{"gene":"AEBP1","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2018,"finding":"ACLP (AEBP1 extracellular isoform) enhances collagen polymerization and binds directly to several fibrillar collagens via its discoidin domain, as demonstrated by in vitro collagen polymerization assays and binding experiments; loss-of-function bi-allelic AEBP1 variants cause defective collagen fibril assembly in patient skin biopsies.","method":"In vitro collagen polymerization assay, direct binding assays, electron microscopy of patient skin biopsies, exome sequencing with functional validation","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — direct in vitro reconstitution of collagen binding and polymerization, validated by ultrastructural analysis of patient tissue, replicated across multiple families","pmids":["29606302"],"is_preprint":false},{"year":2006,"finding":"AEBP1 functions as a transcriptional repressor of the aP2 gene; its DNA-binding domain was mapped to a C-terminal basic region by EMSA, but wild-type AEBP1 does not interact strongly with DNA, suggesting it acts predominantly as a corepressor. The carboxypeptidase domain is critical for transcriptional repressor activity. AEBP1 also interacts with Ca2+/calmodulin through the same basic C-terminal region.","method":"Luciferase reporter assay in CHO cells, electrophoretic mobility shift assay (EMSA), deletion/point mutagenesis, homology modeling","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro functional assays with mutagenesis in a single study, single lab","pmids":["16538615"],"is_preprint":false},{"year":2010,"finding":"AEBP1 physically interacts with IκBα and promotes NF-κB transcriptional activity in macrophages; AEBP1-mediated downregulation of IκBα leads to enhanced NF-κB activation, establishing AEBP1 as a positive regulator of the canonical NF-κB pathway in macrophages.","method":"Protein-protein interaction (physical interaction with IκBα demonstrated), NF-κB reporter assays, macrophage gain/loss-of-function experiments","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct physical interaction reported, functional consequences in macrophages demonstrated, but primarily a review summarizing original findings; methodology details limited in abstract","pmids":["20396415"],"is_preprint":false},{"year":2010,"finding":"AEBP1 negatively regulates PPARγ1 and LXRα transcriptional activity in macrophages, thereby impeding cholesterol efflux mediators (ABCA1, ABCG1, ApoE) and promoting foam cell formation.","method":"Reporter assays, macrophage cholesterol efflux assays, gain/loss-of-function in macrophages","journal":"Nuclear receptor signaling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional regulation of PPARγ1 and LXRα demonstrated in macrophage context, primarily a review of original findings; single lab","pmids":["20419060"],"is_preprint":false},{"year":2005,"finding":"AEBP1 negatively regulates PTEN through a direct protein-protein interaction; transgenic overexpression of AEBP1 leads to reduced PTEN levels and hyperactivation of survival signaling in adipose tissue, promoting adipocyte hyperplasia and diet-induced obesity in female mice.","method":"Transgenic mouse model (AEBP1 overexpression), protein-protein interaction, western blot for PTEN levels, histological analysis of adipose tissue","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-protein interaction with PTEN reported, in vivo genetic model with defined phenotype, single lab","pmids":["16307171"],"is_preprint":false},{"year":2013,"finding":"Recombinant ACLP induces myofibroblast differentiation (SMA and collagen expression) in lung fibroblasts. ACLP-induced SMA expression occurs via TGFβ receptor-dependent Smad3 phosphorylation and nuclear translocation, while ACLP-induced collagen expression is TGFβ receptor-independent. ACLP knockdown slows fibroblast-to-myofibroblast transition.","method":"Recombinant protein treatment, siRNA knockdown, phospho-Smad3 immunoblot, nuclear translocation assay, TGFβ receptor kinase inhibitor, bleomycin fibrosis mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant protein reconstitution, receptor inhibition, phosphorylation readout, both gain- and loss-of-function, multiple cell types including human cells","pmids":["24344132"],"is_preprint":false},{"year":2013,"finding":"AEBP1 is upregulated in PLX4032-resistant melanoma cells due to hyperactivation of PI3K/Akt-CREB signaling, and AEBP1 in turn activates NF-κB by accelerating IκBα degradation, establishing a PI3K/Akt-CREB-AEBP1-NF-κB pathway that confers resistance to BRAF inhibition.","method":"PI3K/Akt pathway inhibition, AEBP1 overexpression/knockdown, IκBα degradation assay, NF-κB reporter assay, patient tumor samples","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with inhibitors and KD/OE, validated in patient tumors; single lab with multiple methods","pmids":["24201813"],"is_preprint":false},{"year":2011,"finding":"Macrophage-specific AEBP1 overexpression promotes atherosclerosis via reduced expression of PPARγ1, LXRα, ABCA1, and ABCG1 and increased inflammatory mediators IL-6 and TNFα. Ablation of AEBP1 significantly attenuates atherosclerosis. Bone marrow transplantation experiments confirmed that the pro-atherogenic effects are macrophage-mediated.","method":"Transgenic mouse model, AEBP1 knockout mice, bone marrow transplantation into ApoE-/- and LDLR-/- mice, quantitative lesion analysis, gene expression","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with gain- and loss-of-function, bone marrow transplantation epistasis, replicated across multiple mouse models","pmids":["21687917"],"is_preprint":false},{"year":2012,"finding":"Stromal macrophage AEBP1 overexpression induces mammary epithelial hyperplasia via NF-κB/TNFα-mediated paracrine signaling and induction of sonic hedgehog (Shh) in macrophages, leading to Gli1 and Bmi1 expression in mammary epithelium. Bone marrow transplantation of AEBP1-transgenic cells into non-transgenic mice recapitulates alveolar hyperplasia.","method":"Transgenic mouse model, bone marrow transplantation, co-culture experiments, conditioned media, TNFα neutralizing antibody, reporter assays for NF-κB","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — bone marrow transplantation epistasis, neutralizing antibody rescue, co-culture mechanistic dissection, multiple orthogonal methods","pmids":["22995915"],"is_preprint":false},{"year":2012,"finding":"AEBP1 occupies genomic promoter sites in glioma cells (U87MG) and regulates a large set of genes involved in proliferation and apoptosis. A consensus binding motif GAAAT was identified in 66% of ChIP-chip-identified target promoters and validated by luciferase reporter assay. AEBP1 silencing reduces glioma cell proliferation and survival and promotes apoptosis.","method":"ChIP-chip with Agilent human promoter tiling array, ChIP-PCR validation, siRNA knockdown, luciferase reporter assay, qRT-PCR","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ChIP-chip with validation by ChIP-PCR and reporter assay, combined with functional KD phenotype; single lab","pmids":["22723309"],"is_preprint":false},{"year":2011,"finding":"AEBP1-null female mice display failed mammary gland secretory activation at parturition, with cytoplasmic lipid droplet accumulation in mammary epithelial cells and milk protein accumulation, resulting in 100% neonatal lethality. Transplanting wild-type bone marrow (stromal AEBP1 restoration) rescues the mammary gland defect, indicating AEBP1 controls stromal-epithelial crosstalk.","method":"AEBP1 knockout mouse model, bone marrow transplantation rescue, histological analysis, immunostaining","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific phenotypic readout, rescue by bone marrow transplantation establishing stromal mechanism","pmids":["22114697"],"is_preprint":false},{"year":2019,"finding":"AEBP1 down-regulation in PTEN-deficient glioma cells (U87MG, U138MG) triggers PARP-1 hyperactivation (parthanatos-like cell death) rather than caspase-dependent apoptosis, with AIF mitochondrial release and nuclear translocation. In PTEN-proficient cells, AEBP1 knockdown induces caspase-dependent apoptosis. AEBP1 positively regulates PI3KCβ by binding the AE-1 element in its promoter, and loss of PI3KCβ causes excessive DNA damage.","method":"siRNA knockdown, PARP-1 activation assay, AIF translocation imaging, caspase activity assay, ChIP/promoter binding assay, PIK3CB overexpression rescue, PTEN-reconstitution experiment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding demonstrated by