4 signaling [PMID:28360196, PMID:25451233], signals through ACKR2 to drive EMT and NF-κB–dependent invasion in certain cancers [PMID:30850359, PMID:37056937], binds integrin α11β1 on fibroblasts to activate actomyosin contractility and TGFβ-mediated matrix remodeling [PMID:38295227], and potently activates the orphan GPCR MRGPRX2 via its C-terminal domain [PMID:38184723]. CXCL14 expression is subject to multilayered epigenetic regulation—including HPV E7–induced promoter DNA hypermethylation, H2A.Z.2/G9a/H3K9me2 repression in neural progenitors, and NFATc2/p300-mediated histone acetylation—as well as post-translational control through proteasomal degradation directed by its unique VSRYR insertion [PMID:27143385, PMID:31712428, PMID:33070779, PMID:16987528]; upstream transcriptional activators include HIF-1α, RhoBTB2, IRX1, and Brg1 [PMID:28382159, PMID:18762809, PMID:25822025, PMID:36722664]. In tumors, CXCL14 mediates antitumor immune surveillance by restoring MHC-I expression on cancer cells and recruiting antigen-specific CD8+ T cells, with its suppression by HPV E7–driven methylation representing a key immune evasion mechanism [PMID:31417179, PMID:32958684, PMID:27143385]."},"prefetch_data":{"uniprot":{"accession":"O95715","full_name":"C-X-C motif chemokine 14","aliases":["Chemokine BRAK","MIP-2G","Small-inducible cytokine B14"],"length_aa":111,"mass_kda":13.1,"function":"Potent chemoattractant for neutrophils, and weaker for dendritic cells. Not chemotactic for T-cells, B-cells, monocytes, natural killer cells or granulocytes. Does not inhibit proliferation of myeloid progenitors in colony formation assays","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O95715/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CXCL14","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CXCL14","total_profiled":1310},"omim":[{"mim_id":"621003","title":"TRANSCRIPTION FACTOR Sp9; SP9","url":"https://www.omim.org/entry/621003"},{"mim_id":"620008","title":"H2A.Z VARIANT HISTONE 2; H2AZ2","url":"https://www.omim.org/entry/620008"},{"mim_id":"611387","title":"CXC CHEMOKINE LIGAND 17; CXCL17","url":"https://www.omim.org/entry/611387"},{"mim_id":"604186","title":"CHEMOKINE, CXC MOTIF, LIGAND 14; CXCL14","url":"https://www.omim.org/entry/604186"},{"mim_id":"602646","title":"G PROTEIN-COUPLED RECEPTOR 35; GPR35","url":"https://www.omim.org/entry/602646"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":767.1}],"url":"https://www.proteinatlas.org/search/CXCL14"},"hgnc":{"alias_symbol":["BRAK","NJAC","bolekine","Kec","MIP-2g","BMAC","KS1"],"prev_symbol":["SCYB14"]},"alphafold":{"accession":"O95715","domains":[{"cath_id":"2.40.50.40","chopping":"11-111","consensus_level":"medium","plddt":88.0406,"start":11,"end":111}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95715","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95715-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95715-F1-predicted_aligned_error_v6.png","plddt_mean":85.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CXCL14","jax_strain_url":"https://www.jax.org/strain/search?query=CXCL14"},"sequence":{"accession":"O95715","fasta_url":"https://rest.uniprot.org/uniprotkb/O95715.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95715/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95715"}},"corpus_meta":[{"pmid":"15548693","id":"PMC_15548693","title":"BRAK/CXCL14 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assay (iDC), transwell chemotaxis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal in vitro and in vivo assays with quantitative binding data, single lab but rigorous\",\n      \"pmids\": [\"15548693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CXCL14 (BRAK) is a selective chemoattractant for monocytes (not other blood leukocytes, monocyte-derived DCs, or macrophages); the chemotactic response is pertussis toxin-sensitive (Gi-coupled) and is enhanced by cAMP-elevating agents (PGE2, forskolin), indicating receptor coupling to a Gi protein.\",\n      \"method\": \"Transwell migration assay, Ca2+ mobilization assay with pertussis toxin inhibition, cell-type specificity panel\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional assays (migration + Ca2+ + PTX inhibition) demonstrating Gi-coupling and cell selectivity\",\n      \"pmids\": [\"11561000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CXCL14 attracts dendritic cells in vitro and promotes their infiltration into tumors in vivo; CXCL14 upregulates DC maturation markers, enhances allogeneic T cell proliferation in MLR, and activates NF-κB in DCs.\",\n      \"method\": \"Transwell chemotaxis assay, chimeric animal model DC infiltration, DC maturation marker FACS, MLR, NF-κB reporter assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro chemotaxis, in vivo infiltration, signaling assays) in single lab\",\n      \"pmids\": [\"15843547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cutaneous CXCL14 produced constitutively in healthy epidermis attracts CD14+ DC precursors (from CD34+ progenitors or blood), directs their suprabasal positioning in epidermal equivalents, promotes their survival, and drives their differentiation into Langerhans cell-like cells with antigen-presentation function.\",\n      \"method\": \"Transwell migration assay, 3D human epidermal equivalent tissue model, FACS phenotyping, antigen presentation functional assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in tissue model and primary cells, consistent with parallel in vivo expression data\",\n      \"pmids\": [\"16169505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CXCL14 stimulates migration of activated human NK cells and an NK leukemia cell line (NKL); this chemotactic effect is blocked by anti-CXCL14 antisera or pertussis toxin, indicating Gi-coupled receptor signaling, but CXCL14 does not affect NK cell proliferation or cytotoxic activity.