{"gene":"PLA2G4A","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2019,"finding":"PLA2G4A/cPLA2-alpha activation causes lysosomal membrane permeabilization (LMP) in neurons, leading to inhibition of autophagy flux and neuronal cell death following traumatic brain injury; pharmacological inhibition of PLA2G4A attenuated TBI-induced LMP, autophagy impairment, and neuronal loss in vivo, and limited amyloid-β-induced LMP in vitro.","method":"LC-MS/MS lysosomal membrane lipid profiling, pharmacological inhibition (AACOCF3), in vitro cell line and primary neuron assays, in vivo CCI mouse model with LC3/autophagy flux markers and neuronal death quantification","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (lipidomics, pharmacological inhibition, genetic loss-of-function context, in vitro and in vivo models), replicated across cell lines, primary neurons, and mouse model","pmids":["31238788"],"is_preprint":false},{"year":2003,"finding":"cPLA2-alpha (PLA2G4A) is the primary enzyme responsible for arachidonic acid (AA) release in mesangial cells under oxidative stress; secretory PLA2s (group IIa and V) act as upstream regulators that depend on cPLA2-alpha activity and ERK1/2 and PKC signaling pathways to effect AA release.","method":"Genetic knockout mesangial cells (MC-/-) lacking cPLA2-alpha with recombinant adenovirus re-expression of specific PLA2 isoforms; pharmacological inhibition of MEK-1 (U0126), PKC (GF109203x), and calcium chelation (BAPTA-AM); AA release assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with isoform-specific re-expression and pharmacological pathway dissection, multiple orthogonal approaches","pmids":["12676927"],"is_preprint":false},{"year":2004,"finding":"cPLA2-alpha (PLA2G4A) is necessary for neutrophil arachidonate release and platelet-activating factor (PAF) biosynthesis, but not for NADPH oxidase activation, granule secretion, or phagocytosis; cPLA2-alpha is required for efficient bacterial killing in vitro (partially rescued by exogenous AA or PAF) and for pulmonary innate immune defense in vivo.","method":"Pharmacological inhibition (Pyrrolidine-1) in human neutrophils; cPLA2-alpha gene-disrupted mice; AA release assays, PAF biosynthesis assays, NADPH oxidase activation, bacterial killing assays, in vivo E. coli pulmonary infection model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse combined with pharmacological inhibition and multiple functional readouts across two biological systems","pmids":["15475363"],"is_preprint":false},{"year":2005,"finding":"The C2 domain of cPLA2-alpha (PLA2G4A) binds to phospholipid monolayers in a Ca2+-dependent manner, with the calcium-binding loops CBL1 and CBL3 penetrating 2 Å into the lipid tail region; Ca2+-bound protein places its Ca2+ ions within 1 Å of the lipid phosphate group, and binding involves loss of headgroup-associated water molecules (entropic contribution) alongside electrostatic and hydrophobic interactions.","method":"X-ray reflectivity of cPLA2-alpha C2 domain adsorbed onto Langmuir monolayers of SOPC; domain mutants and calcium-free controls; crystallographic structure-based electron density profile analysis","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural method with functional validation via mutants, single lab but multiple orthogonal analyses (X-ray reflectivity + structural fitting + mutagenesis controls)","pmids":["15994899"],"is_preprint":false},{"year":2003,"finding":"In response to Ca2+ elevation, cPLA2-alpha (PLA2G4A) translocates from cytosol and nuclei to the trans-Golgi stack and trans-Golgi network in A549 lung epithelial cells, where it co-localizes specifically with cyclooxygenase-1 (COX-1) but not COX-2; this Golgi association was confirmed by sensitivity to brefeldin A.","method":"High-resolution confocal microscopy with Ca2+ ionophore A23187 stimulation; double staining with Golgi subcompartment markers and rhodamine-wheat germ agglutinin; brefeldin A disruption assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional perturbation (brefeldin A), co-localization with specific Golgi marker and COX-1, single lab","pmids":["12711701"],"is_preprint":false},{"year":2006,"finding":"cPLA2-alpha (PLA2G4A) is not required for PMA-stimulated NADPH oxidase activation or voltage-gated proton channel enhanced gating in human eosinophils