ChIP, rescue by PIK3CB overexpression, mechanistic dissection across PTEN-proficient/deficient isogenic systems, multiple orthogonal methods","pmids":["31601918"],"is_preprint":false},{"year":2019,"finding":"AEBP1 promotes AAA development by activating the NF-κB pathway in vascular smooth muscle cells, leading to upregulation of pro-inflammatory factors and matrix metalloproteinases (MMPs). In vivo AEBP1 knockdown via intra-adventitial adenovirus suppresses AAA progression in a rat elastase model.","method":"Rat AAA model (elastase), in vivo adenoviral AEBP1 silencing, siRNA/overexpression in human vascular smooth muscle cells, NF-κB inhibitor BAY 11-7082, western blot, ELISA","journal":"Journal of atherosclerosis and thrombosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro genetic manipulation with pathway inhibitor validation; single lab, multiple methods","pmids":["31462616"],"is_preprint":false},{"year":2021,"finding":"ACT001 (parthenolide derivative) blocks TGF-β-activated AEBP1/AKT signaling in glioma stem-like cells. AEBP1 knockdown impairs AKT phosphorylation and GSC proliferation, and constitutively active AKT rescues AEBP1 depletion-inhibited proliferation, placing AEBP1 upstream of PI3K/AKT in GSCs.","method":"siRNA knockdown, constitutively active AKT rescue, PI3K inhibitor, ACT001 treatment, orthotopic xenograft model, RNA-Seq","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via constitutively active AKT rescue, in vivo xenograft, but single lab","pmids":["33391492"],"is_preprint":false},{"year":2023,"finding":"AEBP1 siRNA knockdown in human retinal pericytes (high glucose conditions) reduces expression of profibrotic markers, and AEBP1 is upregulated in myofibroblast clusters of proliferative diabetic retinopathy fibrovascular membranes, establishing a role for AEBP1 in pericyte-to-myofibroblast transdifferentiation.","method":"Single-cell RNA-seq (scRNA-seq) of patient membranes, siRNA knockdown in human retinal pericytes under high-glucose conditions, fibrotic marker immunostaining","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — scRNA-seq discovery validated by siRNA functional experiment in primary human cells; single lab","pmids":["37917183"],"is_preprint":false},{"year":2023,"finding":"ACLP in cancer-associated fibroblasts (CAFs) of oral squamous cell carcinoma is induced by cancer-cell-derived TGF-β1; ACLP contributes to CAF activation (collagen gel contraction), promotes cancer cell migration and invasion, and attenuates CD8+ T cell migration into tumors.","method":"Co-culture with OSCC cells and TGF-β1 treatment, collagen gel contraction assay, Boyden chamber migration assay, in vivo tumor formation, immunohistochemistry","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TGF-β1 induction established by treatment experiment, functional assays for CAF activation and T cell exclusion; single lab, multiple methods","pmids":["37686580"],"is_preprint":false},{"year":2022,"finding":"In pancreatic cancer CAFs, ACLP promotes CAF activation and cancer cell invasion via upregulation of MMP1 and MMP3. An ACLP-PPARγ-ACLP positive feedback loop was identified in PDAC CAFs, where ACLP suppresses PPARγ (which normally represses ACLP), sustaining CAF activation.","method":"siRNA/overexpression in CAFs, CAF activation marker assays, MMP1/MMP3 expression analysis, PPARγ modulation, invasion assays, in vivo metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic feedback loop established by gain/loss-of-function with PPARγ modulation; single lab","pmids":["35732215"],"is_preprint":false},{"year":2023,"finding":"AEBP1 knockdown in renal tubular cells and in vivo (UUO model) inhibits renal fibrosis by blocking nuclear β-catenin and its downstream targets (Axin2, Myc, Ccnd1). Constitutively active β-catenin-S33Y restores fibrotic gene expression after AEBP1 silencing, placing AEBP1 upstream of the Wnt/β-catenin pathway in renal fibrosis.","method":"siRNA knockdown, UUO mouse model, constitutively active β-catenin rescue, western blot, collagen staining, EMT marker analysis","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis confirmed by β-catenin rescue experiment, in vivo model; single lab","pmids":["36738398"],"is_preprint":false},{"year":2024,"finding":"AEBP1 promotes papillary thyroid cancer progression by directly binding the BMP4 promoter and driving its transcription (established by dual-luciferase reporter and ChIP assay). BMP4 overexpression rescues the growth/invasion inhibition caused by AEBP1 knockout, placing AEBP1 upstream of BMP4 in PTC.","method":"AEBP1 CRISPR knockout, RNA-sequencing, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), BMP4 overexpression rescue, xenograft mouse model","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct promoter binding by ChIP, reporter assay, epistasis rescue, in vivo xenograft; multiple orthogonal methods in single lab","pmids":["38237535"],"is_preprint":false},{"year":2024,"finding":"AEBP1 transcriptionally represses PRKCA expression (established by luciferase reporter and ChIP). Loss of PI3K/AKT signaling due to reduced PRKCA after AEBP1 silencing leads to neuron ferroptosis and impaired microglia M2 polarization in cerebral ischemia/reperfusion; PRKCA inhibition reverses the protective effects of AEBP1 knockdown.","method":"siRNA knockdown, luciferase reporter assay, ChIP, PRKCA/PI3K-AKT inhibitor rescue, OGD/R cell model, MCAO mouse model, ROS/GSH/iron assays","journal":"Drug development research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding for PRKCA by ChIP and reporter, epistasis with inhibitors; single lab, multiple methods","pmids":["39670965"],"is_preprint":false},{"year":2025,"finding":"Autocrine AEBP1 in cancer-associated fibroblasts binds CKAP4 on the CAF surface, activating AKT/PD-L1 signaling to suppress T cell cytotoxicity. Fibroblast-specific AEBP1 deletion enhances T cell cytotoxicity and suppresses tumor growth. A small molecule (Chem-0199) identified by molecular docking disrupts the AEBP1-CKAP4 interaction and synergizes with anti-PD-1.","method":"RNA-seq, scRNA-seq, fibroblast-specific AEBP1 knockout mice, molecular docking, direct protein-protein interaction assay (AEBP1-CKAP4), AKT/PD-L1 signaling assays, syngeneic tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein-protein interaction (AEBP1-CKAP4) established, in vivo fibroblast-specific KO, pharmacological validation, multiple orthogonal approaches","pmids":["40890191"],"is_preprint":false},{"year":2025,"finding":"AEBP1 directly binds the DDR2 promoter to drive its transcription, promoting LPS-induced ferroptosis and inflammatory/M1 microglial polarization via STAT3/P53 signaling in BV2 cells. DDR2 knockdown counteracted the pathological effects of AEBP1.","method":"Luciferase reporter assay, ChIP assay (AEBP1 binding to DDR2 promoter), siRNA knockdown, STAT3/P53 pathway inhibition, ferroptosis markers, microglial polarization assays","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated by ChIP and luciferase, DDR2 KD epistasis; single lab","pmids":["41083137"],"is_preprint":false},{"year":2025,"finding":"AEBP1 directly interacts with PI3K (p110β subunit) as demonstrated by protein docking, co-immunoprecipitation, and surface plasmon resonance (SPR). AEBP1 overexpression impairs insulin signaling and glucose transport in skeletal muscle cells, exacerbating insulin resistance; AEBP1 knockdown reverses these changes.","method":"Protein docking, co-immunoprecipitation (co-IP), surface plasmon resonance (SPR), AEBP1 overexpression/knockdown in C2C12 and human skeletal muscle cells, insulin signaling assays","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct protein-protein interaction validated by three orthogonal methods (docking, co-IP, SPR); functional insulin signaling phenotype confirmed; single lab but rigorous","pmids":["40618921"],"is_preprint":false},{"year":2026,"finding":"ACLP (AEBP1 extracellular isoform) regulates pro-fibrotic transcription factors and genes including MRTFB, RUNX2, SM22, and COL1A1 in cardiac fibroblasts. Fibroblast-specific and cardiac-specific Aebp1 knockout in mice improves cardiac function in ischemia and pressure-overload models. In ex vivo human myocardial tissue, ACLP overexpression in non-failing hearts induces pathological remodeling, while AEBP1 knockdown in failing hearts induces structural reverse remodeling.","method":"Fibroblast-specific knockout mice (myocardial ischemia and pressure-overload models), cardiac-specific knockdown, ex vivo human myocardial tissue culture (ACLP overexpression/AEBP1 KD), RNA sequencing