\",\n      \"method\": \"Transwell chemotaxis assay, pertussis toxin inhibition, antisera neutralization\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional assays with PTX and antibody inhibition, single lab\",\n      \"pmids\": [\"16863917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CXCL14 protein stability in cancer cell lines is regulated by the 26S proteasome via polyubiquitylation; a unique five-amino-acid insertion (41VSRYR45) not found in other CXC chemokines mediates proteasomal targeting, as shown by NMR structure determination and deletion/substitution mutagenesis.\",\n      \"method\": \"NMR structure determination, site-directed mutagenesis, proteasome inhibitor assays, ubiquitylation assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure combined with mutagenesis and functional degradation assays\",\n      \"pmids\": [\"16987528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of RhoBTB2 (DBC2) in primary human epithelial cells by RNA interference leads to downregulation of CXCL14 mRNA and protein secretion; reintroduction of RhoBTB2 into HNSCC cell lines lacking CXCL14 restores CXCL14 secretion, placing RhoBTB2 upstream of CXCL14 expression.\",\n      \"method\": \"RNAi knockdown, microarray expression analysis, RT-PCR, CXCL14 protein secretion measurement, RhoBTB2 re-expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by both loss- and gain-of-function in primary and cancer cells\",\n      \"pmids\": [\"18762809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CXCL14 upregulation by reactive oxygen species via the AP-1 signaling pathway promotes breast cancer cell motility by elevating cytosolic Ca2+ through binding to the inositol 1,4,5-trisphosphate receptor (IP3R) on the endoplasmic reticulum; decoy-mediated abrogation of CXCL14 suppresses motility and invasion.\",\n      \"method\": \"Microarray, gene knockdown (decoy), Ca2+ imaging, AP-1 reporter assay, invasion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods linking ROS→AP-1→CXCL14→IP3R→Ca2+ to motility, single lab\",\n      \"pmids\": [\"19276362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CXCL14 inhibits trophoblast invasion and migration in vitro by suppressing MMP-2 and MMP-9 (gelatinase) activities, without affecting proliferation; CXCL14 binds specifically to trophoblast cells but not decidual cells at the maternal-fetal interface.\",\n      \"method\": \"Villous explant Matrigel invasion assay, transwell invasion/migration assay, gelatinase zymography, cell-specific binding assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with mechanism (gelatinase suppression) and cell-type-specific binding, single lab\",\n      \"pmids\": [\"19833716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of CXCL14 expression in prostate cancer cells is caused by CpG island hypermethylation of the CXCL14 promoter; demethylation with 5-aza-2'-deoxycytidine restores CXCL14 mRNA/protein and produces functionally active DC chemoattractant in conditioned medium, confirmed by affinity chromatography depletion.\",\n      \"method\": \"MSP, bisulfite sequencing, RT-PCR, Western blot, 5-aza-dC treatment, DC chemotaxis assay, affinity chromatography depletion\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — epigenetic mechanism established with methylation mapping, restoration, and functional output\",\n      \"pmids\": [\"20460540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CXCL14 expression in HNSCC cells is suppressed by ROS (H2O2, hydroxyl radical) via the EGFR/MEK/ERK pathway, as shown by attenuation with NAC, EGFR inhibitors, and MEK inhibitors.\",\n      \"method\": \"ROS treatment, RT-PCR, pharmacological inhibitors (NAC, EGFR inhibitor, MEK inhibitor)\",\n      \"journal\": \"Free radical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological pathway dissection, single lab, convergent inhibitor data\",\n      \"pmids\": [\"20815772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In the adult mouse dentate gyrus, CXCL14 is expressed by GABAergic interneurons and inhibits GABAergic synaptic transmission (both tonic and phasic GABA) to nestin-EGFP+ neural stem/progenitor cells; CXCL14 also raises [Ca2+]i in cultured neural stem cells, indicating they express the CXCL14 receptor. CXCL12 has the opposite effect on GABA transmission at the same synapses.\",\n      \"method\": \"Immunohistochemistry, electrophysiology (whole-cell patch clamp in brain slices), Ca2+ imaging in cultured neural stem cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — electrophysiology directly demonstrating synaptic modulation, calcium imaging, cell-type-specific expression, replicated with CXCL12 comparison\",\n      \"pmids\": [\"21955359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CXCL14 specifically binds CXCR4 with high affinity and inhibits CXCL12-mediated chemotaxis of human leukemia-derived cell lines and CD34+ hematopoietic progenitor cells; the mechanism involves CXCR4 internalization/inactivation rather than direct competition with CXCL12 for the binding site.\",\n      \"method\": \"Radioligand binding assay, transwell chemotaxis assay, CXCR4 internalization assay, competitive binding\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding + functional inhibition + receptor internalization, clean mechanistic dissection\",\n      \"pmids\": [\"23669361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C-terminal 51–77 amino acid residues of CXCL14 are responsible for CXCR4 binding; a disulfide dimer peptide of CXCL14(51-77) binds CXCR4 with affinity comparable to full-length CXCL14, induces CXCR4 internalization, and inhibits CXCL12-mediated signaling.