{"gene":"SERPINF1","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1997,"finding":"PEDF is a non-inhibitory serpin: it has characteristics of a substrate rather than an inhibitor of serine proteases, and an N-terminal peptide region provides its neurotrophic function while the serpin exposed loop and oligosaccharides are dispensable for this activity.","method":"Structure-function analysis, peptide dissection, serpin biochemical characterization","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structure-function analysis from a single lab, no explicit mutagenesis or reconstitution described in abstract","pmids":["9433504"],"is_preprint":false},{"year":1995,"finding":"EPC-1/PEDF mRNA is induced under growth arrest (density-dependent contact inhibition and serum deprivation) in early-passage but not senescent WI-38 fibroblasts; the regulation is cell-cycle dependent and expression is limited to specific cell types with conserved genomic sequences across mammalian species.","method":"Northern blot, serum stimulation/starvation experiments, interspecies Southern blot","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Northern blot, growth-state manipulation), single lab","pmids":["7814443"],"is_preprint":false},{"year":2000,"finding":"Regulation of EPC-1/PEDF expression in fibroblasts is posttranscriptional: transcription rates are unchanged between proliferating, quiescent and senescent cells; regulation occurs at the hnRNA level, and mRNA stability is reduced when cells exit G0.","method":"Transcriptional run-on assays, RT-PCR of hnRNA, mRNA stability measurements","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — transcriptional assays plus mRNA stability measurements, single lab","pmids":["10972981"],"is_preprint":false},{"year":2003,"finding":"EPC-1/PEDF protein plays a role in G0 growth arrest of human diploid fibroblasts: antibodies blocking EPC-1 increase DNA synthesis in near-plateau early-passage cultures, and addition of recombinant EPC-1 decreases DNA synthesis in logarithmically growing cells; EPC-1 expression is lost with senescence and SV40 transformation.","method":"Antibody neutralization, recombinant protein addition, DNA synthesis assay (BrdU/[3H]-thymidine incorporation), Western blot, mRNA analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function experiments with recombinant protein and neutralizing antibodies, single lab","pmids":["12599204"],"is_preprint":false},{"year":1999,"finding":"PEDF/EPC-1 protein inhibits anchorage-dependent and anchorage-independent proliferation of endometrial carcinoma cells in a dose- and time-dependent manner, but has no effect on stromal fibroblast proliferation; secreted PEDF/EPC-1 levels decline as endometrial stromal fibroblasts age in vitro.","method":"Recombinant protein treatment, cell proliferation assays (anchorage-dependent and soft agar), ELISA, Western blot","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein addition with multiple readouts, single lab","pmids":["10047456"],"is_preprint":false},{"year":2004,"finding":"Retinoic acid (ATRA) upregulates PEDF protein and RNA in retinal and endothelial cells through a functional retinoic acid receptor element (RARE) in the PEDF promoter; dexamethasone also increases PEDF RNA levels; conversely, PEDF treatment alters expression of retinoic acid receptors RARα, RXRγ, RARβ and RXRβ in retinal cells.","method":"Luciferase reporter assay with PEDF promoter-RARE construct, quantitative PCR, Western blot, ATRA treatment","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reporter assay with promoter construct plus multiple orthogonal methods, single lab","pmids":["15051476"],"is_preprint":false},{"year":2005,"finding":"PEDF is a negative acute-phase protein in endotoxin-induced uveitis; intravitreal PEDF injection reduces vascular hyper-permeability in diabetic and oxygen-induced retinopathy models, correlating with decreased retinal VEGF, VEGFR-2, MCP-1, TNF-α, and ICAM-1; siRNA knockdown of PEDF in Müller cells increases VEGF and TNF-α secretion.","method":"Western blot, ELISA, intravitreal injection in rat models, siRNA knockdown, cell culture under hypoxia","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo injection plus siRNA knockdown with multiple cytokine readouts, single lab","pmids":["16368716"],"is_preprint":false},{"year":2008,"finding":"PEDF is the predominant fibroblast chemoattractant in mesenchymal stem cell secretome: immunodepletion of PEDF abolishes fibroblast chemotaxis, and reconstitution restores it; PEDF stimulates fibroblast migration (in contrast to its known inhibition of endothelial cell migration).","method":"Proteomic identification of secretome, immunodepletion and reconstitution, fibroblast chemotaxis assay, immunofluorescence","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunodepletion/reconstitution experiment, single lab","pmids":["18348263"],"is_preprint":false},{"year":2009,"finding":"PEDF inhibits osteoclast differentiation, RANKL-mediated survival, and bone resorption activity in a dose-dependent manner; PEDF upregulates osteoprotegerin (OPG) in primary osteoblasts and osteoclast precursor cells, suggesting PEDF inhibits osteoclast function via OPG regulation.","method":"In vitro osteoclast differentiation assay, bone resorption assay, Western blot/ELISA for OPG expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional differentiation and resorption assays with mechanistic follow-up, single lab","pmids":["19945427"],"is_preprint":false},{"year":2009,"finding":"PEDF-R, a member of the patatin-like phospholipase domain-containing 2 (PNPLA2) family, is a transmembrane phospholipase A2 on the surface of retina and RPE cells with high-affinity specific binding for PEDF; PEDF binding stimulates PEDF-R phospholipase A2 enzymatic activity, releasing fatty acids.","method":"Binding assays, phospholipase A2 enzymatic activity assay, cell surface localization, transmembrane topology analysis","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with receptor binding, single lab, multiple methods","pmids":["20237999"],"is_preprint":false},{"year":2011,"finding":"PEDF inhibits VEGF-induced vascular permeability via a γ-secretase-dependent pathway: PEDF prevents dissociation of adherens junction (VE-cadherin, β-catenin) and tight junction (claudin-5) proteins, regulates VEGF receptor association with adherens junction proteins, and inhibits phosphorylation of VE-cadherin and β-catenin; γ-secretase inhibitor blocks PEDF's anti-permeability effect.","method":"Transendothelial resistance assay, paracellular dextran flux, FITC-albumin leakage in vivo, immunoprecipitation, Western blot, immunohistochemistry with γ-secretase inhibitor","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods with pharmacological inhibitor validation, reciprocal immunoprecipitation","pmids":["21695048"],"is_preprint":false},{"year":2011,"finding":"Truncating mutations in SERPINF1 cause autosomal-recessive osteogenesis imperfecta type VI; PEDF loss is associated with severe bone fragility without impairment of collagen folding, posttranslational modification, or secretion, establishing a collagen-independent role for PEDF in bone homeostasis.","method":"Exome sequencing, homozygosity mapping, Sanger sequencing, collagen biochemical analysis in dermal fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics with multiple affected families plus collagen biochemistry ruling out collagen mechanism, replicated in multiple patients","pmids":["21353196"],"is_preprint":false},{"year":2011,"finding":"Loss-of-function mutations in SERPINF1 cause OI type VI, characterized by increased unmineralized osteoid, establishing PEDF involvement in bone mineralization through a mechanism distinct from collagen processing.","method":"Homozygosity mapping, next-generation sequencing, clinical bone histomorphometry","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics with histomorphometric bone analysis, replicated in multiple families, independent of paper 21353196","pmids":["21826736"],"is_preprint":false},{"year":2012,"finding":"PEDF deficiency combined with oncogenic Kras mutation induces invasive pancreatic ductal adenocarcinoma and adipose-rich stroma in mice; loss of PEDF is associated with enhanced MMP-2 and MMP-9 expression, increased peripancreatic adipocyte hypertrophy, elevated lipid droplet proteins (TIP47, ADRP) and decreased adipose triglyceride lipase.","method":"Genetic mouse model (EL-Kras/PEDF-deficient), histology, immunohistochemistry, Western blot, ELISA","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model with multiple molecular readouts, single lab","pmids":["22234980"],"is_preprint":false},{"year":2013,"finding":"PEDF-R (encoded by PNPLA2) is required for PEDF-mediated retinal cell survival and antiapoptotic activity: the PEDF binding site on PEDF-R is within ectodomain L4 (specifically residues His203-Leu232); siRNA knockdown of PEDF-R abolishes PEDF-mediated cell survival; peptides spanning the binding site block PEDF-PEDF-R interaction and survival activity.","method":"Recombinant protein binding assays with truncation mutants, synthetic peptide competition, siRNA knockdown, cell viability assay, cell surface labeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with truncation mutants, mutagenesis-equivalent deletion analysis, siRNA knockdown, peptide competition, multiple orthogonal methods in single study","pmids":["23818523"],"is_preprint":false},{"year":2013,"finding":"Müller cell-secreted PEDF promotes retinal ganglion cell survival through STAT3 activation via PEDF-R (encoded by PNPLA2): neutralization of PEDF in Müller cell conditioned medium attenuates STAT3 activation; ablation of PEDF-R attenuates conditioned medium-induced STAT3 activation and compromises PEDF-exposed cell viability.","method":"Conditioned medium transfer, PEDF neutralizing antibody, siRNA knockdown of PEDF-R, Western blot for STAT3 phosphorylation, cell viability assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralization plus receptor knockdown with signaling readout, single lab","pmids":["29186716"],"is_preprint":false},{"year":2014,"finding":"PLXDC1 and PLXDC2 are identified as cell-surface transmembrane receptors for PEDF: loss-of-function and gain-of-function studies demonstrate cell type-specific receptor activities; PEDF receptors form homooligomers under basal conditions and PEDF dissociates the homooligomer to activate them; mutations in the intracellular domain profoundly affect receptor activity.","method":"Loss-of-function and gain-of-function cellular assays, receptor oligomerization studies, intracellular domain mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (gain/loss-of-function, mutagenesis, oligomerization assays) establishing receptor identity and activation mechanism","pmids":["25535841"],"is_preprint":false},{"year":2014,"finding":"PEDF protects RPE cells against oxidative