for downstream targets","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo fibroblast-specific KO with functional cardiac readout, ex vivo human tissue validation; preprint, single lab","pmids":["42245802"],"is_preprint":true},{"year":2026,"finding":"In astrocytes, AEBP1 sequesters NPAS3 in the cytoplasm, reducing NPAS3 binding to the LIPA promoter and thereby repressing LIPA (lysosomal acid lipase) expression. AEBP1-mediated LIPA repression leads to lipid droplet accumulation, excess cholesteryl ester storage, and lysosomal Aβ retention. Astrocyte-specific AEBP1 knockdown ameliorates, while overexpression worsens, amyloid-β pathology in 5×FAD mice.","method":"Astrocyte-specific AEBP1 knockdown and overexpression in 5×FAD mice, NPAS3 nuclear/cytoplasmic fractionation, LIPA promoter binding (chromatin analysis), LIPA overexpression rescue, hippocampal transcriptomics and metabolomics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanism established by cytoplasmic sequestration of NPAS3, LIPA promoter binding, rescue by LIPA overexpression, in vivo astrocyte-specific genetic manipulation with multiple readouts","pmids":["41880326"],"is_preprint":false},{"year":2025,"finding":"Aebp1 loss in osteoprogenitors (OsxCre conditional KO) reduces bone mass and impairs osteoblast differentiation. Mechanistically, Aebp1 deletion attenuates Wnt/β-catenin signaling in bone. Restoration of Wnt/β-catenin by injecting BIO (GSK3 inhibitor) substantially rescues bone mass reduction in Aebp1-KO mice.","method":"OsxCre conditional knockout mice, siRNA knockdown in primary osteoblasts, Wnt/β-catenin signaling assays, BIO (GSK3 inhibitor) rescue, bone histomorphometry","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with pharmacological rescue establishing Wnt/β-catenin as downstream pathway; in vitro siRNA confirms cell-autonomous effect; multiple methods","pmids":["41231548"],"is_preprint":false},{"year":2026,"finding":"TWIST1 directly regulates AEBP1 transcription in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis; AEBP1 in turn activates TGFβ signaling to drive fibroblast activation, migration, and proliferation, and induces POSTN expression to promote angiogenesis. Intra-articular AEBP1 modulation and pharmacological TWIST1 inhibition by harmine alters synovial hyperplasia and bone erosion in CIA mice.","method":"Bulk RNA-seq, proteomics, scRNA-seq, functional assays for FLS activation/migration/proliferation, CIA mouse model with AEBP1 intra-articular modulation, harmine (TWIST1 inhibitor) treatment","journal":"Arthritis & rheumatology (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CIA model with pharmacological and genetic modulation, pathway dissection; single lab","pmids":["41787682"],"is_preprint":false},{"year":2025,"finding":"AEBP1 knockout in CAFs (both isoforms) decreases CAF proliferation, collagen gel contractility, and CAF-mediated tumor cell proliferation. AEBP1 KO downregulates collagen biosynthesis and ECM organization pathways in both mouse and human CAFs, reduces tumor EMT signature in vivo, and enhances anti-PD-1 efficacy.","method":"CRISPR gene editing (combined KO of both isoforms), collagen gel contractility assay, co-implantation mouse model, RNA-seq, anti-PD-1 combination treatment in syngeneic models","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple functional assays, RNA-seq, in vivo model; single lab, multiple methods","pmids":["41024581"],"is_preprint":false},{"year":2025,"finding":"AEBP1 mediates TWIST1-driven endothelial proliferation and COL4A1 upregulation; in atherosclerotic plaques, TWIST1 induces AEBP1 transcription which upregulates COL4A1 to drive endothelial cell proliferation and plaque collagen deposition.","method":"Single-cell RNA-seq of murine atherosclerotic plaques with inducible Twist1 ECKO, transcriptional analysis of AEBP1-COL4A1 axis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional relationship identified in scRNA-seq context; mechanistic detail for AEBP1 specifically is limited in the abstract; preprint, single study","pmids":[],"is_preprint":true},{"year":2024,"finding":"AEBP1 is a negative regulator of skeletal muscle differentiation; AEBP1 knockdown in human skeletal muscle myoblasts upregulates myogenesis-related genes including MYOG, while ectopic AEBP1 expression suppresses these genes. TGF-β1 treatment upregulates AEBP1 and suppresses muscle differentiation genes.","method":"siRNA knockdown, ectopic AEBP1 overexpression, transcriptome analysis, qRT-PCR and western blot for myogenesis markers, TGF-β1 treatment, indirect co-culture with OSCC cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in primary human skeletal muscle cells with transcriptomic validation; single lab","pmids":["39521917"],"is_preprint":false}],"current_model":"AEBP1 encodes two protein isoforms — an intracellular transcriptional repressor (AEBP1) and a secreted extracellular matrix protein (ACLP) — that mechanistically regulate collagen fibrillogenesis (via discoidin domain-mediated fibrillar collagen binding and polymerization), NF-κB signaling (by physically interacting with IκBα to promote its degradation), PPARγ/LXRα-mediated cholesterol efflux in macrophages, fibroblast-to-myofibroblast differentiation (via TGFβ receptor-dependent Smad3 phosphorylation for SMA and a TGFβ receptor-independent pathway for collagen), Wnt/β-catenin signaling in osteoblasts, PI3K (p110β) signaling in skeletal muscle insulin resistance, NPAS3-LIPA-mediated lysosomal cholesterol catabolism in astrocytes, and T cell dysfunction through autocrine AEBP1-CKAP4-AKT/PD-L1 signaling in cancer-associated fibroblasts."},"narrative":{"mechanistic_narrative":"AEBP1 encodes two functionally distinct isoforms — an intracellular transcriptional regulator (AEBP1) and a secreted extracellular matrix protein (ACLP) — that together govern collagen matrix assembly, fibroblast activation, and signaling-dependent proliferation across many tissues [PMID:29606302, PMID:24344132]. As a secreted protein, ACLP binds fibrillar collagens directly through its discoidin domain and promotes collagen polymerization; bi-allelic loss-of-function AEBP1 variants produce defective collagen fibril assembly in patient skin, establishing a Mendelian connective-tissue disorder [PMID:29606302]. ACLP drives fibroblast-to-myofibroblast differentiation, inducing SMA via TGFβ-receptor-dependent Smad3 phosphorylation and collagen via a TGFβ-receptor-independent route [PMID:24344132], a fibrogenic program recurrently deployed in cancer-associated fibroblasts, where cancer-cell-derived TGFβ1 induces ACLP to sustain CAF activation and matrix contraction [PMID:37686580, PMID:35732215]. In its intracellular role, AEBP1 acts as a transcriptional regulator with a C-terminal DNA-binding region, functioning largely as a corepressor whose carboxypeptidase domain is required for repressor activity [PMID:16538615]; it occupies promoters genome-wide and directly binds defined target promoters to either activate (BMP4, DDR2, PI3KCβ) or repress (PRKCA, LIPA) transcription [PMID:22723309, PMID:38237535, PMID:41083137, PMID:31601918, PMID:39670965, PMID:41880326]. AEBP1 amplifies multiple proliferative and inflammatory signaling axes: it physically interacts with IκBα to accelerate its degradation and potentiate canonical NF-κB signaling in macrophages and vascular smooth muscle [PMID:20396415, PMID:31462616], represses PPARγ/LXRα to impair macrophage cholesterol efflux and promote atherosclerosis [PMID:20419060, PMID:21687917], and feeds into PI3K/AKT signaling — binding the p110β subunit directly to impair insulin signaling in skeletal muscle [PMID:40618921] and acting upstream of AKT in glioma [PMID:33391492]. In vivo genetic models establish that AEBP1 controls stromal-epithelial crosstalk in the mammary gland, Wnt/β-catenin-dependent osteoblast differentiation and bone mass, and astrocyte cholesterol catabolism via cytoplasmic sequestration of NPAS3 and consequent LIPA repression in amyloid pathology [PMID:22114697, PMID:41231548, PMID:41880326]. At the tumor-stroma interface, autocrine AEBP1 binds CKAP4 on the CAF surface to drive AKT/PD-L1 signaling and suppress T cell cytotoxicity [PMID:40890191].","teleology":[{"year":2005,"claim":"Established AEBP1 as an in vivo regulator of survival signaling, showing it lowers PTEN levels through direct interaction to promote adipocyte hyperplasia and obesity.","evidence":"AEBP1-overexpressing transgenic mice with protein-interaction and PTEN immunoblot","pmids":["16307171"],"confidence":"Medium","gaps":["Interaction surface and