\",\n      \"method\": \"Binding assay, CXCR4 internalization assay, chemotaxis inhibition, peptide mutagenesis/truncation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional validation, single lab\",\n      \"pmids\": [\"24161674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CXCL14 restores CXCL14 expression suppressed by HPV E7 through epigenetic (DNA hypermethylation) mechanisms; restoration of Cxcl14 in HPV+ mouse oropharyngeal cancer clears tumors in immunocompetent but not Rag1-deficient mice, and increases NK, CD4+, and CD8+ T cell infiltration into tumor-draining lymph nodes via chemotaxis.\",\n      \"method\": \"Gene expression analysis, promoter methylation assay, syngeneic mouse tumor model, Rag1 KO mice, transwell migration assay, flow cytometry\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic linkage E7→DNA methylation→CXCL14 suppression, immunodeficient mouse epistasis, multiple immune cell readouts\",\n      \"pmids\": [\"27143385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CXCL14 does not directly modulate CXCR4 signaling: in CXCR4-transfected HEK293 and Jurkat T cells, CXCL14 had no effect on CXCL12-induced CXCR4 phosphorylation, G protein-mediated Ca2+ mobilization, ERK1/2 phosphorylation, dynamic mass redistribution, or CXCR4 internalization, suggesting CXCL14–CXCL12 pathway interactions require an unidentified CXCL14 receptor.\",\n      \"method\": \"CXCR4-transfected cell assays, Ca2+ mobilization, dynamic mass redistribution, ERK phosphorylation, receptor internalization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — comprehensive signaling assay panel in defined overexpression system, provides important mechanistic counter-evidence\",\n      \"pmids\": [\"25451233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IRX1 overexpression driven by promoter hypomethylation upregulates CXCL14/NF-κB signaling to promote osteosarcoma cell migration, invasion, anoikis resistance, and lung metastasis in murine models; IRX1 modulation epistasis places IRX1 upstream of CXCL14 in this pathway.\",\n      \"method\": \"MeDIP microarray, overexpression/knockdown, migration/invasion assay, anoikis assay, murine metastasis model, NF-κB reporter\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (IRX1→CXCL14→NF-κB) established with gain and loss of function in vitro and in vivo\",\n      \"pmids\": [\"25822025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In CXCL14 transgenic mice, NK cell activity (depleted with anti-asialo-GM1 antibody) is required for CXCL14-mediated suppression of tumor growth and metastasis, demonstrating that CXCL14 acts through NK cells to suppress tumors in vivo.\",\n      \"method\": \"CXCL14 transgenic mice, NK cell depletion (anti-asialo-GM1 antibody), tumor xenograft and metastasis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo epistasis with antibody-mediated NK cell depletion reversing CXCL14 antitumor effect\",\n      \"pmids\": [\"25765541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HPV oncoprotein E7 induces CXCL14 promoter DNA hypermethylation, suppressing CXCL14 expression in HPV-positive head/neck and cervical cancers; this mechanism is E7-dependent and leads to reduced antitumor immune surveillance.\",\n      \"method\": \"Promoter methylation assay, E7 knockdown/overexpression, gene expression analysis, patient tissue specimens\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — E7 dependence established with gain/loss of function + methylation mapping, multiple tissue types\",\n      \"pmids\": [\"27143385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CXCL14 acts as a positive allosteric modulator of CXCR4: it binds CXCR4 with high affinity and induces cell-surface CXCR4 redistribution, but does not itself trigger chemotaxis, Ca2+ mobilization, ERK1/2, or Rac1 signaling in CXCR4+ cells; it synergizes with subactive concentrations of CXCL12 to produce supramaximal chemotaxis and enhances HIV-1 infection by >3-fold.\",\n      \"method\": \"Chemotaxis assay, Ca2+ mobilization, ERK/Rac1 phosphorylation, CXCR4 redistribution (confocal), HIV-1 infection assay, competitive binding\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling and functional assays with primary human lymphoid cells and cell lines, mechanistic allosteric model supported by breadth of assays\",\n      \"pmids\": [\"28360196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CXCL14 upregulates STAR expression and progesterone synthesis in human luteinized granulosa (hGL) cells via CREB phosphorylation downstream of p38 and JNK pathways; p38 and JNK inhibitors attenuate CXCL14-induced STAR expression and progesterone production.\",\n      \"method\": \"Primary hGL cell culture, CXCL14 treatment, Western blot (CREB phosphorylation, STAR), CREB inhibitor, p38/JNK inhibitors, progesterone ELISA\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway dissection with multiple inhibitors in primary cells, single lab\",\n      \"pmids\": [\"33129993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HIF-1α directly binds the CXCL14 promoter and drives hypoxia/ischemia-dependent CXCL14 expression in the brain; CXCL14 promotes adhesion, migration, and homing of circulating CD11c+ iDCs to ischemic tissue via upregulation of PrPC, PECAM-1, and MMPs; accumulated iDCs then secrete IL-2 to promote Treg differentiation and reduce infarct volume.\",\n      \"method\": \"ChIP assay (HIF-1α on CXCL14 promoter), flow cytometry, migration/adhesion assays, CXCL14 depletion/supplementation in stroke mouse model, Treg differentiation assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional in vivo rescue experiments, single lab\",\n      \"pmids\": [\"28382159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cxcl14 depletion in myoblasts promotes cell cycle withdrawal in an ERK1/2-dependent manner, accelerating myogenic differentiation in vitro; in vivo, Cxcl14 knockout mice show accelerated muscle regeneration after injury, with reduced cell proliferation, and impaired regeneration in aged mice is fully restored by Cxcl14 depletion.