stress by stabilizing mitochondrial networks and function through PI3K/Akt signaling: PEDF unblocks PI3K/Akt and MAPK signaling inhibited by oxidative stress; PI3K/Akt pathway (not MAPK) is specifically required for mitochondrial stabilization; PEDF controls ROS via UCP2 regulation (PEDF-induced UCP2 expression decreases ROS in UCP2-deficient cells).","method":"Pharmacological inhibitors (LY294002, SH6, U0126), Western blot, mitochondrial membrane potential and ATP measurements, ROS assay, UCP2-deficient cell rescue","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection plus UCP2-deficient cell rescue, single lab","pmids":["25212780"],"is_preprint":false},{"year":2015,"finding":"PEDF and its 44-mer peptide stimulate cardiac triglyceride degradation via adipose triglyceride lipase (ATGL): an ATGL-specific inhibitor (atglistatin) and ATGL siRNA knockdown abolish PEDF/44mer-induced triglyceride lipolysis in cardiomyocytes.","method":"ATGL pharmacological inhibition, ATGL siRNA knockdown, Oil Red O staining, triglyceride assay, PEDF lentiviral overexpression/knockdown in AMI mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus genetic knockdown with functional lipid readout, single lab","pmids":["25890298"],"is_preprint":false},{"year":2015,"finding":"In-frame SERPINF1 mutations causing OI type VI result in retention of PEDF in the endoplasmic reticulum (for deletion mutations p.F277del and exon 5 deletion) or intracellular degradation (for p.Ala91_Ser93dup) without ER retention; both mechanisms block PEDF secretion; stable expression of p.Ala91_Ser93dup PEDF in osteoblasts decreases collagen type I deposition and mineralization.","method":"Immunofluorescence localization in transfected osteoblastic cells, ER stress assay, RT-PCR, mineralization assay in stably transfected MC3T3-E1 cells","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with functional mineralization consequence, single lab","pmids":["25868797"],"is_preprint":false},{"year":2016,"finding":"PEDF inhibits NLRP3 inflammasome activation in hypoxic cardiomyocytes through PEDF-R/iPLA2: PEDF reduces Drp1-induced mitochondrial fission, limits cytosolic release of mitochondrial DNA and mitochondrial ROS (which activate NLRP3), acting via PEDF-R/iPLA2 signaling.","method":"PEDF-R siRNA knockdown, iPLA2 inhibition, mitochondrial fission assay, NLRP3 inflammasome activation assay, mtDNA and mtROS measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor knockdown with mechanistic pathway dissection, single lab","pmids":["27973457"],"is_preprint":false},{"year":2016,"finding":"PEDF and 44-mer peptide reduce oxidative stress and apoptosis in OGD-treated cardiomyocytes via PEDF-R and subsequent PPARγ activation: PEDF-R siRNA or PPARγ antagonist abolishes PEDF/44mer-mediated ROS reduction and anti-apoptotic effects; PEDF/44mer increase LPA, PLA2 activity, and PPARγ expression downstream of PEDF-R.","method":"PEDF-R siRNA knockdown, PPARγ antagonist (GW9662), ROS assay, TUNEL/caspase-3 apoptosis assay, ELISA for LPA and PLA2, qPCR and Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor knockdown plus pharmacological inhibition with multiple downstream readouts, single lab","pmids":["26966066"],"is_preprint":false},{"year":2017,"finding":"PEDF is a direct antiangiogenic factor secreted by corneal mesenchymal stromal cells (Co-MSCs): immunoprecipitation removal of PEDF from Co-MSC secretome significantly diminishes antiangiogenic effects; SERPINF1-/- Co-MSCs have significantly reduced antiangiogenic activity compared to wild-type.","method":"Immunoprecipitation depletion from secretome, HUVEC tube formation assay, fibrin gel bead assay, SERPINF1-/- mouse-derived Co-MSC comparison, in vivo corneal neovascularization model","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — immunodepletion plus genetic knockout model with both in vitro and in vivo functional readouts, replicated across methods","pmids":["29075761"],"is_preprint":false},{"year":2018,"finding":"PEDF deficiency (PEDF-/-) in retinal endothelial cells alters proangiogenic properties through changes in cell adhesion mechanisms: PEDF-/- retinal EC are more proliferative, less apoptotic under H2O2 challenge, less migratory and less adherent; PEDF loss increases tenascin-C, fibronectin, thrombospondin-1 and collagen IV and alters integrin expression (α2, αv, β1, β8, αvβ3) and cell-cell adhesion molecules (CD31, ZO-1, occludin).","method":"PEDF-/- mouse-derived retinal EC, proliferation/migration/adhesion/apoptosis assays, Western blot for ECM and adhesion proteins, capillary morphogenesis assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null cell model with multiple orthogonal functional assays, single lab","pmids":["28747334"],"is_preprint":false},{"year":2018,"finding":"PEDF regulates MTOC number and lipid metabolism in prostate cancer-associated fibroblasts (CAFs) via an ATGL-dependent lipid-MTOC axis: PEDF and ATGL are co-expressed in normal prostate fibroblasts but nearly absent in CAFs; PEDF treatment suppresses lipid content and MTOC amplification in CAFs.","method":"Primary human NF and CAF isolation, neutral lipid staining, MTOC quantification by immunofluorescence, PEDF treatment, Western blot for ATGL and PEDF","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary cell model with PEDF rescue experiment and multiple readouts, single lab","pmids":["29792311"],"is_preprint":false},{"year":2018,"finding":"PEDF promotes nuclear degradation of ATGL through COP1-mediated proteasomal degradation in hepatocytes: PEDF (itself present in the nuclear compartment) enhances nuclear import of cytosolic ATGL leading to COP1-dependent polyubiquitylation and proteasomal degradation; this controls hepatocyte lipid accumulation and mobilization.","method":"Co-immunoprecipitation, subcellular fractionation, proteasome inhibitor experiments, COP1 knockdown, lipid accumulation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic knockdown with functional lipid readout, single lab","pmids":["30926171"],"is_preprint":false},{"year":2018,"finding":"PEDF promotes mitophagy in OGD-treated cardiomyocytes via a PKCα-ULK1 axis that replaces AMPK: PEDF increases PKCα/p-PKCα, which directly interacts with ULK1 at its serine/threonine-rich domain; phospho-PKCα phosphorylates ULK1 at Ser317/555/777 and Raptor; a ULK1 deletion mutant lacking the PKCα-binding domain is defective in PEDF-induced mitophagy.","method":"Co-immunoprecipitation of PKCα-ULK1, ULK1 deletion mutant assay, Western blot for phosphorylation sites, mitochondrial ROS and DNA release measurement, mitophagy assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — co-IP with deletion mutant and phosphorylation site mapping, single lab","pmids":["30230261"],"is_preprint":false},{"year":2019,"finding":"PEDF induces PEDF-mediated autophagy in endothelial cells via sequential induction of p53 and sestrin2 with downstream mTOR inhibition: p53 siRNA eliminates sestrin2 induction; p53 or sestrin2 siRNA attenuate PEDF-induced autophagy; PEDF-treated cells show reduced p70S6K and 4E-BP1 phosphorylation (mTOR suppression).","method":"p53 and sestrin2 siRNA knockdown, Western blot for LC3 I/II, p62, p70S6K and 4E-BP1 phosphorylation, fluorescence microscopy for autophagosome formation, RT-qPCR","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequential siRNA knockdown pathway dissection with multiple readouts, single lab","pmids":["31173218"],"is_preprint":false},{"year":2019,"finding":"PEDF 34-mer peptide induces apoptosis in prostate cancer cells via the extrinsic death receptor pathway through the laminin receptor: PEDF34 upregulates FasL and activates caspase-8; FasL knockdown or JNK inhibition attenuates PEDF34-induced apoptosis; PPARγ (not NF-κB) is required for FasL upregulation; blocking the laminin receptor abolishes FasL and PPARγ upregulation by PEDF34.","method":"siRNA knockdown (FasL, PPARγ, NF-κB, laminin receptor), pharmacological inhibitors (GW9662, PDTC, JNK inhibitor), caspase-8 activation assay, Western blot, in vivo xenograft","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA knockdowns and pharmacological inhibitors defining pathway, single lab","pmids":["25261795"],"is_preprint":false},{"year":2021,"finding":"PEDF is a direct antiangiogenic factor in intrahepatic cholangiocarcinoma: antibodies blocking PEDF (along with THBS1 and THBS2) restore endothelial tube formation and cell viability inhibited by iCCA extracellular fluid; in transplanted SCID mice, PEDF expression is required for inhibition of blood vessel formation and promotion of lymphangiogenesis.","method":"Quantitative proteomics of extracellular fluid, antibody-blocking of PEDF in 3D vascular assembly assay, endothelial migration/proliferation/viability assays, in vivo heterotopic transplantation in SCID mice","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody neutralization in vitro and in vivo, multiple functional readouts, single lab","pmids":["34329660"],"is_preprint":false},{"year":2021,"finding":"PEDF inhibits angiogenesis by binding directly to the extracellular domain of VEGFR-2 and VEGFR-1, blocking VEGF-A-induced phosphorylation of VEGFR-2 at Tyr951 and Tyr1175, and inhibiting downstream signaling through PI3K, AKT, FAK, Src (Y416), and PLC-γ.","method":"Direct binding assay (ELISA-type), phosphorylation analysis by Western blot, endothelial cell proliferation/migration/tube formation assays","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus phosphorylation site mapping with functional readouts, single lab","pmids":["34742690"],"is_preprint":false},{"year":2022,"finding":"Loss of PEDF in Serpinf1-/- mice activates TGF-β signaling in osteoblasts, delays osteoblast maturation and ECM mineralization, and increases bone vascularization (elevated CD31+/Endomucin+ endothelial cells); PEDF functionally antagonizes TGF-β: TGF-β stimulation and PEDF deficiency have additive effects on suppression of osteogenic markers; exogenous PEDF attenuates TGF-β-induced pro-angiogenic factor expression.","method":"Serpinf1-/- mouse model, primary osteoblast culture, RNA-Seq transcriptome, barium sulfate perfusion for vessel density, immunofluorescence for CD31/Endomucin, TGF-β stimulation with recombinant PEDF rescue","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model plus RNA-Seq plus in vitro rescue experiments defining PEDF-TGF-β antagonism with multiple orthogonal readouts","pmids":["35258129"],"is_preprint":false},{"year":2023,"finding":"PEDF protects RPE cells from ferroptosis by upregulating GPX4 and ferritin heavy chain-1 (FTH1): overexpression of PEDF increases GPX4 and FTH1 expression, inhibiting lipid peroxidation and RPE ferroptosis in sodium iodate-treated mice; PEDF-knockout mice develop dry AMD-like retinal pathology.","method":"PEDF knockout mouse model, PEDF overexpression, lipid peroxidation assay, transmission electron microscopy, Western blot and immunofluorescence for GPX4 