mechanism of PTEN destabilization not mapped","Sex-specific phenotype not explained mechanistically"]},{"year":2006,"claim":"Defined the molecular basis of AEBP1's intracellular transcriptional repressor activity, mapping a C-terminal basic DNA-binding/calmodulin-binding region and showing the carboxypeptidase domain is required for repression.","evidence":"Luciferase reporter and EMSA with deletion/point mutagenesis in CHO cells","pmids":["16538615"],"confidence":"Medium","gaps":["Weak direct DNA binding implies a corepressor mode not fully defined","Catalytic role of carboxypeptidase domain in repression unresolved","Single lab, single study"]},{"year":2010,"claim":"Linked AEBP1 to inflammatory and lipid-handling transcriptional programs in macrophages, showing it potentiates NF-κB by promoting IκBα turnover and represses PPARγ/LXRα-driven cholesterol efflux.","evidence":"IκBα physical interaction, NF-κB and nuclear-receptor reporter assays, macrophage cholesterol efflux assays","pmids":["20396415","20419060"],"confidence":"Medium","gaps":["Mechanism of IκBα degradation (E3 recruitment vs. direct) not defined","How a transcriptional repressor mechanistically downregulates PPARγ/LXRα activity unclear"]},{"year":2011,"claim":"Provided in vivo proof that macrophage AEBP1 is pro-atherogenic and that stromal AEBP1 controls mammary secretory activation, establishing cell-non-autonomous AEBP1 functions.","evidence":"Transgenic and knockout mice with bone marrow transplantation into ApoE/LDLR models and mammary rescue","pmids":["21687917","22114697"],"confidence":"High","gaps":["Direct molecular targets in vivo not pinpointed","Relative contribution of NF-κB vs PPARγ/LXRα arms in atherosclerosis not separated"]},{"year":2012,"claim":"Connected stromal AEBP1 to epithelial transformation and mapped genome-wide AEBP1 promoter occupancy, defining a GAAAT consensus motif and proliferation/apoptosis target set.","evidence":"Bone marrow transplantation with TNFα neutralization and co-culture; ChIP-chip with ChIP-PCR and reporter validation in glioma cells","pmids":["22995915","22723309"],"confidence":"High","gaps":["Direct vs corepressor binding at GAAAT sites not resolved","Co-factors mediating activation vs repression at targets unknown"]},{"year":2013,"claim":"Mechanistically separated ACLP-induced myofibroblast outputs and placed AEBP1 in a drug-resistance signaling circuit, showing SMA induction is TGFβ-receptor/Smad3-dependent while collagen induction is receptor-independent.","evidence":"Recombinant ACLP treatment with TGFβ receptor inhibitor and phospho-Smad3 readout; PI3K/Akt-CREB-AEBP1-NF-κB pathway dissection in PLX4032-resistant melanoma","pmids":["24344132","24201813"],"confidence":"High","gaps":["Receptor/signaling intermediate for TGFβ-independent collagen induction unidentified","How ACLP engages the TGFβ receptor not defined"]},{"year":2019,"claim":"Defined AEBP1 as a direct transcriptional activator of PI3KCβ and a determinant of death-pathway choice in glioma, and established its pro-inflammatory role in aneurysm.","evidence":"ChIP/promoter binding (AE-1 element) with PIK3CB overexpression rescue in PTEN-isogenic glioma cells; rat elastase AAA model with adenoviral silencing","pmids":["31601918","31462616"],"confidence":"High","gaps":["How PTEN status switches caspase-dependent vs parthanatos death not fully resolved","Direct vs corepressor binding at the AE-1 element unclear"]},{"year":2022,"claim":"Established ACLP as a self-reinforcing driver of CAF activation, identifying an ACLP-PPARγ-ACLP feedback loop and MMP1/MMP3 induction in pancreatic cancer stroma.","evidence":"Gain/loss-of-function in CAFs with PPARγ modulation, invasion and in vivo metastasis assays","pmids":["35732215"],"confidence":"Medium","gaps":["Mechanism by which ACLP suppresses PPARγ not defined","Direct ACLP receptor on CAFs not identified"]},{"year":2023,"claim":"Generalized ACLP/AEBP1 as a TGFβ-inducible driver of stromal fibrosis and immune exclusion across tissues, from OSCC CAFs to diabetic retinal pericytes and renal tubular Wnt/β-catenin signaling.","evidence":"TGFβ1 co-culture, collagen contraction and T cell migration assays; scRNA-seq with pericyte siRNA; UUO model with constitutively active β-catenin rescue","pmids":["37686580","37917183","36738398"],"confidence":"Medium","gaps":["Mechanism connecting AEBP1 to β-catenin stabilization not defined","Whether intracellular AEBP1 or secreted ACLP drives each phenotype not always disambiguated"]},{"year":2024,"claim":"Extended the direct-promoter-binding repertoire of AEBP1, showing transcriptional activation of BMP4 in thyroid cancer and repression of PRKCA in cerebral ischemia, and identified AEBP1 as a negative regulator of myogenesis.","evidence":"CRISPR KO with ChIP/reporter and BMP4 rescue; ChIP/reporter with PRKCA inhibitor rescue in MCAO model; gain/loss-of-function in human myoblasts","pmids":["38237535","39670965","39521917"],"confidence":"Medium","gaps":["What dictates AEBP1 activation vs repression at different promoters unknown","Co-regulators at BMP4/PRKCA promoters not identified"]},{"year":2025,"claim":"Resolved direct AEBP1 protein interactions driving signaling — binding p110β to impair insulin signaling, binding CKAP4 to drive AKT/PD-L1-mediated T cell suppression — and established Wnt/β-catenin-dependent control of bone mass.","evidence":"Docking/co-IP/SPR for p110β with skeletal-muscle insulin assays; 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/41880326","citation_count":0,"is_preprint":false},{"pmid":"40825823","id":"PMC_40825823","title":"Identification of foam cell like M2 macrophages, AEBP1 biomarkers, and resveratrol as potential therapeutic in MASLD using Ecotyper and WGCNA.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40825823","citation_count":0,"is_preprint":false},{"pmid":"41024581","id":"PMC_41024581","title":"Targeting AEBP1 to Mitigate Protumor Activity of Cancer-Associated Fibroblasts and Increase Therapeutic Efficacy of Anti-PD-1.","date":"2026","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41024581","citation_count":0,"is_preprint":false},{"pmid":"42149287","id":"PMC_42149287","title":"Single-cell profiling and machine learning identify cuproptosis-related fibroblast subpopulations and fibrogenesis modulator AEBP1 in endometriosis.","date":"2026","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/42149287","citation_count":0,"is_preprint":false},{"pmid":"41787682","id":"PMC_41787682","title":"TWIST1-Mediated Induction of AEBP1 in Fibroblast-Like Synoviocytes Activates Transforming Growth Factor β Signaling to Drive Angiogenesis and Promote Rheumatoid Arthritis.","date":"2026","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/41787682","citation_count":0,"is_preprint":false},{"pmid":"42245802","id":"PMC_42245802","title":"Adipocyte Enhancer Binding Protein 1 (AEBP1) Inhibition as a Potential Anti-Fibrotic Therapy in Heart Failure.","date":"2026","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/42245802","citation_count":0,"is_preprint":false},{"pmid":"23975792","id":"PMC_23975792","title":"Analysis of in vivo occupancy of Aebp1, a transcription factor, using high resolution tiling array.","date":"2013","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/23975792","citation_count":0,"is_preprint":false},{"pmid":"42191857","id":"PMC_42191857","title":"Gastrointestinal involvement in Ehlers-Danlos syndrome classical-like type 2 associated with a novel AEBP1 splice-site variant.","date":"2026","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/42191857","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.19.654847","title":"TWIST1 drives endothelial-to-mesenchymal-transition to stabilize atherosclerotic plaques","date":"2025-05-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.19.654847","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.10.602878","title":"Defining a Muscle Stem Cell matrisome signature: from transcriptome data to extracellular matrix niche topology","date":"2024-07-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.10.602878","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39651,"output_tokens":8210,"usd":0.121052,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17979,"output_tokens":5033,"usd":0.10786,"stage2_stop_reason":"end_turn"},"total_usd":0.228912,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"ACLP (AEBP1 extracellular isoform) enhances collagen polymerization and binds directly to several fibrillar collagens via its discoidin domain, as demonstrated by in vitro collagen polymerization assays and binding experiments; loss-of-function bi-allelic AEBP1 variants cause defective collagen fibril assembly in patient skin biopsies.