\",\n      \"method\": \"siRNA knockdown, ERK1/2 inhibition, differentiation assays, BrdU incorporation, murine muscle injury/regeneration model\",\n      \"journal\": \"NPJ Regenerative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanism (ERK1/2) corroborated by in vivo KO phenotype, single lab\",\n      \"pmids\": [\"28775895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fibroblast-derived CXCL14 stimulates breast cancer epithelial-to-mesenchymal transition (EMT), migration, invasion, and lung colonization; the atypical chemokine receptor ACKR2 mediates these CXCL14-stimulated responses, and downregulation of ACKR2 or CXCL14-induced NOS1 attenuates pro-EMT and migratory effects.\",\n      \"method\": \"Co-culture with CXCL14-overexpressing fibroblasts, ACKR2 loss-of-function (siRNA/shRNA), invasion/migration assays, xenograft and tail-vein metastasis models, NOS1 inhibition\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor identified by loss-of-function, multiple in vitro and in vivo models, downstream NOS1 mechanistic link\",\n      \"pmids\": [\"30850359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXCL14 expression restores MHC class I (MHC-I) expression on HPV-positive head and neck cancer cells downregulated by HPV; MHC-I knockdown abolishes CXCL14-mediated tumor suppression; CD8+ T cell-receptor transgenic experiments show that CXCL14-mediated antitumor CD8+ T cell responses require antigen specificity.\",\n      \"method\": \"MHC-I knockdown, CD8+ T cell depletion, TCR transgenic mouse model, tumor growth assays in immunocompetent syngeneic mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with MHC-I KD and TCR transgenic model, mechanistic link to antigen-specific CD8+ T cells\",\n      \"pmids\": [\"31417179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NMR spectroscopy and computational modeling show that CXCL14 interacts with glycosaminoglycans (GAGs) with distinct binding modes depending on GAG sulfation pattern (heparin, hyaluronic acid, chondroitin sulfate-A/C/D, dermatan sulfate), with specificity beyond simple electrostatic interactions.\",\n      \"method\": \"NMR spectroscopy, microscale thermophoresis, heparin affinity chromatography, molecular docking, molecular dynamics simulations, free energy calculations\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure combined with multiple biophysical and computational methods\",\n      \"pmids\": [\"31264681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In the embryonic mouse brain, H2A.Z.2 in neural progenitor cells recruits G9a to the Cxcl14 promoter, promoting H3K9me2 modification to repress Cxcl14 transcription; conditional deletion of H2A.Z.2 in NPCs leads to increased Cxcl14 expression and abnormal accumulation of microglia in the ventricular zone.\",\n      \"method\": \"Conditional knockout (NPC-specific H2A.Z.2 deletion), ChIP assay (H2A.Z.2, G9a, H3K9me2 at Cxcl14 promoter), immunohistochemistry, flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP demonstrating epigenetic writer (G9a/H3K9me2) recruited by H2A.Z.2 to Cxcl14 promoter, KO phenotype\",\n      \"pmids\": [\"31712428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CXCL14 preferentially synergizes with homeostatic chemokine receptor systems (CXCR4/CXCL12, CXCR5/CXCL13, CCR7/CCL19/CCL21) but not efficiently with inflammatory chemokines (CXCR3, CCR5); CXCL14 itself does not activate any known conventional or atypical chemokine receptor in β-arrestin recruitment or chemotaxis assays; CXCL14 binds to 300-19 cells and interferes with CCL19 binding to CCR7, suggesting receptor-surface interactions underlie synergy.\",\n      \"method\": \"Chemotaxis assay, β-arrestin recruitment assay, Ca2+ flux, competitive binding (CCL19/CCR7)\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic receptor panel with multiple assays across multiple chemokine systems, mechanistic binding interference demonstrated\",\n      \"pmids\": [\"33123134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NFATc2 binds the CXCL14 promoter region (identified by ChIP-seq) in the spinal dorsal horn after paclitaxel treatment; NFATc2 interaction with p300 increases histone H4 acetylation at the CXCL14 promoter, epigenetically upregulating CXCL14 expression and contributing to mechanical allodynia; NFATc2 and CXCL14 knockdown both attenuate paclitaxel-induced pain.\",\n      \"method\": \"ChIP-seq, ChIP (NFATc2, p300, H4 acetylation), siRNA knockdown, microarray, behavioral pain testing\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq binding site identification + histone acetylation + functional knockdown in vivo\",\n      \"pmids\": [\"33070779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Malignant cell-specific (not fibroblast or non-malignant cell) CXCL14 expression reduces oral squamous cell carcinoma tumor growth and increases tumor-infiltrating T lymphocytes in immunocompetent mice; CXCL14 knockdown reduces TILs and increases tumor growth, while overexpression has the opposite effect; both effects are abrogated by T cell depletion.\",\n      \"method\": \"shRNA knockdown, overexpression, syngeneic immunocompetent murine model, T cell depletion, flow cytometry, scRNA-seq\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — T cell depletion epistasis in vivo establishes T cell requirement for CXCL14 antitumor effect\",\n      \"pmids\": [\"32958684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CXCL14 directly interacts with CXCR4 on platelets (verified by immunoprecipitation and confocal microscopy) and mediates platelet migration via CXCR4; CXCL14-deficient platelets show reduced thrombus formation under flow that is restored by recombinant CXCL14; CXCR4-deficient murine platelets and human iPSC-derived CXCR4-KO platelets do not respond to CXCL14-mediated migration.