or murine granulocytes; PKC activity (not cPLA2-alpha) is required for sustained activation of both proton channels and NADPH oxidase.","method":"cPLA2-alpha gene knockout mice; three specific cPLA2-alpha inhibitors (Wyeth-1, pyrrolidine-2, AACOCF3) in human eosinophils; perforated-patch electrophysiology; PKC inhibitors (GFX, staurosporine); okadaic acid phosphatase inhibition","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout replicated with three independent pharmacological inhibitors, electrophysiology as direct functional readout, replicated across species","pmids":["17185330"],"is_preprint":false},{"year":2022,"finding":"PTRF (Polymerase I and transcript release factor) stabilizes PLA2G4A protein by decreasing its proteasome-mediated degradation; PTRF overexpression enhances PLA2G4A activity and stability, promoting lipid metabolism reprogramming, mitochondrial bioenergetics changes, oxidative damage, autophagy, lipid peroxidation, and ferroptosis in neuronal cells after cerebral ischemia-reperfusion injury. HIF-1α and STAT3 regulate PTRF expression by binding its promoter.","method":"ChIP assay, luciferase assay, Co-IP, lentiviral-sgRNA knockout, AAV-shRNA knockdown in primary neurons and in vivo mouse I/R model; proteasome inhibition experiments; Western blot for PLA2G4A stability","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, genetic KO/KD in vitro and in vivo), single lab","pmids":["35547748"],"is_preprint":false},{"year":2022,"finding":"ATF6α transcriptionally activates PLA2G4A expression (confirmed by ChIP), leading to increased AA release and PGE2 production; this ATF6α-PLA2G4A axis protects prostate cancer cells against ferroptosis, and inhibition of ATF6α reduces PLA2G4A-mediated AA/PGE2 signaling to promote ferroptotic cell death.","method":"ChIP assay, Western blot, qPCR, AA and PGE2 ELISA assays; genetic and pharmacological ATF6α inhibition; cell death assays in prostate cancer cell lines","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct transcriptional regulation, functional assays confirm downstream AA/PGE2 changes and ferroptosis outcome, single lab","pmids":["35089606"],"is_preprint":false},{"year":2006,"finding":"PLA2G4A mRNA and protein expression is upregulated in bovine granulosa cells of ovulatory follicles in response to hCG via the adenylyl cyclase/cAMP pathway (confirmed by forskolin stimulation), implicating PLA2G4A in arachidonic acid release for prostaglandin biosynthesis during ovulation.","method":"In vivo bovine model with timed hCG injection; quantitative RT-PCR; Western blot; immunohistochemistry; in vitro forskolin stimulation of granulosa cells","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct expression regulation confirmed by both in vivo and in vitro experiments with pathway perturbation (cAMP agonist), single lab","pmids":["16510840"],"is_preprint":false},{"year":2021,"finding":"PLA2G4A overexpression in colorectal cancer cells induces CD39+γδ Treg polarization through activation of the PLA2G4A/arachidonic acid metabolic pathway, which inhibits the anti-tumor immune response; this was demonstrated using in vitro co-culture and an orthotopic murine CRC model.","method":"Quantitative mass spectrometry, in vitro co-culture system, orthotopic murine CRC model with Pla2g4a-overexpressing CT26 cells, flow cytometry for CD39+γδ Treg quantification","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with defined cellular phenotype and pathway identification via mass spectrometry, single lab","pmids":["34283812"],"is_preprint":false},{"year":2025,"finding":"CENPF interacts physically with PLA2G4A (confirmed by molecular docking and Co-IP), and this interaction promotes glioma cell growth via mTORC1 and NF-κB pathways; silencing CENPF combined with PLA2G4A inhibitor AACOCF3 induced glioma cell apoptosis synergistically.","method":"Molecular docking, Co-IP, CENPF silencing (siRNA/shRNA), Western blot for mTORC1/NF-κB pathway proteins, CCK-8 proliferation assay, flow cytometry for apoptosis/cell cycle","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP confirms interaction but mechanistic details of how PLA2G4A mediates downstream signaling are not deeply resolved","pmids":["40025532"],"is_preprint":false},{"year":2025,"finding":"Pirin (PIR) transcriptionally regulates PLA2G4A expression