\",\n      \"method\": \"In vitro collagen polymerization assay, direct binding assays, electron microscopy of patient skin biopsies, exome sequencing with functional validation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — direct in vitro reconstitution of collagen binding and polymerization, validated by ultrastructural analysis of patient tissue, replicated across multiple families\",\n      \"pmids\": [\"29606302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AEBP1 functions as a transcriptional repressor of the aP2 gene; its DNA-binding domain was mapped to a C-terminal basic region by EMSA, but wild-type AEBP1 does not interact strongly with DNA, suggesting it acts predominantly as a corepressor. The carboxypeptidase domain is critical for transcriptional repressor activity. AEBP1 also interacts with Ca2+/calmodulin through the same basic C-terminal region.\",\n      \"method\": \"Luciferase reporter assay in CHO cells, electrophoretic mobility shift assay (EMSA), deletion/point mutagenesis, homology modeling\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro functional assays with mutagenesis in a single study, single lab\",\n      \"pmids\": [\"16538615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AEBP1 physically interacts with IκBα and promotes NF-κB transcriptional activity in macrophages; AEBP1-mediated downregulation of IκBα leads to enhanced NF-κB activation, establishing AEBP1 as a positive regulator of the canonical NF-κB pathway in macrophages.\",\n      \"method\": \"Protein-protein interaction (physical interaction with IκBα demonstrated), NF-κB reporter assays, macrophage gain/loss-of-function experiments\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct physical interaction reported, functional consequences in macrophages demonstrated, but primarily a review summarizing original findings; methodology details limited in abstract\",\n      \"pmids\": [\"20396415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AEBP1 negatively regulates PPARγ1 and LXRα transcriptional activity in macrophages, thereby impeding cholesterol efflux mediators (ABCA1, ABCG1, ApoE) and promoting foam cell formation.\",\n      \"method\": \"Reporter assays, macrophage cholesterol efflux assays, gain/loss-of-function in macrophages\",\n      \"journal\": \"Nuclear receptor signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional regulation of PPARγ1 and LXRα demonstrated in macrophage context, primarily a review of original findings; single lab\",\n      \"pmids\": [\"20419060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"AEBP1 negatively regulates PTEN through a direct protein-protein interaction; transgenic overexpression of AEBP1 leads to reduced PTEN levels and hyperactivation of survival signaling in adipose tissue, promoting adipocyte hyperplasia and diet-induced obesity in female mice.\",\n      \"method\": \"Transgenic mouse model (AEBP1 overexpression), protein-protein interaction, western blot for PTEN levels, histological analysis of adipose tissue\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-protein interaction with PTEN reported, in vivo genetic model with defined phenotype, single lab\",\n      \"pmids\": [\"16307171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Recombinant ACLP induces myofibroblast differentiation (SMA and collagen expression) in lung fibroblasts. ACLP-induced SMA expression occurs via TGFβ receptor-dependent Smad3 phosphorylation and nuclear translocation, while ACLP-induced collagen expression is TGFβ receptor-independent. ACLP knockdown slows fibroblast-to-myofibroblast transition.\",\n      \"method\": \"Recombinant protein treatment, siRNA knockdown, phospho-Smad3 immunoblot, nuclear translocation assay, TGFβ receptor kinase inhibitor, bleomycin fibrosis mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant protein reconstitution, receptor inhibition, phosphorylation readout, both gain- and loss-of-function, multiple cell types including human cells\",\n      \"pmids\": [\"24344132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AEBP1 is upregulated in PLX4032-resistant melanoma cells due to hyperactivation of PI3K/Akt-CREB signaling, and AEBP1 in turn activates NF-κB by accelerating IκBα degradation, establishing a PI3K/Akt-CREB-AEBP1-NF-κB pathway that confers resistance to BRAF inhibition.\",\n      \"method\": \"PI3K/Akt pathway inhibition, AEBP1 overexpression/knockdown, IκBα degradation assay, NF-κB reporter assay, patient tumor samples\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with inhibitors and KD/OE, validated in patient tumors; single lab with multiple methods\",\n      \"pmids\": [\"24201813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Macrophage-specific AEBP1 overexpression promotes atherosclerosis via reduced expression of PPARγ1, LXRα, ABCA1, and ABCG1 and increased inflammatory mediators IL-6 and TNFα. Ablation of AEBP1 significantly attenuates atherosclerosis. Bone marrow transplantation experiments confirmed that the pro-atherogenic effects are macrophage-mediated.\",\n      \"method\": \"Transgenic mouse model, AEBP1 knockout mice, bone marrow transplantation into ApoE-/- and LDLR-/- mice, quantitative lesion analysis, gene expression\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with gain- and loss-of-function, bone marrow transplantation epistasis, replicated across multiple mouse models\",\n      \"pmids\": [\"21687917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Stromal macrophage AEBP1 overexpression induces mammary epithelial hyperplasia via NF-κB/TNFα-mediated paracrine signaling and induction of sonic hedgehog (Shh) in macrophages, leading to Gli1 and Bmi1 expression in mammary epithelium. Bone marrow transplantation of AEBP1-transgenic cells into non-transgenic mice recapitulates alveolar hyperplasia.\",\n      \"method\": \"Transgenic mouse model, bone marrow transplantation, co-culture experiments, conditioned media, TNFα neutralizing antibody, reporter assays for NF-κB\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bone marrow transplantation epistasis, neutralizing antibody rescue, co-culture mechanistic dissection, multiple orthogonal methods\",\n      \"pmids\": [\"22995915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AEBP1 occupies genomic promoter sites in glioma cells (U87MG) and regulates a large set of genes involved in proliferation and apoptosis. A consensus binding motif GAAAT was identified in 66% of ChIP-chip-identified target promoters and validated by luciferase reporter assay. AEBP1 silencing reduces glioma cell proliferation and survival and promotes apoptosis.\",\n      \"method\": \"ChIP-chip with Agilent human promoter tiling array, ChIP-PCR validation, siRNA knockdown, luciferase reporter assay, qRT-PCR\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ChIP-chip with validation by ChIP-PCR and reporter assay, combined with functional KD phenotype; single lab\",\n      \"pmids\": [\"22723309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AEBP1-null female mice display failed mammary gland secretory activation at parturition, with cytoplasmic lipid droplet accumulation in mammary epithelial cells and milk protein accumulation, resulting in 100% neonatal lethality. Transplanting wild-type bone marrow (stromal AEBP1 restoration) rescues the mammary gland defect, indicating AEBP1 controls stromal-epithelial crosstalk.\",\n      \"method\": \"AEBP1 knockout mouse model, bone marrow transplantation rescue, histological analysis, immunostaining\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific phenotypic readout, rescue by bone marrow transplantation establishing stromal mechanism\",\n      \"pmids\": [\"22114697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AEBP1 down-regulation in PTEN-deficient glioma cells (U87MG, U138MG) triggers PARP-1 hyperactivation (parthanatos-like cell death) rather than caspase-dependent apoptosis, with AIF mitochondrial release and nuclear translocation. In PTEN-proficient cells, AEBP1 knockdown induces caspase-dependent apoptosis. AEBP1 positively regulates PI3KCβ by binding the AE-1 element in its promoter, and loss of PI3KCβ causes excessive DNA damage.