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, flow chamber thrombus assay, CXCL14-KO mouse platelets, CXCR4-KO mouse/iPSC-derived platelets, migration assay\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct CXCL14–CXCR4 interaction confirmed by Co-IP + confocal, functional validation with multiple KO models\",\n      \"pmids\": [\"32239134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Brg1 transcriptionally activates CXCL14 expression in hepatocytes during alcoholic liver disease; Brg1 deficiency reduces CXCL14 and hepatic Ly6G+ neutrophil infiltration; CXCL14 knockdown alleviates and CXCL14 overexpression enhances ALD; pharmacological Brg1 inhibition (PFI-3) or CXCL14 receptor antagonism ameliorates ALD pathogenesis.\",\n      \"method\": \"RNA-seq, Brg1 KO/overexpression, CXCL14 KO/OE in mice, flow cytometry (neutrophils), PFI-3 pharmacological inhibition, CXCL14 receptor antagonist\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis (Brg1→CXCL14→neutrophil infiltration) established with multiple genetic and pharmacological tools\",\n      \"pmids\": [\"36722664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CXCL14 promotes non-small cell lung cancer metastasis via ACKR2; ACKR2 knockdown abolishes CXCL14-induced cancer cell motility; ACKR2 mediates CXCL14-triggered PLCβ3/PKCα/c-Src signaling, leading to NF-κB activation, EMT marker upregulation, and lung metastasis in an orthotopic model.\",\n      \"method\": \"ACKR2 siRNA knockdown, migration/wound healing assays, luciferase NF-κB reporter, Western blot (PLCβ3, PKCα, c-Src, EMT markers), orthotopic lung cancer model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor knockdown with downstream signaling pathway mapping, single lab\",\n      \"pmids\": [\"37056937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In chronic myeloid leukemia, restoration of CXCL14 (lost from the BM niche) inhibits CML leukemia-initiating stem cell (LSC) maintenance and sensitizes LSCs to imatinib in vitro; in vivo, CXCL14 dramatically inhibits CML engraftment in patient-derived xenograft (PDX) NSG-SGM3 mice; mechanistically, CXCL14 upregulates inflammatory cytokine signaling but downregulates mTOR signaling and oxidative phosphorylation in CML LSCs.\",\n      \"method\": \"Long-term culture initiating cell assay, RNA-seq, CXCL14 treatment in vitro, PDX mouse model, pathway analysis (mTOR, oxidative phosphorylation)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional evidence with pathway-level mechanistic data, single lab\",\n      \"pmids\": [\"37018663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CXCL14 binds to integrin α11β1 on fibroblasts, activating actomyosin contractility and matrix remodeling; CXCL14-stimulated fibroblasts produce TGFβ, which increases osteosarcoma invasion and migration; anti-CXCL14/integrin α11β1 antibodies inhibit fibroblast TGFβ production, enhance CD8+ T cell antitumor immunity, and suppress osteosarcoma lung metastasis.\",\n      \"method\": \"scRNA-seq, Co-IP/binding assay (CXCL14–integrin α11β1), actomyosin contractility assay, TGFβ ELISA, CD8+ T cell assay, anti-CXCL14/integrin mAb in vivo, metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct receptor–ligand interaction with downstream signaling and in vivo antibody epistasis across multiple endpoints\",\n      \"pmids\": [\"38295227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CXCL14 is a potent and selective activator of the orphan GPCR MRGPRX2 (and mouse ortholog MRGPRB2); activation involves G protein-dependent signaling and β-arrestin recruitment; C-terminal domain sequences of CXCL14 (4–11 amino acids) have similar or greater potency than the full 77-amino acid protein at MRGPRX2, as established by mutagenesis and computational docking.\",\n      \"method\": \"GPCR panel screening (G protein signaling, β-arrestin recruitment assays), MRGPRX2/B2 antagonist inhibition, truncation/mutagenesis of CXCL14, computational docking\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — receptor identification with functional assays, mutagenesis defining pharmacophore, and computational validation\",\n      \"pmids\": [\"38184723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p21+ perinecrotic hepatocytes secrete CXCL14 after severe APAP overdose; CXCL14-neutralizing antibody treatment greatly enhances liver recovery and reduces acute liver failure, while targeting p21+ senescent hepatocytes with senolytics (dasatinib/quercetin) has no effect, establishing CXCL14 secretion (not cellular senescence per se) as the critical pathogenic mechanism.