and FTH1, electroretinography, OCT","journal":"GeroScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus overexpression with mechanistic protein targets (GPX4, FTH1), single lab","pmids":["38153666"],"is_preprint":false},{"year":2009,"finding":"PEDF 34-mer peptide (Asp44-Asn77) carries the anti-angiogenic activity of full-length PEDF: cleaved PEDF and 34-mer peptide inhibit ex vivo vessel sprouting and reduce CNV lesion volumes in rats; the 44-mer peptide (Val78-Thr121) has no antiangiogenic effect in these assays.","method":"Chymotrypsin limited proteolysis, ex vivo chick aortic vessel sprouting assay, rat laser-induced CNV model, subconjunctival injection, confocal immunofluorescence","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-function with cleaved protein and synthetic peptides validated in both ex vivo and in vivo models by multiple methods","pmids":["19850839"],"is_preprint":false}],"current_model":"PEDF (SERPINF1) is a secreted non-inhibitory serpin that exerts multiple context-dependent functions through at least seven identified cell-surface receptors (including PEDF-R/PNPLA2, PLXDC1, PLXDC2, VEGFR-1, VEGFR-2, laminin receptor, and F1-ATP synthase): it inhibits angiogenesis by binding VEGFR-2 to block downstream PI3K/AKT/Src signaling and by acting through a γ-secretase pathway to preserve vascular junction integrity; it promotes retinal neuron and RPE cell survival via PEDF-R–mediated phospholipase A2 activation leading to PPARγ and STAT3 signaling; it regulates lipid metabolism by promoting COP1-mediated nuclear degradation of ATGL in hepatocytes and stimulating cardiac triglyceride degradation via ATGL; it controls bone homeostasis by antagonizing TGF-β signaling in osteoblasts and upregulating OPG to suppress osteoclasts, with loss-of-function SERPINF1 mutations causing OI type VI through collagen-independent mechanisms; and its anti-angiogenic and neurotrophic activities are carried by distinct peptide domains (34-mer and 44-mer, respectively) within the PEDF polypeptide."},"narrative":{"mechanistic_narrative":"SERPINF1 encodes PEDF, a secreted non-inhibitory serpin that acts as a multifunctional extracellular signaling factor coordinating angiogenesis, cell survival, lipid metabolism, and bone homeostasis through distinct cell-surface receptors and peptide domains [PMID:9433504, PMID:25535841]. Its anti-angiogenic activity is mediated by direct binding to the extracellular domains of VEGFR-1 and VEGFR-2, blocking VEGF-A-induced receptor phosphorylation and downstream PI3K/AKT/FAK/Src/PLC-γ signaling [PMID:34742690], and by a γ-secretase-dependent pathway that preserves adherens and tight junction integrity to limit vascular permeability [PMID:21695048]; this anti-angiogenic function is carried by the 34-mer peptide region, whereas the 44-mer is inactive in angiogenesis [PMID:19850839]. PEDF promotes retinal and RPE cell survival by binding PEDF-R (PNPLA2) at ectodomain L4, stimulating its phospholipase A2 activity to drive PPARγ and STAT3 signaling and protect against oxidative stress, ferroptosis, and apoptosis [PMID:20237999, PMID:23818523, PMID:29186716, PMID:38153666], and signals additionally through the transmembrane receptors PLXDC1 and PLXDC2, which it activates by dissociating their basal homooligomers [PMID:25535841]. PEDF controls lipid homeostasis by acting on adipose triglyceride lipase (ATGL): it stimulates ATGL-dependent triglyceride degradation in cardiomyocytes and promotes COP1-mediated nuclear proteasomal degradation of ATGL in hepatocytes [PMID:25890298, PMID:30926171]. In bone, loss of PEDF activates TGF-β signaling in osteoblasts, delaying maturation and mineralization and elevating bone vascularization, while PEDF suppresses osteoclasts via osteoprotegerin upregulation [PMID:19945427, PMID:35258129]. Truncating and in-frame loss-of-function mutations in SERPINF1 cause autosomal-recessive osteogenesis imperfecta type VI through a collagen-independent mechanism, with mutant PEDF retained in the ER or degraded intracellularly [PMID:21353196, PMID:21826736, PMID:25868797].","teleology":[{"year":1997,"claim":"Establishing that PEDF is a non-inhibitory serpin reframed it as a signaling protein rather than a protease inhibitor and localized its neurotrophic activity to an N-terminal peptide region.","evidence":"serpin biochemical characterization and peptide dissection","pmids":["9433504"],"confidence":"Medium","gaps":["No receptor identified for the neurotrophic activity in this study","Serpin loop role left undefined beyond being dispensable"]},{"year":2000,"claim":"Growth-arrest induction of EPC-1/PEDF was shown to be governed posttranscriptionally through mRNA stability rather than transcription, defining how its expression tracks cell-cycle state.","evidence":"transcriptional run-on, hnRNA RT-PCR and mRNA stability measurement in WI-38 fibroblasts (extends 1995 Northern-blot work)","pmids":["10972981","7814443"],"confidence":"Medium","gaps":["The stability-determining RNA elements/factors were not identified","Link to a downstream growth-arrest effector not established"]},{"year":2003,"claim":"Reciprocal antibody-neutralization and recombinant-protein addition established that PEDF protein causally enforces G0 growth arrest and proliferation control, going beyond a correlation with expression.","evidence":"antibody neutralization and recombinant protein addition with DNA synthesis assays in fibroblasts and carcinoma cells","pmids":["12599204","10047456"],"confidence":"Medium","gaps":["Receptor and signaling pathway for growth arrest not defined","Cell-type selectivity mechanism unexplained"]},{"year":2005,"claim":"Identification of a functional RARE in the PEDF promoter and reciprocal regulation of retinoic acid receptors connected PEDF expression to retinoid signaling in retinal and endothelial cells.","evidence":"luciferase reporter with PEDF promoter-RARE construct, qPCR and Western blot with ATRA treatment","pmids":["15051476"],"confidence":"Medium","gaps":["Whether retinoid regulation operates in vivo not shown","Mechanism of PEDF feedback on RAR/RXR expression unresolved"]},{"year":2005,"claim":"In vivo and knockdown studies placed PEDF as a negative regulator of vascular permeability and inflammatory cytokine output in retinopathy models, anchoring its anti-angiogenic/anti-inflammatory role.","evidence":"intravitreal injection in rat retinopathy models, siRNA knockdown in Müller cells, cytokine ELISA","pmids":["16368716"],"confidence":"Medium","gaps":["Receptor mediating the anti-permeability effect not identified here","Direct vs indirect VEGF suppression not separated"]},{"year":2009,"claim":"Identification of PEDF-R/PNPLA2 as a high-affinity cell-surface phospholipase A2 receptor for PEDF provided the first defined receptor-coupled biochemical activity, linking PEDF binding to fatty-acid release.","evidence":"binding assays, PLA2 enzymatic activity assays and topology analysis on retina/RPE cells","pmids":["20237999"],"confidence":"Medium","gaps":["Downstream lipid mediators not yet mapped to a survival pathway","Binding interface on PEDF-R not localized in this study"]},{"year":2009,"claim":"Demonstrating that PEDF inhibits osteoclast differentiation and resorption while upregulating OPG defined an active role for PEDF in bone remodeling, distinct from its vascular activities.","evidence":"osteoclast differentiation and bone resorption assays with OPG expression analysis","pmids":["19945427"],"confidence":"Medium","gaps":["Receptor mediating osteoblast OPG induction not identified","In vivo bone relevance addressed only later by genetics"]},{"year":2009,"claim":"Limited proteolysis and synthetic peptides localized the anti-angiogenic activity to the 34-mer (Asp44-Asn77) and showed the 44-mer is inactive in angiogenesis, separating PEDF's functional domains.","evidence":"chymotrypsin proteolysis, ex vivo aortic sprouting and rat laser-induced CNV models with synthetic peptides","pmids":["19850839"],"confidence":"High","gaps":["Receptor engaged by the 34-mer in angiogenesis not defined here","Structural basis of peptide activity not resolved"]},{"year":2011,"claim":"Human genetics established SERPINF1 loss-of-function as the cause of osteogenesis imperfecta type VI through a collagen-independent mechanism, converting PEDF's bone activity from in vitro observation to causal disease biology.","evidence":"exome sequencing, homozygosity mapping and collagen biochemistry across multiple families with bone histomorphometry","pmids":["21353196","21826736"],"confidence":"High","gaps":["The molecular pathway linking PEDF loss to defective mineralization was not yet defined","Whether secreted PEDF acts on osteoblasts or osteoclasts in vivo unresolved at this stage"]},{"year":2011,"claim":"Mechanistic dissection showed PEDF blocks VEGF-induced permeability via a γ-secretase-dependent pathway that stabilizes adherens and tight junctions, providing a junctional mechanism for its vascular barrier protection.","evidence":"transendothelial resistance, paracellular flux, in vivo leakage, reciprocal immunoprecipitation and γ-secretase inhibitor","pmids":["21695048"],"confidence":"High","gaps":["The receptor coupling PEDF to γ-secretase not identified","γ-secretase substrate driving junction stabilization not named"]},{"year":2013,"claim":"Mapping the PEDF binding site to PEDF-R ectodomain L4 (His203-Leu232) and showing knockdown abolishes survival defined the receptor element required for PEDF's retinal pro-survival and STAT3-activating activity.","evidence":"truncation-mutant binding, peptide competition, siRNA knockdown and viability assays; conditioned-medium STAT3 activation","pmids":["23818523","29186716"],"confidence":"High","gaps":["How PLA2 activation couples to STAT3 not fully traced","Contribution of PEDF-R vs other receptors to survival in vivo not separated"]},{"year":2014,"claim":"Identification of PLXDC1 and PLXDC2 as PEDF receptors that are activated by PEDF-induced dissociation of their basal homooligomers expanded the receptor repertoire and defined a distinct activation mechanism.","evidence":"gain/loss-of-function cellular assays, oligomerization studies and intracellular-domain mutagenesis","pmids":["25535841"],"confidence":"High","gaps":["Cell-type-specific downstream signaling of PLXDC receptors not mapped","Relative use of PLXDC vs PEDF-R vs VEGFRs in a given tissue unresolved"]},{"year":2014,"claim":"PEDF was shown to protect RPE cells from oxidative stress by stabilizing mitochondria through PI3K/Akt signaling and controlling ROS via UCP2, connecting receptor engagement to mitochondrial protection.","evidence":"pharmacological pathway inhibitors, mitochondrial membrane potential/ATP/ROS assays and UCP2-deficient cell rescue","pmids":["25212780"],"confidence":"Medium","gaps":["Receptor upstream of PI3K/Akt in this context not specified","Mechanism of UCP2 induction not defined"]},{"year":2015,"claim":"PEDF