\",\n      \"method\": \"siRNA knockdown, PARP-1 activation assay, AIF translocation imaging, caspase activity assay, ChIP/promoter binding assay, PIK3CB overexpression rescue, PTEN-reconstitution experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding demonstrated by ChIP, rescue by PIK3CB overexpression, mechanistic dissection across PTEN-proficient/deficient isogenic systems, multiple orthogonal methods\",\n      \"pmids\": [\"31601918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AEBP1 promotes AAA development by activating the NF-κB pathway in vascular smooth muscle cells, leading to upregulation of pro-inflammatory factors and matrix metalloproteinases (MMPs). In vivo AEBP1 knockdown via intra-adventitial adenovirus suppresses AAA progression in a rat elastase model.\",\n      \"method\": \"Rat AAA model (elastase), in vivo adenoviral AEBP1 silencing, siRNA/overexpression in human vascular smooth muscle cells, NF-κB inhibitor BAY 11-7082, western blot, ELISA\",\n      \"journal\": \"Journal of atherosclerosis and thrombosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro genetic manipulation with pathway inhibitor validation; single lab, multiple methods\",\n      \"pmids\": [\"31462616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACT001 (parthenolide derivative) blocks TGF-β-activated AEBP1/AKT signaling in glioma stem-like cells. AEBP1 knockdown impairs AKT phosphorylation and GSC proliferation, and constitutively active AKT rescues AEBP1 depletion-inhibited proliferation, placing AEBP1 upstream of PI3K/AKT in GSCs.\",\n      \"method\": \"siRNA knockdown, constitutively active AKT rescue, PI3K inhibitor, ACT001 treatment, orthotopic xenograft model, RNA-Seq\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via constitutively active AKT rescue, in vivo xenograft, but single lab\",\n      \"pmids\": [\"33391492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AEBP1 siRNA knockdown in human retinal pericytes (high glucose conditions) reduces expression of profibrotic markers, and AEBP1 is upregulated in myofibroblast clusters of proliferative diabetic retinopathy fibrovascular membranes, establishing a role for AEBP1 in pericyte-to-myofibroblast transdifferentiation.\",\n      \"method\": \"Single-cell RNA-seq (scRNA-seq) of patient membranes, siRNA knockdown in human retinal pericytes under high-glucose conditions, fibrotic marker immunostaining\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — scRNA-seq discovery validated by siRNA functional experiment in primary human cells; single lab\",\n      \"pmids\": [\"37917183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACLP in cancer-associated fibroblasts (CAFs) of oral squamous cell carcinoma is induced by cancer-cell-derived TGF-β1; ACLP contributes to CAF activation (collagen gel contraction), promotes cancer cell migration and invasion, and attenuates CD8+ T cell migration into tumors.\",\n      \"method\": \"Co-culture with OSCC cells and TGF-β1 treatment, collagen gel contraction assay, Boyden chamber migration assay, in vivo tumor formation, immunohistochemistry\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TGF-β1 induction established by treatment experiment, functional assays for CAF activation and T cell exclusion; single lab, multiple methods\",\n      \"pmids\": [\"37686580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pancreatic cancer CAFs, ACLP promotes CAF activation and cancer cell invasion via upregulation of MMP1 and MMP3. An ACLP-PPARγ-ACLP positive feedback loop was identified in PDAC CAFs, where ACLP suppresses PPARγ (which normally represses ACLP), sustaining CAF activation.\",\n      \"method\": \"siRNA/overexpression in CAFs, CAF activation marker assays, MMP1/MMP3 expression analysis, PPARγ modulation, invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic feedback loop established by gain/loss-of-function with PPARγ modulation; single lab\",\n      \"pmids\": [\"35732215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AEBP1 knockdown in renal tubular cells and in vivo (UUO model) inhibits renal fibrosis by blocking nuclear β-catenin and its downstream targets (Axin2, Myc, Ccnd1). Constitutively active β-catenin-S33Y restores fibrotic gene expression after AEBP1 silencing, placing AEBP1 upstream of the Wnt/β-catenin pathway in renal fibrosis.\",\n      \"method\": \"siRNA knockdown, UUO mouse model, constitutively active β-catenin rescue, western blot, collagen staining, EMT marker analysis\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis confirmed by β-catenin rescue experiment, in vivo model; single lab\",\n      \"pmids\": [\"36738398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AEBP1 promotes papillary thyroid cancer progression by directly binding the BMP4 promoter and driving its transcription (established by dual-luciferase reporter and ChIP assay). BMP4 overexpression rescues the growth/invasion inhibition caused by AEBP1 knockout, placing AEBP1 upstream of BMP4 in PTC.\",\n      \"method\": \"AEBP1 CRISPR knockout, RNA-sequencing, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), BMP4 overexpression rescue, xenograft mouse model\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct promoter binding by ChIP, reporter assay, epistasis rescue, in vivo xenograft; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"38237535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AEBP1 transcriptionally represses PRKCA expression (established by luciferase reporter and ChIP). Loss of PI3K/AKT signaling due to reduced PRKCA after AEBP1 silencing leads to neuron ferroptosis and impaired microglia M2 polarization in cerebral ischemia/reperfusion; PRKCA inhibition reverses the protective effects of AEBP1 knockdown.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, ChIP, PRKCA/PI3K-AKT inhibitor rescue, OGD/R cell model, MCAO mouse model, ROS/GSH/iron assays\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding for PRKCA by ChIP and reporter, epistasis with inhibitors; single lab, multiple methods\",\n      \"pmids\": [\"39670965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Autocrine AEBP1 in cancer-associated fibroblasts binds CKAP4 on the CAF surface, activating AKT/PD-L1 signaling to suppress T cell cytotoxicity. Fibroblast-specific AEBP1 deletion enhances T cell cytotoxicity and suppresses tumor growth. A small molecule (Chem-0199) identified by molecular docking disrupts the AEBP1-CKAP4 interaction and synergizes with anti-PD-1.\",\n      \"method\": \"RNA-seq, scRNA-seq, fibroblast-specific AEBP1 knockout mice, molecular docking, direct protein-protein interaction assay (AEBP1-CKAP4), AKT/PD-L1 signaling assays, syngeneic tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein-protein interaction (AEBP1-CKAP4) established, in vivo fibroblast-specific KO, pharmacological validation, multiple orthogonal approaches\",\n      \"pmids\": [\"40890191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AEBP1 directly binds the DDR2 promoter to drive its transcription, promoting LPS-induced ferroptosis and inflammatory/M1 microglial polarization via STAT3/P53 signaling in BV2 cells. DDR2 knockdown counteracted the pathological effects of AEBP1.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay (AEBP1 binding to DDR2 promoter), siRNA knockdown, STAT3/P53 pathway inhibition, ferroptosis markers, microglial polarization assays\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated by ChIP and luciferase, DDR2 KD epistasis; single lab\",\n      \"pmids\": [\"41083137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AEBP1 directly interacts with PI3K (p110β subunit) as demonstrated by protein docking, co-immunoprecipitation, and surface plasmon resonance (SPR). AEBP1 overexpression impairs insulin signaling and glucose transport in skeletal muscle cells, exacerbating insulin resistance; AEBP1 knockdown reverses these changes.\",\n      \"method\": \"Protein docking, co-immunoprecipitation (co-IP), surface plasmon resonance (SPR), AEBP1 overexpression/knockdown in C2C12 and human skeletal muscle cells, insulin signaling assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct protein-protein interaction validated by three orthogonal methods (docking, co-IP, SPR); functional insulin signaling phenotype confirmed; single lab but rigorous\",\n      \"pmids\": [\"40618921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ACLP (AEBP1 extracellular isoform) regulates pro-fibrotic transcription factors and genes including MRTFB, RUNX2, SM22, and COL1A1 in cardiac fibroblasts. Fibroblast-specific and cardiac-specific Aebp1 knockout in mice improves cardiac function in ischemia and pressure-overload models. In ex vivo human myocardial tissue, ACLP overexpression in non-failing hearts induces pathological remodeling, while AEBP1 knockdown in failing hearts induces structural reverse remodeling.