\",\n      \"method\": \"Single-nuclei RNA-seq, spatial transcriptomics, CXCL14 neutralizing antibody, senolytic treatment, liver injury biochemical markers, mouse APAP overdose model\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antibody epistasis in vivo with spatial transcriptomics mechanistic localization, human data supporting relevance\",\n      \"pmids\": [\"38614205\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CXCL14 is a homeostatic CXC chemokine constitutively expressed in epithelial tissues that functions as a selective chemoattractant for monocytes, immature dendritic cells, and activated NK cells via Gi-coupled receptor signaling; it inhibits angiogenesis by blocking endothelial chemotaxis; it acts as a positive allosteric modulator of CXCR4 (synergizing with CXCL12) and also directly inhibits CXCR4 via receptor internalization, while additionally signaling through ACKR2 (promoting EMT/invasion in some cancers) and MRGPRX2 (a newly identified cognate receptor); its expression is regulated by epigenetic silencing (DNA methylation induced by the HPV oncoprotein E7, and by H2A.Z.2/G9a/H3K9me2 in neural progenitors) and by proteasomal degradation via a unique VSRYR insertion; upstream regulators include RhoBTB2, HIF-1α, NFATc2/p300-mediated histone acetylation, and Brg1; downstream, CXCL14 modulates NF-κB, AP-1/Ca2+/IP3R, p38/JNK/CREB, and ERK1/2 pathways and—through antigen-specific CD8+ T cells recruited via restored MHC-I expression—mediates antitumor immune surveillance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CXCL14 is a homeostatic CXC chemokine constitutively expressed in epithelial and stromal tissues that orchestrates innate and adaptive immune cell recruitment, modulates angiogenesis, and shapes tissue remodeling across developmental and pathological contexts. It functions as a selective chemoattractant for monocytes, immature dendritic cells, NK cells, and neutrophils through pertussis toxin–sensitive Gi-coupled receptor signaling [PMID:11561000, PMID:15548693, PMID:16169505, PMID:16863917], acts as a positive allosteric modulator of CXCR4 that synergizes with CXCL12 for supramaximal chemotaxis without itself activating canonical CXCR4 signaling [PMID:28360196, PMID:25451233], signals through ACKR2 to drive EMT and NF-κB–dependent invasion in certain cancers [PMID:30850359, PMID:37056937], binds integrin α11β1 on fibroblasts to activate actomyosin contractility and TGFβ-mediated matrix remodeling [PMID:38295227], and potently activates the orphan GPCR MRGPRX2 via its C-terminal domain [PMID:38184723]. CXCL14 expression is subject to multilayered epigenetic regulation—including HPV E7–induced promoter DNA hypermethylation, H2A.Z.2/G9a/H3K9me2 repression in neural progenitors, and NFATc2/p300-mediated histone acetylation—as well as post-translational control through proteasomal degradation directed by its unique VSRYR insertion [PMID:27143385, PMID:31712428, PMID:33070779, PMID:16987528]; upstream transcriptional activators include HIF-1α, RhoBTB2, IRX1, and Brg1 [PMID:28382159, PMID:18762809, PMID:25822025, PMID:36722664]. In tumors, CXCL14 mediates antitumor immune surveillance by restoring MHC-I expression on cancer cells and recruiting antigen-specific CD8+ T cells, with its suppression by HPV E7–driven methylation representing a key immune evasion mechanism [PMID:31417179, PMID:32958684, PMID:27143385].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The first mechanistic characterization of CXCL14 established it as a selective monocyte chemoattractant signaling through a Gi-coupled receptor, distinguishing it from other CXC chemokines and defining its basic signaling mode.\",\n      \"evidence\": \"Transwell migration, Ca²⁺ mobilization with pertussis toxin inhibition, cell-type specificity panel\",\n      \"pmids\": [\"11561000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cognate receptor identity unknown\", \"Mechanism of monocyte selectivity undefined\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"CXCL14 was shown to be a potent angiogenesis inhibitor and high-affinity ligand for immature dendritic cells, expanding its functional repertoire beyond monocyte chemotaxis to include vascular and DC biology.\",\n      \"evidence\": \"Rat corneal micropocket assay, radioligand binding (Kd ~2 nM on iDCs), endothelial chemotaxis inhibition\",\n      \"pmids\": [\"15548693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on iDCs and endothelial cells not identified\", \"Anti-angiogenic mechanism of action unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"CXCL14 was established as a constitutive epidermal chemokine that recruits DC precursors, directs their suprabasal positioning, promotes Langerhans cell differentiation, and activates NF-κB in DCs—defining its role in cutaneous immune homeostasis.\",\n      \"evidence\": \"3D epidermal equivalents, DC maturation/antigen presentation assays, NF-κB reporter, chimeric animal DC infiltration models\",\n      \"pmids\": [\"15843547\", \"16169505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DC-expressed CXCL14 receptor still unidentified\", \"Whether CXCL14 is required (not just sufficient) for Langerhans cell homeostasis not tested genetically\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two independent advances resolved structural determinants of CXCL14 turnover and extended its chemotactic target cells to NK cells: the NMR structure revealed a unique VSRYR insertion mediating proteasomal degradation, while NK chemotaxis was shown to be Gi-dependent.\",\n      \"evidence\": \"NMR structure/mutagenesis/ubiquitylation assays; NK transwell migration with PTX and antibody neutralization\",\n      \"pmids\": [\"16987528\", \"16863917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase targeting VSRYR not identified\", \"NK cell CXCL14 receptor unknown\", \"Whether proteasomal regulation occurs in vivo not shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"RhoBTB2 was placed upstream of CXCL14 expression through loss- and gain-of-function experiments, providing the first upstream regulator linking GTPase signaling to CXCL14 transcription.\",\n      \"evidence\": \"RNAi in primary epithelial cells, RhoBTB2 re-expression in HNSCC lines restoring CXCL14 secretion\",\n      \"pmids\": [\"18762809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RhoBTB2 acts directly on the CXCL14 promoter or through intermediaries unknown\", \"Not replicated in independent labs\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Context-dependent CXCL14 signaling was revealed: in breast cancer, ROS/AP-1 induces CXCL14 to elevate cytosolic Ca²⁺ via IP3R promoting motility, while in trophoblasts CXCL14 inhibits invasion by suppressing MMP-2/9—demonstrating cell-type-specific functional outcomes.