downstream of NRF2; PIR loss downregulates PLA2G4A (cPLA2α), increasing polyunsaturated fatty acid (PUFA)-containing phospholipids and shifting the lipidome toward a ferroptosis-permissive state. Restoration of PLA2G4A rescues ferroptosis resistance in PIR-deficient colorectal cancer cells, defining an NRF2-PIR-PLA2G4A circuit.","method":"NRF2 ChIP at PIR promoter, lipidomics, PIR genetic deletion (in vitro and intestinal epithelium-specific in vivo), PLA2G4A rescue experiments, pharmacological inhibition with AACOCF3, AOM/DSS tumorigenesis model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, lipidomics, genetic rescue, in vivo model), single lab","pmids":["41400081"],"is_preprint":false},{"year":2019,"finding":"ANXA10 upregulates PLA2G4A expression, which increases PGE2 production and activates STAT3 signaling, thereby facilitating epithelial-mesenchymal transition (EMT) and promoting metastasis in perihilar cholangiocarcinoma.","method":"mRNA sequencing after ANXA10 manipulation, Western blot, ELISA for PGE2, in vitro migration/invasion assays, in vivo metastasis model, correlation analysis of ANXA10 and PLA2G4A expression","journal":"EBioMedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — regulatory relationship between ANXA10 and PLA2G4A identified by mRNA sequencing, mechanistic detail of how PLA2G4A connects to STAT3/EMT relies on pathway inhibition rather than direct mechanistic dissection of PLA2G4A's role","pmids":["31492557"],"is_preprint":false},{"year":2026,"finding":"GSK3β regulates PLA2G4A expression via an NF-κB-mediated transcriptional mechanism; pharmacological suppression of GSK3β with AS1842856 reduces NF-κB-driven PLA2G4A expression, restoring lysosomal membrane integrity and enhancing lysosomal degradation of amyloid-β in Alzheimer's disease models. Knockdown experiments established that GSK3β (but not GSK3α) specifically suppresses PLA2G4A.","method":"AS1842856 treatment in APP/PS1 mice and N2a-sw cells; GSK3α/β and PLA2G4A knockdown experiments; lysosomal integrity assays; cognitive function testing; Western blot for pathway proteins","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (knockdown) and pharmacological dissection of pathway, in vivo and in vitro confirmation, single lab","pmids":["42047940"],"is_preprint":false},{"year":2025,"finding":"The lncRNA PACERR interacts with an enhancer element affecting cPLA2/PLA2G4A transcriptional activation and escorts the cPLA2 protein to the nuclear membrane in response to HDL, where PLA2G4A releases arachidonic acid to further activate COX-2 and limit LXR/RXR-dependent ABCA1/ABCG1 transcription.","method":"PACERR antisense oligonucleotide silencing, humanized mouse model, RNA-protein interaction assays, ChIP/enhancer analysis, COX-2 and cholesterol efflux functional readouts","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic details for PLA2G4A specifically are part of a larger study; direct evidence for PLA2G4A nuclear membrane localization by PACERR is not independently validated","pmids":[],"is_preprint":true}],"current_model":"PLA2G4A (cPLA2-alpha) is a Ca2+-dependent cytosolic phospholipase that translocates to intracellular membranes (including the Golgi apparatus and lysosomal membranes) via its C2 domain in a calcium-dependent manner, where it cleaves arachidonic acid from membrane phospholipids; this AA release fuels eicosanoid (prostaglandins, PAF, leukotrienes) biosynthesis through coupling with COX-1 and downstream enzymes, and PLA2G4A activity is regulated upstream by secretory PLA2s (requiring cPLA2-alpha for their effect), by ERK1/2 and PKC signaling, and transcriptionally by ATF6α, NRF2-PIR, GSK3β/NF-κB, and STAT3/HIF-1α/PTRF axes; at the lysosome, excess PLA2G4A activity causes lysosomal membrane permeabilization, blocking autophagy and promoting neurodegeneration, while in cancer cells PLA2G4A-mediated AA/PGE2 production suppresses ferroptosis and modulates immune responses."