and its 44-mer were shown to drive cardiac triglyceride degradation through ATGL, establishing ATGL as a key effector of PEDF lipid metabolism and assigning the 44-mer a metabolic role distinct from the anti-angiogenic 34-mer.","evidence":"ATGL inhibitor (atglistatin), ATGL siRNA, lipid assays and PEDF manipulation in an AMI mouse model","pmids":["25890298"],"confidence":"Medium","gaps":["Receptor coupling PEDF to ATGL activation in cardiomyocytes not pinned down","Directness of PEDF-ATGL link not established"]},{"year":2015,"claim":"Demonstrating that OI type VI in-frame mutants are retained in the ER or degraded intracellularly and impair mineralization showed the disease arises from loss of secreted PEDF function.","evidence":"immunofluorescence localization, ER stress assays and mineralization assays in transfected osteoblastic cells","pmids":["25868797"],"confidence":"Medium","gaps":["Whether ER retention contributes additional toxicity beyond loss of secretion unresolved","Direct osteoblast signaling defect not yet linked to TGF-β"]},{"year":2018,"claim":"Identifying COP1-mediated nuclear proteasomal degradation of ATGL in hepatocytes, and an ATGL/lipid-MTOC axis in fibroblasts, broadened PEDF's lipid-metabolic role to nuclear regulation of lipase abundance.","evidence":"co-IP, subcellular fractionation, proteasome inhibition and COP1 knockdown in hepatocytes; lipid/MTOC quantification in prostate fibroblasts","pmids":["30926171","29792311"],"confidence":"Medium","gaps":["How extracellular PEDF reaches the nuclear compartment unexplained","COP1 recruitment mechanism to nuclear ATGL not defined"]},{"year":2018,"claim":"Cardioprotective signaling was extended by showing PEDF engages PEDF-R/iPLA2 to limit NLRP3 inflammasome activation and drives mitophagy via a PKCα-ULK1 axis, linking PEDF to mitochondrial quality control.","evidence":"PEDF-R siRNA, iPLA2 inhibition, co-IP of PKCα-ULK1 with deletion mutant and phosphorylation-site mapping in OGD cardiomyocytes","pmids":["27973457","30230261"],"confidence":"Medium","gaps":["How PEDF-R signaling connects to PKCα activation not traced","In vivo cardioprotection contribution of mitophagy not quantified"]},{"year":2019,"claim":"Pathway dissection showed PEDF triggers protective autophagy in endothelial cells via p53→sestrin2→mTOR inhibition and induces 34-mer-driven apoptosis in prostate cancer through the laminin receptor, FasL and PPARγ, defining receptor-specific survival/death outcomes.","evidence":"sequential siRNA knockdowns, autophagy markers, caspase-8 activation and laminin-receptor blockade with xenograft","pmids":["31173218","25261795"],"confidence":"Medium","gaps":["Why PEDF promotes survival in some cells and apoptosis in others mechanistically unresolved","Direct PEDF-laminin receptor binding not structurally characterized"]},{"year":2021,"claim":"Direct binding of PEDF to VEGFR-1 and VEGFR-2 extracellular domains, blocking specific receptor phosphorylation sites and downstream signaling, provided a defined molecular mechanism for its anti-angiogenic activity validated across multiple tumor and ocular settings.","evidence":"direct binding assay and phosphorylation-site Western blots with endothelial functional assays; antibody-neutralization in iCCA and corneal models","pmids":["34742690","34329660","29075761"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of PEDF-VEGFR binding not resolved","Integration of VEGFR blockade with γ-secretase and receptor-dissociation mechanisms not reconciled"]},{"year":2022,"claim":"A Serpinf1-/- mouse model defined PEDF as a functional antagonist of TGF-β signaling in osteoblasts, explaining delayed maturation, defective mineralization and increased bone vascularization in PEDF loss and linking the OI type VI phenotype to a signaling pathway.","evidence":"Serpinf1-/- mice, primary osteoblast culture, RNA-Seq, vessel-density imaging and recombinant PEDF rescue of TGF-β effects","pmids":["35258129"],"confidence":"High","gaps":["Receptor mediating PEDF-TGF-β antagonism in osteoblasts not identified","Relationship between osteoblast TGF-β antagonism and the earlier OPG/osteoclast mechanism not integrated"]},{"year":2023,"claim":"PEDF was shown to protect RPE cells from ferroptosis by upregulating GPX4 and FTH1, with PEDF-knockout mice developing dry AMD-like pathology, extending PEDF's cytoprotective repertoire to ferroptosis defense.","evidence":"PEDF knockout and overexpression, lipid peroxidation assays, GPX4/FTH1 Western blot and retinal imaging","pmids":["38153666"],"confidence":"Medium","gaps":["Receptor and signaling cascade upstream of GPX4/FTH1 induction not defined","Whether ferroptosis protection is direct or secondary to broader survival signaling unresolved"]},{"year":null,"claim":"How PEDF selects among its multiple receptors (PEDF-R, PLXDC1/2, VEGFR-1/2, laminin receptor) to produce opposing outcomes (survival vs apoptosis, autophagy vs proliferation arrest) in a given cell type remains the central unresolved question.","evidence":"no single study reconciles the receptor repertoire with context-specific outcomes","pmids":[],"confidence":"Medium","gaps":["No unified model of receptor selection or competition","Structural basis distinguishing 34-mer vs 44-mer receptor engagement not established","How extracellular PEDF accesses nuclear ATGL/COP1 machinery unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[30,10,31,16]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[9,14,16,30]},{"term_id":"GO:0060089","term_label":"molecular transducer 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29351407","citation_count":26,"is_preprint":false},{"pmid":"27855634","id":"PMC_27855634","title":"Identification of novel targets of diabetic nephropathy and PEDF peptide treatment using RNA-seq.","date":"2016","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27855634","citation_count":26,"is_preprint":false},{"pmid":"31024806","id":"PMC_31024806","title":"Autophagy: a new mechanism for regulating VEGF and PEDF expression in retinal pigment epithelium cells.","date":"2019","source":"International journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/31024806","citation_count":26,"is_preprint":false},{"pmid":"10972981","id":"PMC_10972981","title":"Regulation of EPC-1/PEDF in normal human fibroblasts is posttranscriptional.","date":"2000","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10972981","citation_count":26,"is_preprint":false},{"pmid":"27747237","id":"PMC_27747237","title":"C3a Increases VEGF and Decreases PEDF mRNA Levels in Human Retinal Pigment Epithelial Cells.","date":"2016","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/27747237","citation_count":26,"is_preprint":false},{"pmid":"30455080","id":"PMC_30455080","title":"MicroRNA-93 promotes bladder cancer proliferation and invasion by targeting PEDF.","date":"2018","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30455080","citation_count":25,"is_preprint":false},{"pmid":"19075591","id":"PMC_19075591","title":"PEDF as an emerging therapeutic candidate for osteosarcoma.","date":"2008","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/19075591","citation_count":25,"is_preprint":false},{"pmid":"25261795","id":"PMC_25261795","title":"Proapoptotic PEDF functional peptides inhibit prostate tumor growth--a mechanistic study.","date":"2014","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25261795","citation_count":25,"is_preprint":false},{"pmid":"22690122","id":"PMC_22690122","title":"Cell and molecular biology underpinning the effects of PEDF on cancers in general and osteosarcoma in particular.","date":"2012","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22690122","citation_count":24,"is_preprint":false},{"pmid":"29792311","id":"PMC_29792311","title":"PEDF regulates plasticity of a novel lipid-MTOC axis in prostate cancer-associated fibroblasts.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29792311","citation_count":23,"is_preprint":false},{"pmid":"27796462","id":"PMC_27796462","title":"Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI.","date":"2016","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/27796462","citation_count":22,"is_preprint":false},{"pmid":"28747334","id":"PMC_28747334","title":"PEDF expression affects retinal endothelial cell proangiogenic properties through alterations in cell adhesive mechanisms.","date":"2017","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28747334","citation_count":22,"is_preprint":false},{"pmid":"30123797","id":"PMC_30123797","title":"Chemerin and PEDF Are Metaflammation-Related Biomarkers of Disease Activity and Obesity in Rheumatoid Arthritis.","date":"2018","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30123797","citation_count":22,"is_preprint":false},{"pmid":"25868797","id":"PMC_25868797","title":"The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI.","date":"2015","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/25868797","citation_count":21,"is_preprint":false},{"pmid":"26942449","id":"PMC_26942449","title":"pEPito-driven PEDF Expression Ameliorates Diabetic Retinopathy Hallmarks.","date":"2016","source":"Human gene therapy methods","url":"https://pubmed.ncbi.nlm.nih.gov/26942449","citation_count":21,"is_preprint":false},{"pmid":"33396450","id":"PMC_33396450","title":"Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33396450","citation_count":21,"is_preprint":false},{"pmid":"9565647","id":"PMC_9565647","title":"Structural and comparative analysis of the mouse gene for pigment epithelium-derived factor (PEDF).","date":"1998","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/9565647","citation_count":21,"is_preprint":false},{"pmid":"24769282","id":"PMC_24769282","title":"Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium.","date":"2014","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24769282","citation_count":21,"is_preprint":false},{"pmid":"31884652","id":"PMC_31884652","title":"Signaling Mechanisms Involved in PEDF-Mediated Retinoprotection.","date":"2019","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/31884652","citation_count":20,"is_preprint":false},{"pmid":"24318110","id":"PMC_24318110","title":"PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium.","date":"2013","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24318110","citation_count":20,"is_preprint":false},{"pmid":"31582735","id":"PMC_31582735","title":"The contrary intracellular and extracellular functions of PEDF in HCC development.