\",\n      \"evidence\": \"Ca²⁺ imaging, AP-1 reporter, invasion assays in breast cancer cells; gelatinase zymography and villous explant invasion assays for trophoblasts\",\n      \"pmids\": [\"19276362\", \"19833716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating trophoblast or breast cancer cell responses not identified\", \"Mechanism of MMP suppression not defined\", \"Single-lab findings for each\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Epigenetic silencing of CXCL14 by promoter CpG hypermethylation was established in prostate cancer, with demethylation restoring functional DC-chemoattractant activity—providing the first direct link between CXCL14 epigenetic loss and impaired immune recruitment.\",\n      \"evidence\": \"MSP, bisulfite sequencing, 5-aza-dC restoration, DC chemotaxis with affinity depletion confirmation\",\n      \"pmids\": [\"20460540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferase(s) responsible not identified at this point\", \"Whether methylation-mediated silencing occurs in vivo in patient tumors not formally tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CXCL14 was identified as a high-affinity CXCR4 binder that inhibits CXCL12-mediated chemotaxis via receptor internalization, with the C-terminal domain (residues 51–77) mapped as the CXCR4-binding determinant; however, a contradicting study found no direct CXCR4 modulation in reconstituted systems, leaving the CXCL14–CXCR4 relationship unresolved.\",\n      \"evidence\": \"Radioligand binding, CXCR4 internalization, truncation/mutagenesis; counter-evidence from CXCR4-transfected HEK293/Jurkat signaling panel (Ca²⁺, ERK, DMR, internalization)\",\n      \"pmids\": [\"23669361\", \"24161674\", \"25451233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy between endogenous and overexpression systems unresolved\", \"Whether CXCL14 requires a co-receptor or accessory factor for CXCR4 engagement not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies established CXCL14's antitumor immune mechanism in vivo: IRX1 was placed upstream of CXCL14/NF-κB in osteosarcoma metastasis, while transgenic CXCL14 suppressed tumors through an NK cell–dependent mechanism demonstrated by antibody depletion.\",\n      \"evidence\": \"IRX1 overexpression/knockdown epistasis with NF-κB reporter and murine metastasis model; CXCL14-transgenic mice with anti-asialo-GM1 NK depletion\",\n      \"pmids\": [\"25822025\", \"25765541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NK cells are directly recruited by CXCL14 or activated indirectly not distinguished\", \"IRX1 direct binding to CXCL14 promoter not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The HPV E7 oncoprotein was shown to induce CXCL14 promoter DNA hypermethylation, mechanistically explaining CXCL14 loss in HPV-positive cancers; restoration of CXCL14 cleared tumors in immunocompetent but not Rag1-knockout mice, proving adaptive immunity is required.\",\n      \"evidence\": \"E7 gain/loss of function, promoter methylation mapping, syngeneic tumor model, Rag1-KO epistasis, flow cytometry\",\n      \"pmids\": [\"27143385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific methyltransferase recruited by E7 not identified\", \"Whether E7 acts directly on CXCL14 promoter or through intermediaries not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The CXCL14–CXCR4 discrepancy was resolved by showing CXCL14 acts as a positive allosteric modulator of CXCR4: it binds CXCR4, redistributes it on the cell surface, and synergizes with sub-active CXCL12 for supramaximal chemotaxis and enhanced HIV-1 infection, without triggering canonical CXCR4 signaling alone.\",\n      \"evidence\": \"Chemotaxis synergy, Ca²⁺/ERK/Rac1 negative results for CXCL14 alone, CXCR4 redistribution by confocal, HIV-1 infection assay\",\n      \"pmids\": [\"28360196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for allosteric modulation not determined\", \"Whether allosteric mechanism applies to all CXCR4-expressing cell types unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple new biological contexts for CXCL14 were established: HIF-1α directly binds the CXCL14 promoter to drive ischemia-dependent expression and DC homing in stroke; CXCL14 activates p38/JNK/CREB to regulate steroidogenesis; and Cxcl14 depletion accelerates myogenic differentiation through ERK1/2-dependent cell cycle withdrawal.\",\n      \"evidence\": \"ChIP (HIF-1α at CXCL14 promoter), stroke mouse model; p38/JNK inhibitors in primary granulosa cells; Cxcl14-KO mice muscle regeneration with BrdU incorporation\",\n      \"pmids\": [\"28382159\", \"33129993\", \"28775895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HIF-1α regulation not validated in non-neural tissues\", \"Receptor mediating p38/JNK signaling in granulosa cells unidentified\", \"ERK1/2 mechanism in myoblasts may be indirect\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ACKR2 was identified as a functional CXCL14 receptor mediating fibroblast-to-cancer cell paracrine EMT signaling; CXCL14 was shown to restore MHC-I on HPV+ cancer cells and recruit antigen-specific CD8+ T cells; and GAG interactions were structurally characterized, revealing sulfation-dependent specificity.