},"narrative":{"mechanistic_narrative":"PLA2G4A (cytosolic phospholipase A2-alpha, cPLA2-alpha) is the principal Ca2+-dependent enzyme that liberates arachidonic acid (AA) from membrane phospholipids to fuel eicosanoid biosynthesis across inflammation, immune defense, reproduction, and cancer [PMID:12676927, PMID:15475363]. Calcium elevation drives its C2 domain to insert into lipid membranes, with the calcium-binding loops CBL1 and CBL3 penetrating the phospholipid tail region and positioning bound Ca2+ ions adjacent to the headgroup phosphate [PMID:15994899]; this Ca2+-triggered translocation relocates cPLA2-alpha to the trans-Golgi where it co-localizes specifically with COX-1 to couple AA release to prostaglandin synthesis [PMID:12711701]. In innate immunity, cPLA2-alpha is required for neutrophil AA release, PAF biosynthesis, and efficient bacterial killing and pulmonary defense, while being dispensable for NADPH oxidase activation, granule secretion, and phagocytosis [PMID:15475363, PMID:17185330]. PLA2G4A expression and activity are controlled at multiple levels: transcriptionally by ATF6alpha, the NRF2-PIR circuit, and GSK3beta/NF-kappaB, and post-translationally by PTRF, which stabilizes the protein against proteasomal degradation [PMID:35547748, PMID:35089606, PMID:41400081, PMID:42047940]. Through these inputs, cPLA2-alpha-mediated AA/PGE2 production suppresses ferroptosis in prostate and colorectal cancer and reprograms the tumor immune microenvironment by polarizing CD39+ gamma-delta Tregs [PMID:35089606, PMID:34283812, PMID:41400081]. In the nervous system, excessive cPLA2-alpha activity causes lysosomal membrane permeabilization that blocks autophagy flux and drives neuronal death following traumatic brain injury and in Alzheimer's models [PMID:31238788, PMID:42047940].","teleology":[{"year":2003,"claim":"Establishing which phospholipase carries out stimulus-coupled arachidonic acid release resolved cPLA2-alpha as the obligate effector downstream of secretory PLA2s and ERK/PKC signaling.","evidence":"cPLA2-alpha-knockout mesangial cells with isoform-specific adenoviral re-expression and pharmacological MEK/PKC/Ca2+ blockade, AA release assays","pmids":["12676927"],"confidence":"High","gaps":["Did not resolve how sPLA2 activity mechanistically depends on cPLA2-alpha","Restricted to mesangial cells under oxidative stress"]},{"year":2003,"claim":"Defining where the activated enzyme acts showed that Ca2+ drives cPLA2-alpha to the trans-Golgi to co-localize with COX-1, providing a spatial basis for AA-to-prostaglandin coupling.","evidence":"Confocal microscopy after Ca2+ ionophore stimulation with Golgi-subcompartment and COX markers, brefeldin A perturbation in A549 cells","pmids":["12711701"],"confidence":"Medium","gaps":["Single cell line","Did not establish the targeting determinant for trans-Golgi versus other membranes"]},{"year":2004,"claim":"Dissecting cPLA2-alpha's immune role showed it is specifically required for neutrophil AA/PAF generation and antibacterial defense but not for the oxidative burst, separating lipid signaling from other effector functions.","evidence":"Gene-disrupted mice plus pharmacological inhibition in human neutrophils, AA/PAF assays, bacterial killing, in vivo E. coli pulmonary infection","pmids":["15475363"],"confidence":"High","gaps":["Partial rescue by exogenous AA/PAF left other contributing pathways unresolved"]},{"year":2005,"claim":"Determining how cPLA2-alpha engages membranes showed the C2 domain inserts CBL loops into the lipid tail region with Ca2+ ions at the phosphate, explaining the calcium dependence of translocation.","evidence":"X-ray reflectivity of the C2 domain on lipid monolayers with domain mutants and Ca2+-free controls","pmids":["15994899"],"confidence":"High","gaps":["Isolated C2 domain rather than full-length enzyme","Model membrane rather than native bilayer"]},{"year":2006,"claim":"Testing functional specificity confirmed PKC, not cPLA2-alpha, drives NADPH oxidase and proton channel gating, sharpening the boundary of cPLA2-alpha's effector functions.","evidence":"Knockout mice and three independent inhibitors in eosinophils/granulocytes with perforated-patch electrophysiology","pmids":["17185330"],"confidence":"High","gaps":["Negative result for a specific pathway; does not address other granulocyte functions"]},{"year":2006,"claim":"Linking cPLA2-alpha to reproduction showed hCG induces its expression via cAMP signaling in ovulatory granulosa cells, implicating it in prostaglandin production during ovulation.","evidence":"Timed hCG injection in bovine model, RT-PCR/Western/IHC, in vitro forskolin stimulation","pmids":["16510840"],"confidence":"Medium","gaps":["Correlative