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31582735","citation_count":20,"is_preprint":false},{"pmid":"32933011","id":"PMC_32933011","title":"Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus.","date":"2020","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32933011","citation_count":20,"is_preprint":false},{"pmid":"25948043","id":"PMC_25948043","title":"Recombinant pigment epithelium-derived factor PEDF binds vascular endothelial growth factor receptors 1 and 2.","date":"2015","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/25948043","citation_count":20,"is_preprint":false},{"pmid":"32873283","id":"PMC_32873283","title":"PEDF promotes the repair of bone marrow endothelial cell injury and accelerates hematopoietic reconstruction after bone marrow transplantation.","date":"2020","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/32873283","citation_count":20,"is_preprint":false},{"pmid":"32721425","id":"PMC_32721425","title":"PEDF deficiency increases the susceptibility of rd10 mice to retinal degeneration.","date":"2020","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/32721425","citation_count":19,"is_preprint":false},{"pmid":"31173218","id":"PMC_31173218","title":"p53 mediates PEDF‑induced autophagy in human umbilical vein endothelial cells through sestrin2 signaling.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31173218","citation_count":19,"is_preprint":false},{"pmid":"34648865","id":"PMC_34648865","title":"MiR-186-5p Dysregulation Leads to Depression-like Behavior by De-repressing SERPINF1 in Hippocampus.","date":"2021","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34648865","citation_count":18,"is_preprint":false},{"pmid":"30926171","id":"PMC_30926171","title":"PEDF promotes nuclear degradation of ATGL through COP1.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30926171","citation_count":18,"is_preprint":false},{"pmid":"38191093","id":"PMC_38191093","title":"Tissue-targeted and localized AAV5-DCN and AAV5-PEDF combination gene therapy abrogates corneal fibrosis and concurrent neovascularization in rabbit eyes in vivo.","date":"2024","source":"The ocular surface","url":"https://pubmed.ncbi.nlm.nih.gov/38191093","citation_count":18,"is_preprint":false},{"pmid":"26966066","id":"PMC_26966066","title":"PEDF and PEDF-derived peptide 44mer inhibit oxygen-glucose deprivation-induced oxidative stress through upregulating PPARγ via PEDF-R in H9c2 cells.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26966066","citation_count":18,"is_preprint":false},{"pmid":"30230261","id":"PMC_30230261","title":"PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30230261","citation_count":18,"is_preprint":false},{"pmid":"35258129","id":"PMC_35258129","title":"Antagonism Between PEDF and TGF-β Contributes to Type VI Osteogenesis Imperfecta Bone and Vascular Pathogenesis.","date":"2022","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/35258129","citation_count":17,"is_preprint":false},{"pmid":"30025136","id":"PMC_30025136","title":"PEDF Reduces the Severity of Herpetic Simplex Keratitis in Mice.","date":"2018","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/30025136","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50555,"output_tokens":8662,"usd":0.140797,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18670,"output_tokens":6760,"usd":0.131175,"stage2_stop_reason":"end_turn"},"total_usd":0.271972,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"PEDF is a non-inhibitory serpin: it has characteristics of a substrate rather than an inhibitor of serine proteases, and an N-terminal peptide region provides its neurotrophic function while the serpin exposed loop and oligosaccharides are dispensable for this activity.\",\n      \"method\": \"Structure-function analysis, peptide dissection, serpin biochemical characterization\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structure-function analysis from a single lab, no explicit mutagenesis or reconstitution described in abstract\",\n      \"pmids\": [\"9433504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"EPC-1/PEDF mRNA is induced under growth arrest (density-dependent contact inhibition and serum deprivation) in early-passage but not senescent WI-38 fibroblasts; the regulation is cell-cycle dependent and expression is limited to specific cell types with conserved genomic sequences across mammalian species.\",\n      \"method\": \"Northern blot, serum stimulation/starvation experiments, interspecies Southern blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Northern blot, growth-state manipulation), single lab\",\n      \"pmids\": [\"7814443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Regulation of EPC-1/PEDF expression in fibroblasts is posttranscriptional: transcription rates are unchanged between proliferating, quiescent and senescent cells; regulation occurs at the hnRNA level, and mRNA stability is reduced when cells exit G0.\",\n      \"method\": \"Transcriptional run-on assays, RT-PCR of hnRNA, mRNA stability measurements\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — transcriptional assays plus mRNA stability measurements, single lab\",\n      \"pmids\": [\"10972981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EPC-1/PEDF protein plays a role in G0 growth arrest of human diploid fibroblasts: antibodies blocking EPC-1 increase DNA synthesis in near-plateau early-passage cultures, and addition of recombinant EPC-1 decreases DNA synthesis in logarithmically growing cells; EPC-1 expression is lost with senescence and SV40 transformation.\",\n      \"method\": \"Antibody neutralization, recombinant protein addition, DNA synthesis assay (BrdU/[3H]-thymidine incorporation), Western blot, mRNA analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function experiments with recombinant protein and neutralizing antibodies, single lab\",\n      \"pmids\": [\"12599204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PEDF/EPC-1 protein inhibits anchorage-dependent and anchorage-independent proliferation of endometrial carcinoma cells in a dose- and time-dependent manner, but has no effect on stromal fibroblast proliferation; secreted PEDF/EPC-1 levels decline as endometrial stromal fibroblasts age in vitro.\",\n      \"method\": \"Recombinant protein treatment, cell proliferation assays (anchorage-dependent and soft agar), ELISA, Western blot\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein addition with multiple readouts, single lab\",\n      \"pmids\": [\"10047456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Retinoic acid (ATRA) upregulates PEDF protein and RNA in retinal and endothelial cells through a functional retinoic acid receptor element (RARE) in the PEDF promoter; dexamethasone also increases PEDF RNA levels; conversely, PEDF treatment alters expression of retinoic acid receptors RARα, RXRγ, RARβ and RXRβ in retinal cells.\",\n      \"method\": \"Luciferase reporter assay with PEDF promoter-RARE construct, quantitative PCR, Western blot, ATRA treatment\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reporter assay with promoter construct plus multiple orthogonal methods, single lab\",\n      \"pmids\": [\"15051476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PEDF is a negative acute-phase protein in endotoxin-induced uveitis; intravitreal PEDF injection reduces vascular hyper-permeability in diabetic and oxygen-induced retinopathy models, correlating with decreased retinal VEGF, VEGFR-2, MCP-1, TNF-α, and ICAM-1; siRNA knockdown of PEDF in Müller cells increases VEGF and TNF-α secretion.\",\n      \"method\": \"Western blot, ELISA, intravitreal injection in rat models, siRNA knockdown, cell culture under hypoxia\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo injection plus siRNA knockdown with multiple cytokine readouts, single lab\",\n      \"pmids\": [\"16368716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PEDF is the predominant fibroblast chemoattractant in mesenchymal stem cell secretome: immunodepletion of PEDF abolishes fibroblast chemotaxis, and reconstitution restores it; PEDF stimulates fibroblast migration (in contrast to its known inhibition of endothelial cell migration).\",\n      \"method\": \"Proteomic identification of secretome, immunodepletion and reconstitution, fibroblast chemotaxis assay, immunofluorescence\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunodepletion/reconstitution experiment, single lab\",\n      \"pmids\": [\"18348263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PEDF inhibits osteoclast differentiation, RANKL-mediated survival, and bone resorption activity in a dose-dependent manner; PEDF upregulates osteoprotegerin (OPG) in primary osteoblasts and osteoclast precursor cells, suggesting PEDF inhibits osteoclast function via OPG regulation.\",\n      \"method\": \"In vitro osteoclast differentiation assay, bone resorption assay, Western blot/ELISA for OPG expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional differentiation and resorption assays with mechanistic follow-up, single lab\",\n      \"pmids\": [\"19945427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PEDF-R, a member of the patatin-like phospholipase domain-containing 2 (PNPLA2) family, is a transmembrane phospholipase A2 on the surface of retina and RPE cells with high-affinity specific binding for PEDF; PEDF binding stimulates PEDF-R phospholipase A2 enzymatic activity, releasing fatty acids.\",\n      \"method\": \"Binding assays, phospholipase A2 enzymatic activity assay, cell surface localization, transmembrane topology analysis\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with receptor binding, single lab, multiple methods\",\n      \"pmids\": [\"20237999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PEDF inhibits VEGF-induced vascular permeability via a γ-secretase-dependent pathway: PEDF prevents dissociation of adherens junction (VE-cadherin, β-catenin) and tight junction (claudin-5) proteins, regulates VEGF receptor association with adherens junction proteins, and inhibits phosphorylation of VE-cadherin and β-catenin; γ-secretase inhibitor blocks PEDF's anti-permeability effect.\",\n      \"method\": \"Transendothelial resistance assay, paracellular dextran flux, FITC-albumin leakage in vivo, immunoprecipitation, Western blot, immunohistochemistry with γ-secretase inhibitor\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods with pharmacological inhibitor validation, reciprocal immunoprecipitation\",\n      \"pmids\": [\"21695048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Truncating mutations in SERPINF1 cause autosomal-recessive osteogenesis imperfecta type VI; PEDF loss is associated with severe bone fragility without impairment of collagen folding, posttranslational modification, or secretion, establishing a collagen-independent role for PEDF in bone homeostasis.\",\n      \"method\": \"Exome sequencing, homozygosity mapping, Sanger sequencing, collagen biochemical analysis in dermal fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics with multiple affected families plus collagen biochemistry ruling out collagen mechanism, replicated in multiple patients\",\n      \"pmids\": [\"21353196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in SERPINF1 cause OI type VI, characterized by increased unmineralized osteoid, establishing PEDF involvement in bone mineralization through a mechanism distinct from collagen processing.