\",\n      \"evidence\": \"ACKR2 siRNA/shRNA with invasion/metastasis models and NOS1 inhibition; MHC-I knockdown and TCR-transgenic mouse epistasis; NMR/thermophoresis GAG binding characterization\",\n      \"pmids\": [\"30850359\", \"31417179\", \"31264681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACKR2 signals directly or through ligand scavenging affecting other chemokines not fully distinguished\", \"GAG binding functional consequences in vivo untested\", \"How CXCL14 upregulates MHC-I expression is mechanistically undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Epigenetic repression of Cxcl14 in neural progenitors was shown to depend on H2A.Z.2 recruiting G9a to deposit H3K9me2 at the promoter, with conditional deletion causing microglial accumulation—linking CXCL14 to brain immune homeostasis during development.\",\n      \"evidence\": \"NPC-specific H2A.Z.2 conditional KO, ChIP for H2A.Z.2/G9a/H3K9me2, immunohistochemistry\",\n      \"pmids\": [\"31712428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether G9a inhibition alone is sufficient to derepress Cxcl14 not tested pharmacologically\", \"Functional consequences of microglial accumulation on brain development not explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Systematic receptor screening showed CXCL14 does not activate any known conventional or atypical chemokine receptor in β-arrestin or chemotaxis assays but preferentially synergizes with homeostatic chemokine systems (CXCR4/CXCL12, CXCR5/CXCL13, CCR7/CCL19), reinforcing the allosteric modulator model; NFATc2/p300 was identified as an epigenetic activator depositing H4 acetylation at the CXCL14 promoter in neuropathic pain; and T cell depletion in oral cancer proved CXCL14 antitumor effects require T cell–mediated immunity.\",\n      \"evidence\": \"GPCR panel screening, β-arrestin/Ca²⁺/chemotaxis assays, CCL19 competitive binding; ChIP-seq/ChIP for NFATc2/p300/H4Ac; shRNA/OE with T cell depletion in syngeneic model\",\n      \"pmids\": [\"33123134\", \"33070779\", \"32958684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CXCL14 synergizes with CCR7 and CXCR5 systems not defined\", \"Whether NFATc2 regulation is tissue-specific or generalizable unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Direct CXCL14–CXCR4 interaction on platelets was confirmed by co-immunoprecipitation and functional validation using both CXCL14-KO and CXCR4-KO platelets, establishing a CXCR4-dependent role for CXCL14 in platelet migration and thrombus formation.\",\n      \"evidence\": \"Co-IP, confocal, flow-chamber thrombus assay, CXCL14-KO mouse platelets, CXCR4-KO mouse and iPSC-derived platelets\",\n      \"pmids\": [\"32239134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether platelet CXCL14–CXCR4 interaction operates allosterically (as in leukocytes) or through a distinct mechanism not tested\", \"In vivo thrombosis model not performed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Downstream signaling through ACKR2 was elaborated: CXCL14 activates PLCβ3/PKCα/c-Src/NF-κB to drive EMT and lung metastasis in NSCLC; Brg1 was identified as a direct transcriptional activator of CXCL14 in hepatocytes driving neutrophil recruitment in alcoholic liver disease; and CXCL14 was shown to inhibit CML leukemia-initiating stem cells by downregulating mTOR and oxidative phosphorylation.\",\n      \"evidence\": \"ACKR2 knockdown with PLCβ3/PKCα/c-Src/NF-κB signaling in NSCLC orthotopic model; Brg1 KO/OE epistasis with CXCL14 in ALD mouse model; RNA-seq and PDX model for CML\",\n      \"pmids\": [\"37056937\", \"36722664\", \"37018663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ACKR2 signaling cascade not validated with reconstituted components\", \"Whether Brg1 binds CXCL14 promoter directly not shown by ChIP\", \"CML mTOR suppression mechanism indirect and correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two major receptor discoveries emerged: CXCL14 binds integrin α11β1 on fibroblasts to activate actomyosin contractility and TGFβ secretion promoting osteosarcoma invasion; and MRGPRX2 was identified as a bona fide cognate GPCR for CXCL14, activated potently by the C-terminal domain through G protein and β-arrestin pathways. Additionally, CXCL14 secreted by p21+ perinecrotic hepatocytes was shown to be the critical pathogenic mediator in APAP-induced liver failure.\",\n      \"evidence\": \"Co-IP of CXCL14–integrin α11β1, anti-CXCL14/integrin mAb in vivo metastasis model; GPCR panel screen, MRGPRX2 antagonist, truncation/mutagenesis defining C-terminal pharmacophore; spatial transcriptomics, CXCL14-neutralizing antibody vs senolytics in APAP model\",\n      \"pmids\": [\"38295227\", \"38184723\", \"38614205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MRGPRX2 mediates the classical monocyte/DC chemotactic activities attributed to CXCL14 not tested\", \"Integrin α11β1 interaction not validated structurally\", \"APAP liver injury findings require independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: which receptor(s) mediate CXCL14's chemotactic activity toward monocytes and immature DCs (MRGPRX2, CXCR4, ACKR2, integrin α11β1, or an unidentified receptor); the structural basis for CXCL14's allosteric modulation of CXCR4 and synergy with homeostatic chemokine systems; and how CXCL14 restores MHC-I expression on tumor cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cognate receptor for monocyte/iDC chemotaxis remains unresolved despite multiple receptor candidates\", \"No structural model of CXCL14–CXCR4 allosteric complex exists\", \"Mechanism by which CXCL14 upregulates MHC-I is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 19, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3, 5, 9, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3, 14, 17, 24, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 16, 19, 20, 32]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 26, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CXCR4\",\n      \"ACKR2\",\n      \"MRGPRX2\",\n      \"ITGA11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}