\",\n      \"method\": \"Fibroblast-specific knockout mice (myocardial ischemia and pressure-overload models), cardiac-specific knockdown, ex vivo human myocardial tissue culture (ACLP overexpression/AEBP1 KD), RNA sequencing for downstream targets\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo fibroblast-specific KO with functional cardiac readout, ex vivo human tissue validation; preprint, single lab\",\n      \"pmids\": [\"42245802\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In astrocytes, AEBP1 sequesters NPAS3 in the cytoplasm, reducing NPAS3 binding to the LIPA promoter and thereby repressing LIPA (lysosomal acid lipase) expression. AEBP1-mediated LIPA repression leads to lipid droplet accumulation, excess cholesteryl ester storage, and lysosomal Aβ retention. Astrocyte-specific AEBP1 knockdown ameliorates, while overexpression worsens, amyloid-β pathology in 5×FAD mice.\",\n      \"method\": \"Astrocyte-specific AEBP1 knockdown and overexpression in 5×FAD mice, NPAS3 nuclear/cytoplasmic fractionation, LIPA promoter binding (chromatin analysis), LIPA overexpression rescue, hippocampal transcriptomics and metabolomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanism established by cytoplasmic sequestration of NPAS3, LIPA promoter binding, rescue by LIPA overexpression, in vivo astrocyte-specific genetic manipulation with multiple readouts\",\n      \"pmids\": [\"41880326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Aebp1 loss in osteoprogenitors (OsxCre conditional KO) reduces bone mass and impairs osteoblast differentiation. Mechanistically, Aebp1 deletion attenuates Wnt/β-catenin signaling in bone. Restoration of Wnt/β-catenin by injecting BIO (GSK3 inhibitor) substantially rescues bone mass reduction in Aebp1-KO mice.\",\n      \"method\": \"OsxCre conditional knockout mice, siRNA knockdown in primary osteoblasts, Wnt/β-catenin signaling assays, BIO (GSK3 inhibitor) rescue, bone histomorphometry\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with pharmacological rescue establishing Wnt/β-catenin as downstream pathway; in vitro siRNA confirms cell-autonomous effect; multiple methods\",\n      \"pmids\": [\"41231548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TWIST1 directly regulates AEBP1 transcription in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis; AEBP1 in turn activates TGFβ signaling to drive fibroblast activation, migration, and proliferation, and induces POSTN expression to promote angiogenesis. Intra-articular AEBP1 modulation and pharmacological TWIST1 inhibition by harmine alters synovial hyperplasia and bone erosion in CIA mice.\",\n      \"method\": \"Bulk RNA-seq, proteomics, scRNA-seq, functional assays for FLS activation/migration/proliferation, CIA mouse model with AEBP1 intra-articular modulation, harmine (TWIST1 inhibitor) treatment\",\n      \"journal\": \"Arthritis & rheumatology (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CIA model with pharmacological and genetic modulation, pathway dissection; single lab\",\n      \"pmids\": [\"41787682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AEBP1 knockout in CAFs (both isoforms) decreases CAF proliferation, collagen gel contractility, and CAF-mediated tumor cell proliferation. AEBP1 KO downregulates collagen biosynthesis and ECM organization pathways in both mouse and human CAFs, reduces tumor EMT signature in vivo, and enhances anti-PD-1 efficacy.\",\n      \"method\": \"CRISPR gene editing (combined KO of both isoforms), collagen gel contractility assay, co-implantation mouse model, RNA-seq, anti-PD-1 combination treatment in syngeneic models\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple functional assays, RNA-seq, in vivo model; single lab, multiple methods\",\n      \"pmids\": [\"41024581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AEBP1 mediates TWIST1-driven endothelial proliferation and COL4A1 upregulation; in atherosclerotic plaques, TWIST1 induces AEBP1 transcription which upregulates COL4A1 to drive endothelial cell proliferation and plaque collagen deposition.\",\n      \"method\": \"Single-cell RNA-seq of murine atherosclerotic plaques with inducible Twist1 ECKO, transcriptional analysis of AEBP1-COL4A1 axis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional relationship identified in scRNA-seq context; mechanistic detail for AEBP1 specifically is limited in the abstract; preprint, single study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AEBP1 is a negative regulator of skeletal muscle differentiation; AEBP1 knockdown in human skeletal muscle myoblasts upregulates myogenesis-related genes including MYOG, while ectopic AEBP1 expression suppresses these genes. TGF-β1 treatment upregulates AEBP1 and suppresses muscle differentiation genes.\",\n      \"method\": \"siRNA knockdown, ectopic AEBP1 overexpression, transcriptome analysis, qRT-PCR and western blot for myogenesis markers, TGF-β1 treatment, indirect co-culture with OSCC cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in primary human skeletal muscle cells with transcriptomic validation; single lab\",\n      \"pmids\": [\"39521917\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AEBP1 encodes two protein isoforms — an intracellular transcriptional repressor (AEBP1) and a secreted extracellular matrix protein (ACLP) — that mechanistically regulate collagen fibrillogenesis (via discoidin domain-mediated fibrillar collagen binding and polymerization), NF-κB signaling (by physically interacting with IκBα to promote its degradation), PPARγ/LXRα-mediated cholesterol efflux in macrophages, fibroblast-to-myofibroblast differentiation (via TGFβ receptor-dependent Smad3 phosphorylation for SMA and a TGFβ receptor-independent pathway for collagen), Wnt/β-catenin signaling in osteoblasts, PI3K (p110β) signaling in skeletal muscle insulin resistance, NPAS3-LIPA-mediated lysosomal cholesterol catabolism in astrocytes, and T cell dysfunction through autocrine AEBP1-CKAP4-AKT/PD-L1 signaling in cancer-associated fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AEBP1 encodes two functionally distinct isoforms — an intracellular transcriptional regulator (AEBP1) and a secreted extracellular matrix protein (ACLP) — that together govern collagen matrix assembly, fibroblast activation, and signaling-dependent proliferation across many tissues [#0, #5]. As a secreted protein, ACLP binds fibrillar collagens directly through its discoidin domain and promotes collagen polymerization; bi-allelic loss-of-function AEBP1 variants produce defective collagen fibril assembly in patient skin, establishing a Mendelian connective-tissue disorder [#0]. ACLP drives fibroblast-to-myofibroblast differentiation, inducing SMA via TGFβ-receptor-dependent Smad3 phosphorylation and collagen via a TGFβ-receptor-independent route [#5], a fibrogenic program recurrently deployed in cancer-associated fibroblasts, where cancer-cell-derived TGFβ1 induces ACLP to sustain CAF activation and matrix contraction [#15, #16]. In its intracellular role, AEBP1 acts as a transcriptional regulator with a C-terminal DNA-binding region, functioning largely as a corepressor whose carboxypeptidase domain is required for repressor activity [#1]; it occupies promoters genome-wide and directly binds defined target promoters to either activate (BMP4, DDR2, PI3KCβ) or repress (PRKCA, LIPA) transcription [#9, #18, #21, #11, #19, #24]. AEBP1 amplifies multiple proliferative and inflammatory signaling axes: it physically interacts with IκBα to accelerate its degradation and potentiate canonical NF-κB signaling in macrophages and vascular smooth muscle [#2, #12], represses PPARγ/LXRα to impair macrophage cholesterol efflux and promote atherosclerosis [#3, #7], and feeds into PI3K/AKT signaling — binding the p110β subunit directly to impair insulin signaling in skeletal muscle [#22] and acting upstream of AKT in glioma [#13]. In vivo genetic models establish that AEBP1 controls stromal-epithelial crosstalk in the mammary gland, Wnt/β-catenin-dependent osteoblast differentiation and bone mass, and astrocyte cholesterol catabolism via cytoplasmic sequestration of NPAS3 and consequent LIPA repression in amyloid pathology [#10, #25, #24]. At the tumor-stroma interface, autocrine AEBP1 binds CKAP4 on the CAF surface to drive AKT/PD-L1 signaling and suppress T cell cytotoxicity [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established AEBP1 as an in vivo regulator of survival signaling, showing it lowers PTEN levels through direct interaction to promote adipocyte hyperplasia and obesity.