\",\n      \"method\": \"Homozygosity mapping, next-generation sequencing, clinical bone histomorphometry\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics with histomorphometric bone analysis, replicated in multiple families, independent of paper 21353196\",\n      \"pmids\": [\"21826736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PEDF deficiency combined with oncogenic Kras mutation induces invasive pancreatic ductal adenocarcinoma and adipose-rich stroma in mice; loss of PEDF is associated with enhanced MMP-2 and MMP-9 expression, increased peripancreatic adipocyte hypertrophy, elevated lipid droplet proteins (TIP47, ADRP) and decreased adipose triglyceride lipase.\",\n      \"method\": \"Genetic mouse model (EL-Kras/PEDF-deficient), histology, immunohistochemistry, Western blot, ELISA\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model with multiple molecular readouts, single lab\",\n      \"pmids\": [\"22234980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PEDF-R (encoded by PNPLA2) is required for PEDF-mediated retinal cell survival and antiapoptotic activity: the PEDF binding site on PEDF-R is within ectodomain L4 (specifically residues His203-Leu232); siRNA knockdown of PEDF-R abolishes PEDF-mediated cell survival; peptides spanning the binding site block PEDF-PEDF-R interaction and survival activity.\",\n      \"method\": \"Recombinant protein binding assays with truncation mutants, synthetic peptide competition, siRNA knockdown, cell viability assay, cell surface labeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with truncation mutants, mutagenesis-equivalent deletion analysis, siRNA knockdown, peptide competition, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23818523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Müller cell-secreted PEDF promotes retinal ganglion cell survival through STAT3 activation via PEDF-R (encoded by PNPLA2): neutralization of PEDF in Müller cell conditioned medium attenuates STAT3 activation; ablation of PEDF-R attenuates conditioned medium-induced STAT3 activation and compromises PEDF-exposed cell viability.\",\n      \"method\": \"Conditioned medium transfer, PEDF neutralizing antibody, siRNA knockdown of PEDF-R, Western blot for STAT3 phosphorylation, cell viability assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralization plus receptor knockdown with signaling readout, single lab\",\n      \"pmids\": [\"29186716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PLXDC1 and PLXDC2 are identified as cell-surface transmembrane receptors for PEDF: loss-of-function and gain-of-function studies demonstrate cell type-specific receptor activities; PEDF receptors form homooligomers under basal conditions and PEDF dissociates the homooligomer to activate them; mutations in the intracellular domain profoundly affect receptor activity.\",\n      \"method\": \"Loss-of-function and gain-of-function cellular assays, receptor oligomerization studies, intracellular domain mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (gain/loss-of-function, mutagenesis, oligomerization assays) establishing receptor identity and activation mechanism\",\n      \"pmids\": [\"25535841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PEDF protects RPE cells against oxidative stress by stabilizing mitochondrial networks and function through PI3K/Akt signaling: PEDF unblocks PI3K/Akt and MAPK signaling inhibited by oxidative stress; PI3K/Akt pathway (not MAPK) is specifically required for mitochondrial stabilization; PEDF controls ROS via UCP2 regulation (PEDF-induced UCP2 expression decreases ROS in UCP2-deficient cells).\",\n      \"method\": \"Pharmacological inhibitors (LY294002, SH6, U0126), Western blot, mitochondrial membrane potential and ATP measurements, ROS assay, UCP2-deficient cell rescue\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection plus UCP2-deficient cell rescue, single lab\",\n      \"pmids\": [\"25212780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PEDF and its 44-mer peptide stimulate cardiac triglyceride degradation via adipose triglyceride lipase (ATGL): an ATGL-specific inhibitor (atglistatin) and ATGL siRNA knockdown abolish PEDF/44mer-induced triglyceride lipolysis in cardiomyocytes.\",\n      \"method\": \"ATGL pharmacological inhibition, ATGL siRNA knockdown, Oil Red O staining, triglyceride assay, PEDF lentiviral overexpression/knockdown in AMI mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus genetic knockdown with functional lipid readout, single lab\",\n      \"pmids\": [\"25890298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In-frame SERPINF1 mutations causing OI type VI result in retention of PEDF in the endoplasmic reticulum (for deletion mutations p.F277del and exon 5 deletion) or intracellular degradation (for p.Ala91_Ser93dup) without ER retention; both mechanisms block PEDF secretion; stable expression of p.Ala91_Ser93dup PEDF in osteoblasts decreases collagen type I deposition and mineralization.\",\n      \"method\": \"Immunofluorescence localization in transfected osteoblastic cells, ER stress assay, RT-PCR, mineralization assay in stably transfected MC3T3-E1 cells\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with functional mineralization consequence, single lab\",\n      \"pmids\": [\"25868797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PEDF inhibits NLRP3 inflammasome activation in hypoxic cardiomyocytes through PEDF-R/iPLA2: PEDF reduces Drp1-induced mitochondrial fission, limits cytosolic release of mitochondrial DNA and mitochondrial ROS (which activate NLRP3), acting via PEDF-R/iPLA2 signaling.\",\n      \"method\": \"PEDF-R siRNA knockdown, iPLA2 inhibition, mitochondrial fission assay, NLRP3 inflammasome activation assay, mtDNA and mtROS measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor knockdown with mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"27973457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PEDF and 44-mer peptide reduce oxidative stress and apoptosis in OGD-treated cardiomyocytes via PEDF-R and subsequent PPARγ activation: PEDF-R siRNA or PPARγ antagonist abolishes PEDF/44mer-mediated ROS reduction and anti-apoptotic effects; PEDF/44mer increase LPA, PLA2 activity, and PPARγ expression downstream of PEDF-R.\",\n      \"method\": \"PEDF-R siRNA knockdown, PPARγ antagonist (GW9662), ROS assay, TUNEL/caspase-3 apoptosis assay, ELISA for LPA and PLA2, qPCR and Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor knockdown plus pharmacological inhibition with multiple downstream readouts, single lab\",\n      \"pmids\": [\"26966066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PEDF is a direct antiangiogenic factor secreted by corneal mesenchymal stromal cells (Co-MSCs): immunoprecipitation removal of PEDF from Co-MSC secretome significantly diminishes antiangiogenic effects; SERPINF1-/- Co-MSCs have significantly reduced antiangiogenic activity compared to wild-type.\",\n      \"method\": \"Immunoprecipitation depletion from secretome, HUVEC tube formation assay, fibrin gel bead assay, SERPINF1-/- mouse-derived Co-MSC comparison, in vivo corneal neovascularization model\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — immunodepletion plus genetic knockout model with both in vitro and in vivo functional readouts, replicated across methods\",\n      \"pmids\": [\"29075761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEDF deficiency (PEDF-/-) in retinal endothelial cells alters proangiogenic properties through changes in cell adhesion mechanisms: PEDF-/- retinal EC are more proliferative, less apoptotic under H2O2 challenge, less migratory and less adherent; PEDF loss increases tenascin-C, fibronectin, thrombospondin-1 and collagen IV and alters integrin expression (α2, αv, β1, β8, αvβ3) and cell-cell adhesion molecules (CD31, ZO-1, occludin).\",\n      \"method\": \"PEDF-/- mouse-derived retinal EC, proliferation/migration/adhesion/apoptosis assays, Western blot for ECM and adhesion proteins, capillary morphogenesis assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null cell model with multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"28747334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEDF regulates MTOC number and lipid metabolism in prostate cancer-associated fibroblasts (CAFs) via an ATGL-dependent lipid-MTOC axis: PEDF and ATGL are co-expressed in normal prostate fibroblasts but nearly absent in CAFs; PEDF treatment suppresses lipid content and MTOC amplification in CAFs.\",\n      \"method\": \"Primary human NF and CAF isolation, neutral lipid staining, MTOC quantification by immunofluorescence, PEDF treatment, Western blot for ATGL and PEDF\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary cell model with PEDF rescue experiment and multiple readouts, single lab\",\n      \"pmids\": [\"29792311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEDF promotes nuclear degradation of ATGL through COP1-mediated proteasomal degradation in hepatocytes: PEDF (itself present in the nuclear compartment) enhances nuclear import of cytosolic ATGL leading to COP1-dependent polyubiquitylation and proteasomal degradation; this controls hepatocyte lipid accumulation and mobilization.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, proteasome inhibitor experiments, COP1 knockdown, lipid accumulation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic knockdown with functional lipid readout, single lab\",\n      \"pmids\": [\"30926171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEDF promotes mitophagy in OGD-treated cardiomyocytes via a PKCα-ULK1 axis that replaces AMPK: PEDF increases PKCα/p-PKCα, which directly interacts with ULK1 at its serine/threonine-rich domain; phospho-PKCα phosphorylates ULK1 at Ser317/555/777 and Raptor; a ULK1 deletion mutant lacking the PKCα-binding domain is defective in PEDF-induced mitophagy.\",\n      \"method\": \"Co-immunoprecipitation of PKCα-ULK1, ULK1 deletion mutant assay, Western blot for phosphorylation sites, mitochondrial ROS and DNA release measurement, mitophagy assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — co-IP with deletion mutant and phosphorylation site mapping, single lab\",\n      \"pmids\": [\"30230261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PEDF induces PEDF-mediated autophagy in endothelial cells via sequential induction of p53 and sestrin2 with downstream mTOR inhibition: p53 siRNA eliminates sestrin2 induction; p53 or sestrin2 siRNA attenuate PEDF-induced autophagy; PEDF-treated cells show reduced p70S6K and 4E-BP1 phosphorylation (mTOR suppression).\",\n      \"method\": \"p53 and sestrin2 siRNA knockdown, Western blot for LC3 I/II, p62, p70S6K and 4E-BP1 phosphorylation, fluorescence microscopy for autophagosome formation, RT-qPCR\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequential siRNA knockdown pathway dissection with multiple readouts, single lab\",\n      \"pmids\": [\"31173218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PEDF 34-mer peptide induces apoptosis in prostate cancer cells via the extrinsic death receptor pathway through the laminin receptor: PEDF34 upregulates FasL and activates caspase-8; FasL knockdown or JNK inhibition attenuates PEDF34-induced apoptosis; PPARγ (not NF-κB) is required for FasL upregulation; blocking the laminin receptor abolishes FasL and PPARγ upregulation by PEDF34.\",\n      \"method\": \"siRNA knockdown (FasL, PPARγ, NF-κB, laminin receptor), pharmacological inhibitors (GW9662, PDTC, JNK inhibitor), caspase-8 activation assay, Western blot, in vivo xenograft\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA knockdowns and pharmacological inhibitors defining pathway, single lab\",\n      \"pmids\": [\"25261795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PEDF is a direct antiangiogenic factor in intrahepatic cholangiocarcinoma: antibodies blocking PEDF (along with THBS1 and THBS2) restore endothelial tube formation and cell viability inhibited by iCCA extracellular fluid; in transplanted SCID mice, PEDF expression is required for inhibition of blood vessel formation and promotion of lymphangiogenesis.\",\n      \"method\": \"Quantitative proteomics of extracellular fluid, antibody-blocking of PEDF in 3D vascular assembly assay, endothelial migration/proliferation/viability assays, in vivo heterotopic transplantation in SCID mice\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody neutralization in vitro and in vivo, multiple functional readouts, single lab\",\n      \"pmids\": [\"34329660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PEDF inhibits angiogenesis by binding directly to the extracellular domain of VEGFR-2 and VEGFR-1, blocking VEGF-A-induced phosphorylation of VEGFR-2 at Tyr951 and Tyr1175, and inhibiting downstream signaling through PI3K, AKT, FAK, Src (Y416), and PLC-γ.\",\n      \"method\": \"Direct binding assay (ELISA-type), phosphorylation analysis by Western blot, endothelial cell proliferation/migration/tube formation assays\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus phosphorylation site mapping with functional readouts, single lab\",\n      \"pmids\": [\"34742690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of PEDF in Serpinf1-/- mice activates TGF-β signaling in osteoblasts, delays osteoblast maturation and ECM mineralization, and increases bone vascularization (elevated CD31+/Endomucin+ endothelial cells); PEDF functionally antagonizes TGF-β: TGF-β stimulation and PEDF deficiency have additive effects on suppression of osteogenic markers; exogenous PEDF attenuates TGF-β-induced pro-angiogenic factor expression.\",\n      \"method\": \"Serpinf1-/- mouse model, primary osteoblast culture, RNA-Seq transcriptome, barium sulfate perfusion for vessel density, immunofluorescence for CD31/Endomucin, TGF-β stimulation with recombinant PEDF rescue\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model plus RNA-Seq plus in vitro rescue experiments defining PEDF-TGF-β antagonism with multiple orthogonal readouts\",\n      \"pmids\": [\"35258129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PEDF protects RPE cells from ferroptosis by upregulating GPX4 and ferritin heavy chain-1 (FTH1): overexpression of PEDF increases GPX4 and FTH1 expression, inhibiting lipid peroxidation and RPE ferroptosis in sodium iodate-treated mice; PEDF-knockout mice develop dry AMD-like retinal pathology.\",\n      \"method\": \"PEDF knockout mouse model, PEDF overexpression, lipid peroxidation assay, transmission electron microscopy, Western blot and immunofluorescence for GPX4 and FTH1, electroretinography, OCT\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus overexpression with mechanistic protein targets (GPX4, FTH1), single lab\",\n      \"pmids\": [\"38153666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PEDF 34-mer peptide (Asp44-Asn77) carries the anti-angiogenic activity of full-length PEDF: cleaved PEDF and 34-mer peptide inhibit ex vivo vessel sprouting and reduce CNV lesion volumes in rats; the 44-mer peptide (Val78-Thr121) has no antiangiogenic effect in these assays.\",\n      \"method\": \"Chymotrypsin limited proteolysis, ex vivo chick aortic vessel sprouting assay, rat laser-induced CNV model, subconjunctival injection, confocal immunofluorescence\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-function with cleaved protein and synthetic peptides validated in both ex vivo and in vivo models by multiple methods\",\n      \"pmids\": [\"19850839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEDF (SERPINF1) is a secreted non-inhibitory serpin that exerts multiple context-dependent functions through at least seven identified cell-surface receptors (including PEDF-R/PNPLA2, PLXDC1, PLXDC2, VEGFR-1, VEGFR-2, laminin receptor, and F1-ATP synthase): it inhibits angiogenesis by binding VEGFR-2 to block downstream PI3K/AKT/Src signaling and by acting through a γ-secretase pathway to preserve vascular junction integrity; it promotes retinal neuron and RPE cell survival via PEDF-R–mediated phospholipase A2 activation leading to PPARγ and STAT3 signaling; it regulates lipid metabolism by promoting COP1-mediated nuclear degradation of ATGL in hepatocytes and stimulating cardiac triglyceride degradation via ATGL; it controls bone homeostasis by antagonizing TGF-β signaling in osteoblasts and upregulating OPG to suppress osteoclasts, with loss-of-function SERPINF1 mutations causing OI type VI through collagen-independent mechanisms; and its anti-angiogenic and neurotrophic activities are carried by distinct peptide domains (34-mer and 44-mer, respectively) within the PEDF polypeptide.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SERPINF1 encodes PEDF, a secreted non-inhibitory serpin that acts as a multifunctional extracellular signaling factor coordinating angiogenesis, cell survival, lipid metabolism, and bone homeostasis through distinct cell-surface receptors and peptide domains [#0, #16]. Its anti-angiogenic activity is mediated by direct binding to the extracellular domains of VEGFR-1 and VEGFR-2, blocking VEGF-A-induced receptor phosphorylation and downstream PI3K/AKT/FAK/Src/PLC-γ signaling [#30], and by a γ-secretase-dependent pathway that preserves adherens and tight junction integrity to limit vascular permeability [#10]; this anti-angiogenic function is carried by the 34-mer peptide region, whereas the 44-mer is inactive in angiogenesis [#33]. PEDF promotes retinal and RPE cell survival by binding PEDF-R (PNPLA2) at ectodomain L4, stimulating its phospholipase A2 activity to drive PPARγ and STAT3 signaling and protect against oxidative stress, ferroptosis, and apoptosis [#9, #14, #15, #32], and signals additionally through the transmembrane receptors PLXDC1 and PLXDC2, which it activates by dissociating their basal homooligomers [#16]. PEDF controls lipid homeostasis by acting on adipose triglyceride lipase (ATGL): it stimulates ATGL-dependent triglyceride degradation in cardiomyocytes and promotes COP1-mediated nuclear proteasomal degradation of ATGL in hepatocytes [#18, #25]. In bone, loss of PEDF activates TGF-β signaling in osteoblasts, delaying maturation and mineralization and elevating bone vascularization, while PEDF suppresses osteoclasts via osteoprotegerin upregulation [#8, #31]. Truncating and in-frame loss-of-function mutations in SERPINF1 cause autosomal-recessive osteogenesis imperfecta type VI through a collagen-independent mechanism, with mutant PEDF retained in the ER or degraded intracellularly [#11, #12, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that PEDF is a non-inhibitory serpin reframed it as a signaling protein rather than a protease inhibitor and localized its neurotrophic activity to an N-terminal peptide region.\",\n      \"evidence\": \"serpin biochemical characterization and peptide dissection\",\n      \"pmids\": [\"9433504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified for the neurotrophic activity in this study\", \"Serpin loop role left undefined beyond being dispensable\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Growth-arrest induction of EPC-1/PEDF was shown to be governed posttranscriptionally through mRNA stability rather than transcription, defining how its expression tracks cell-cycle state.\",\n      \"evidence\": \"transcriptional run-on, hnRNA RT-PCR and mRNA stability measurement in WI-38 fibroblasts (extends 1995 Northern-blot work)\",\n      \"pmids\": [\"10972981\", \"7814443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The stability-determining RNA elements/factors were not identified\", \"Link to a downstream growth-arrest effector not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reciprocal antibody-neutralization and recombinant-protein addition established that PEDF protein causally enforces G0 growth arrest and proliferation control, going beyond a correlation with expression.\",\n      \"evidence\": \"antibody neutralization and recombinant protein addition with DNA synthesis assays in fibroblasts and carcinoma cells\",\n      \"pmids\": [\"12599204\", \"10047456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling pathway for growth arrest not defined\", \"Cell-type selectivity mechanism unexplained\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of a functional RARE in the PEDF promoter and reciprocal regulation of retinoic acid receptors connected PEDF expression to retinoid signaling in retinal and endothelial cells.\",\n      \"evidence\": \"luciferase reporter with PEDF promoter-RARE construct, qPCR and Western blot with ATRA treatment\",\n      \"pmids\": [\"15051476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether retinoid regulation operates in vivo not shown\", \"Mechanism of PEDF feedback on RAR/RXR expression unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"In vivo and knockdown studies placed PEDF as a negative regulator of vascular permeability and inflammatory cytokine output in retinopathy models, anchoring its anti-angiogenic/anti-inflammatory role.\",\n      \"evidence\": \"intravitreal injection in rat retinopathy models, siRNA knockdown in Müller cells, cytokine ELISA\",\n      \"pmids\": [\"16368716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the anti-permeability effect not identified here\", \"Direct vs indirect VEGF suppression not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of PEDF-R/PNPLA2 as a high-affinity cell-surface phospholipase A2 receptor for PEDF provided the first defined receptor-coupled biochemical activity, linking PEDF binding to fatty-acid release.