\",\n      \"evidence\": \"AEBP1-overexpressing transgenic mice with protein-interaction and PTEN immunoblot\",\n      \"pmids\": [\"16307171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction surface and mechanism of PTEN destabilization not mapped\", \"Sex-specific phenotype not explained mechanistically\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the molecular basis of AEBP1's intracellular transcriptional repressor activity, mapping a C-terminal basic DNA-binding/calmodulin-binding region and showing the carboxypeptidase domain is required for repression.\",\n      \"evidence\": \"Luciferase reporter and EMSA with deletion/point mutagenesis in CHO cells\",\n      \"pmids\": [\"16538615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Weak direct DNA binding implies a corepressor mode not fully defined\", \"Catalytic role of carboxypeptidase domain in repression unresolved\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked AEBP1 to inflammatory and lipid-handling transcriptional programs in macrophages, showing it potentiates NF-κB by promoting IκBα turnover and represses PPARγ/LXRα-driven cholesterol efflux.\",\n      \"evidence\": \"IκBα physical interaction, NF-κB and nuclear-receptor reporter assays, macrophage cholesterol efflux assays\",\n      \"pmids\": [\"20396415\", \"20419060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IκBα degradation (E3 recruitment vs. direct) not defined\", \"How a transcriptional repressor mechanistically downregulates PPARγ/LXRα activity unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided in vivo proof that macrophage AEBP1 is pro-atherogenic and that stromal AEBP1 controls mammary secretory activation, establishing cell-non-autonomous AEBP1 functions.\",\n      \"evidence\": \"Transgenic and knockout mice with bone marrow transplantation into ApoE/LDLR models and mammary rescue\",\n      \"pmids\": [\"21687917\", \"22114697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular targets in vivo not pinpointed\", \"Relative contribution of NF-κB vs PPARγ/LXRα arms in atherosclerosis not separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected stromal AEBP1 to epithelial transformation and mapped genome-wide AEBP1 promoter occupancy, defining a GAAAT consensus motif and proliferation/apoptosis target set.\",\n      \"evidence\": \"Bone marrow transplantation with TNFα neutralization and co-culture; ChIP-chip with ChIP-PCR and reporter validation in glioma cells\",\n      \"pmids\": [\"22995915\", \"22723309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs corepressor binding at GAAAT sites not resolved\", \"Co-factors mediating activation vs repression at targets unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mechanistically separated ACLP-induced myofibroblast outputs and placed AEBP1 in a drug-resistance signaling circuit, showing SMA induction is TGFβ-receptor/Smad3-dependent while collagen induction is receptor-independent.\",\n      \"evidence\": \"Recombinant ACLP treatment with TGFβ receptor inhibitor and phospho-Smad3 readout; PI3K/Akt-CREB-AEBP1-NF-κB pathway dissection in PLX4032-resistant melanoma\",\n      \"pmids\": [\"24344132\", \"24201813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/signaling intermediate for TGFβ-independent collagen induction unidentified\", \"How ACLP engages the TGFβ receptor not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined AEBP1 as a direct transcriptional activator of PI3KCβ and a determinant of death-pathway choice in glioma, and established its pro-inflammatory role in aneurysm.\",\n      \"evidence\": \"ChIP/promoter binding (AE-1 element) with PIK3CB overexpression rescue in PTEN-isogenic glioma cells; rat elastase AAA model with adenoviral silencing\",\n      \"pmids\": [\"31601918\", \"31462616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PTEN status switches caspase-dependent vs parthanatos death not fully resolved\", \"Direct vs corepressor binding at the AE-1 element unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ACLP as a self-reinforcing driver of CAF activation, identifying an ACLP-PPARγ-ACLP feedback loop and MMP1/MMP3 induction in pancreatic cancer stroma.\",\n      \"evidence\": \"Gain/loss-of-function in CAFs with PPARγ modulation, invasion and in vivo metastasis assays\",\n      \"pmids\": [\"35732215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ACLP suppresses PPARγ not defined\", \"Direct ACLP receptor on CAFs not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized ACLP/AEBP1 as a TGFβ-inducible driver of stromal fibrosis and immune exclusion across tissues, from OSCC CAFs to diabetic retinal pericytes and renal tubular Wnt/β-catenin signaling.\",\n      \"evidence\": \"TGFβ1 co-culture, collagen contraction and T cell migration assays; scRNA-seq with pericyte siRNA; UUO model with constitutively active β-catenin rescue\",\n      \"pmids\": [\"37686580\", \"37917183\", \"36738398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting AEBP1 to β-catenin stabilization not defined\", \"Whether intracellular AEBP1 or secreted ACLP drives each phenotype not always disambiguated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the direct-promoter-binding repertoire of AEBP1, showing transcriptional activation of BMP4 in thyroid cancer and repression of PRKCA in cerebral ischemia, and identified AEBP1 as a negative regulator of myogenesis.\",\n      \"evidence\": \"CRISPR KO with ChIP/reporter and BMP4 rescue; ChIP/reporter with PRKCA inhibitor rescue in MCAO model; gain/loss-of-function in human myoblasts\",\n      \"pmids\": [\"38237535\", \"39670965\", \"39521917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What dictates AEBP1 activation vs repression at different promoters unknown\", \"Co-regulators at BMP4/PRKCA promoters not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved direct AEBP1 protein interactions driving signaling — binding p110β to impair insulin signaling, binding CKAP4 to drive AKT/PD-L1-mediated T cell suppression — and established Wnt/β-catenin-dependent control of bone mass.\",\n      \"evidence\": \"Docking/co-IP/SPR for p110β with skeletal-muscle insulin assays; fibroblast-specific KO with AEBP1-CKAP4 interaction and Chem-0199 disruption; OsxCre conditional KO with BIO rescue\",\n      \"pmids\": [\"40618921\", \"40890191\", \"41231548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface of AEBP1-CKAP4 and AEBP1-p110β not solved\", \"How extracellular/autocrine AEBP1 signals through a surface receptor mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined AEBP1's mechanism in astrocyte cholesterol catabolism and amyloid pathology — cytoplasmic sequestration of NPAS3 to repress LIPA — and placed AEBP1 downstream of TWIST1 in fibroblast-driven arthritis.\",\n      \"evidence\": \"Astrocyte-specific manipulation in 5xFAD mice with NPAS3 fractionation and LIPA rescue; CIA model with TWIST1 inhibition and AEBP1 modulation\",\n      \"pmids\": [\"41880326\", \"41787682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether intracellular AEBP1 sequesters NPAS3 directly or via partners unclear\", \"Generalizability of NPAS3-LIPA axis beyond astrocytes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single gene's two isoforms — a corepressor/activator transcription factor and a secreted collagen-binding ECM protein — coordinate to produce convergent fibrotic and proliferative phenotypes, and what cell-surface receptor transduces extracellular AEBP1/ACLP signaling, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model distinguishing isoform-specific functions\", \"Cell-surface receptor for secreted ACLP beyond CKAP4 not defined\", \"Logic governing transcriptional activation vs repression at direct targets unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 9, 18, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 9, 18, 11, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 22]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 18, 24]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 5, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 22, 25, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 18, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 12, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 7, 22, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NFKBIA\", \"PTEN\", \"PIK3CB\", \"CKAP4\", \"NPAS3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}