\",\n      \"evidence\": \"binding assays, PLA2 enzymatic activity assays and topology analysis on retina/RPE cells\",\n      \"pmids\": [\"20237999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream lipid mediators not yet mapped to a survival pathway\", \"Binding interface on PEDF-R not localized in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that PEDF inhibits osteoclast differentiation and resorption while upregulating OPG defined an active role for PEDF in bone remodeling, distinct from its vascular activities.\",\n      \"evidence\": \"osteoclast differentiation and bone resorption assays with OPG expression analysis\",\n      \"pmids\": [\"19945427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating osteoblast OPG induction not identified\", \"In vivo bone relevance addressed only later by genetics\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Limited proteolysis and synthetic peptides localized the anti-angiogenic activity to the 34-mer (Asp44-Asn77) and showed the 44-mer is inactive in angiogenesis, separating PEDF's functional domains.\",\n      \"evidence\": \"chymotrypsin proteolysis, ex vivo aortic sprouting and rat laser-induced CNV models with synthetic peptides\",\n      \"pmids\": [\"19850839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor engaged by the 34-mer in angiogenesis not defined here\", \"Structural basis of peptide activity not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Human genetics established SERPINF1 loss-of-function as the cause of osteogenesis imperfecta type VI through a collagen-independent mechanism, converting PEDF's bone activity from in vitro observation to causal disease biology.\",\n      \"evidence\": \"exome sequencing, homozygosity mapping and collagen biochemistry across multiple families with bone histomorphometry\",\n      \"pmids\": [\"21353196\", \"21826736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular pathway linking PEDF loss to defective mineralization was not yet defined\", \"Whether secreted PEDF acts on osteoblasts or osteoclasts in vivo unresolved at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mechanistic dissection showed PEDF blocks VEGF-induced permeability via a γ-secretase-dependent pathway that stabilizes adherens and tight junctions, providing a junctional mechanism for its vascular barrier protection.\",\n      \"evidence\": \"transendothelial resistance, paracellular flux, in vivo leakage, reciprocal immunoprecipitation and γ-secretase inhibitor\",\n      \"pmids\": [\"21695048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor coupling PEDF to γ-secretase not identified\", \"γ-secretase substrate driving junction stabilization not named\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the PEDF binding site to PEDF-R ectodomain L4 (His203-Leu232) and showing knockdown abolishes survival defined the receptor element required for PEDF's retinal pro-survival and STAT3-activating activity.\",\n      \"evidence\": \"truncation-mutant binding, peptide competition, siRNA knockdown and viability assays; conditioned-medium STAT3 activation\",\n      \"pmids\": [\"23818523\", \"29186716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PLA2 activation couples to STAT3 not fully traced\", \"Contribution of PEDF-R vs other receptors to survival in vivo not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of PLXDC1 and PLXDC2 as PEDF receptors that are activated by PEDF-induced dissociation of their basal homooligomers expanded the receptor repertoire and defined a distinct activation mechanism.\",\n      \"evidence\": \"gain/loss-of-function cellular assays, oligomerization studies and intracellular-domain mutagenesis\",\n      \"pmids\": [\"25535841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific downstream signaling of PLXDC receptors not mapped\", \"Relative use of PLXDC vs PEDF-R vs VEGFRs in a given tissue unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PEDF was shown to protect RPE cells from oxidative stress by stabilizing mitochondria through PI3K/Akt signaling and controlling ROS via UCP2, connecting receptor engagement to mitochondrial protection.\",\n      \"evidence\": \"pharmacological pathway inhibitors, mitochondrial membrane potential/ATP/ROS assays and UCP2-deficient cell rescue\",\n      \"pmids\": [\"25212780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor upstream of PI3K/Akt in this context not specified\", \"Mechanism of UCP2 induction not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PEDF and its 44-mer were shown to drive cardiac triglyceride degradation through ATGL, establishing ATGL as a key effector of PEDF lipid metabolism and assigning the 44-mer a metabolic role distinct from the anti-angiogenic 34-mer.\",\n      \"evidence\": \"ATGL inhibitor (atglistatin), ATGL siRNA, lipid assays and PEDF manipulation in an AMI mouse model\",\n      \"pmids\": [\"25890298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling PEDF to ATGL activation in cardiomyocytes not pinned down\", \"Directness of PEDF-ATGL link not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that OI type VI in-frame mutants are retained in the ER or degraded intracellularly and impair mineralization showed the disease arises from loss of secreted PEDF function.\",\n      \"evidence\": \"immunofluorescence localization, ER stress assays and mineralization assays in transfected osteoblastic cells\",\n      \"pmids\": [\"25868797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER retention contributes additional toxicity beyond loss of secretion unresolved\", \"Direct osteoblast signaling defect not yet linked to TGF-β\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying COP1-mediated nuclear proteasomal degradation of ATGL in hepatocytes, and an ATGL/lipid-MTOC axis in fibroblasts, broadened PEDF's lipid-metabolic role to nuclear regulation of lipase abundance.\",\n      \"evidence\": \"co-IP, subcellular fractionation, proteasome inhibition and COP1 knockdown in hepatocytes; lipid/MTOC quantification in prostate fibroblasts\",\n      \"pmids\": [\"30926171\", \"29792311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How extracellular PEDF reaches the nuclear compartment unexplained\", \"COP1 recruitment mechanism to nuclear ATGL not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cardioprotective signaling was extended by showing PEDF engages PEDF-R/iPLA2 to limit NLRP3 inflammasome activation and drives mitophagy via a PKCα-ULK1 axis, linking PEDF to mitochondrial quality control.\",\n      \"evidence\": \"PEDF-R siRNA, iPLA2 inhibition, co-IP of PKCα-ULK1 with deletion mutant and phosphorylation-site mapping in OGD cardiomyocytes\",\n      \"pmids\": [\"27973457\", \"30230261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PEDF-R signaling connects to PKCα activation not traced\", \"In vivo cardioprotection contribution of mitophagy not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pathway dissection showed PEDF triggers protective autophagy in endothelial cells via p53→sestrin2→mTOR inhibition and induces 34-mer-driven apoptosis in prostate cancer through the laminin receptor, FasL and PPARγ, defining receptor-specific survival/death outcomes.\",\n      \"evidence\": \"sequential siRNA knockdowns, autophagy markers, caspase-8 activation and laminin-receptor blockade with xenograft\",\n      \"pmids\": [\"31173218\", \"25261795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why PEDF promotes survival in some cells and apoptosis in others mechanistically unresolved\", \"Direct PEDF-laminin receptor binding not structurally characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Direct binding of PEDF to VEGFR-1 and VEGFR-2 extracellular domains, blocking specific receptor phosphorylation sites and downstream signaling, provided a defined molecular mechanism for its anti-angiogenic activity validated across multiple tumor and ocular settings.\",\n      \"evidence\": \"direct binding assay and phosphorylation-site Western blots with endothelial functional assays; antibody-neutralization in iCCA and corneal models\",\n      \"pmids\": [\"34742690\", \"34329660\", \"29075761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of PEDF-VEGFR binding not resolved\", \"Integration of VEGFR blockade with γ-secretase and receptor-dissociation mechanisms not reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A Serpinf1-/- mouse model defined PEDF as a functional antagonist of TGF-β signaling in osteoblasts, explaining delayed maturation, defective mineralization and increased bone vascularization in PEDF loss and linking the OI type VI phenotype to a signaling pathway.\",\n      \"evidence\": \"Serpinf1-/- mice, primary osteoblast culture, RNA-Seq, vessel-density imaging and recombinant PEDF rescue of TGF-β effects\",\n      \"pmids\": [\"35258129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating PEDF-TGF-β antagonism in osteoblasts not identified\", \"Relationship between osteoblast TGF-β antagonism and the earlier OPG/osteoclast mechanism not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PEDF was shown to protect RPE cells from ferroptosis by upregulating GPX4 and FTH1, with PEDF-knockout mice developing dry AMD-like pathology, extending PEDF's cytoprotective repertoire to ferroptosis defense.\",\n      \"evidence\": \"PEDF knockout and overexpression, lipid peroxidation assays, GPX4/FTH1 Western blot and retinal imaging\",\n      \"pmids\": [\"38153666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling cascade upstream of GPX4/FTH1 induction not defined\", \"Whether ferroptosis protection is direct or secondary to broader survival signaling unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PEDF selects among its multiple receptors (PEDF-R, PLXDC1/2, VEGFR-1/2, laminin receptor) to produce opposing outcomes (survival vs apoptosis, autophagy vs proliferation arrest) in a given cell type remains the central unresolved question.\",\n      \"evidence\": \"no single study reconciles the receptor repertoire with context-specific outcomes\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of receptor selection or competition\", \"Structural basis distinguishing 34-mer vs 44-mer receptor engagement not established\", \"How extracellular PEDF accesses nuclear ATGL/COP1 machinery unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [30, 10, 31, 16]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [9, 14, 16, 30]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [16, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 22, 29]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [30, 10, 16, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [18, 25, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [28, 32, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [27, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [31, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PNPLA2\", \"PLXDC1\", \"PLXDC2\", \"KDR\", \"FLT1\", \"ATGL\", \"COP1\", \"ULK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}