expression; did not demonstrate functional requirement in ovulation","Single species"]},{"year":2019,"claim":"Identifying a pathological consequence of excess activity showed cPLA2-alpha drives lysosomal membrane permeabilization that blocks autophagy and kills neurons after brain injury.","evidence":"Lysosomal lipidomics, AACOCF3 inhibition, in vitro neuron assays, in vivo CCI mouse model with autophagy/neuronal-death readouts","pmids":["31238788"],"confidence":"High","gaps":["Used pharmacological rather than genetic loss-of-function in vivo","Mechanism linking AA release to LMP not fully resolved"]},{"year":2021,"claim":"Connecting cPLA2-alpha to tumor immunity showed its AA pathway polarizes CD39+ gamma-delta Tregs to suppress anti-tumor responses in colorectal cancer.","evidence":"Quantitative mass spectrometry, co-culture, orthotopic murine CRC model with Pla2g4a overexpression, flow cytometry","pmids":["34283812"],"confidence":"Medium","gaps":["Relied on overexpression","Downstream AA metabolite mediating Treg polarization not pinpointed"]},{"year":2022,"claim":"Defining upstream control identified two regulatory layers: PTRF stabilizes cPLA2-alpha protein against proteasomal degradation, and ATF6alpha transcriptionally activates it, with both axes feeding AA/ferroptosis outcomes.","evidence":"ChIP, Co-IP, luciferase, proteasome inhibition, genetic KO/KD in neurons and prostate cancer cells with AA/PGE2 ELISA and in vivo models","pmids":["35547748","35089606"],"confidence":"Medium","gaps":["Single labs for each axis","How PTRF binding physically blocks degradation unresolved"]},{"year":2026,"claim":"Extending transcriptional regulation, the NRF2-PIR circuit and GSK3beta/NF-kappaB were shown to set PLA2G4A levels that tune the cellular lipidome toward or away from ferroptosis and govern lysosomal integrity in neurodegeneration.","evidence":"NRF2/PIR ChIP, lipidomics, genetic deletion and PLA2G4A rescue in CRC and AOM/DSS models; GSK3alpha/beta and PLA2G4A knockdown plus AS1842856 in APP/PS1 mice and N2a cells","pmids":["41400081","42047940"],"confidence":"Medium","gaps":["Each regulatory axis from a single lab","Whether these inputs converge on the same enzyme pool unknown"]},{"year":null,"claim":"How the multiple transcriptional and post-translational inputs are integrated to direct cPLA2-alpha between protective and pathological (e.g., Golgi-COX coupling versus lysosomal permeabilization) membrane targets remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking specific upstream regulators to subcellular targeting outcomes","Structural basis for differential membrane targeting beyond the C2 domain not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7,11]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,13]}],"complexes":[],"partners":["PTRF","CENPF","COX-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P47712","full_name":"Cytosolic phospholipase A2","aliases":["Phospholipase A2 group IVA"],"length_aa":749,"mass_kda":85.2,"function":"Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response (PubMed:10358058, PubMed:14709560, PubMed:16617059, PubMed:17472963, PubMed:18451993, PubMed:27642067, PubMed:7794891, PubMed:8619991, PubMed:8702602, PubMed:9425121). Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production (By similarity). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:10358058, PubMed:17472963, PubMed:18451993, PubMed:7794891, PubMed:8619991, PubMed:9425121). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway (PubMed:10358058, PubMed:17472963, PubMed:18451993, PubMed:7794891, PubMed:9425121). In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids (PubMed:27642067). Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific (PubMed:7794891). Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides (PubMed:12672805). Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis (PubMed:7794891)","subcellular_location":"Cytoplasm; Golgi apparatus membrane; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/P47712/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLA2G4A","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000116711","cell_line_id":"CID000352","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"AHSA1","stoichiometry":4.0},{"gene":"LRRC59","stoichiometry":4.0},{"gene":"HSP90AA1","stoichiometry":0.2},{"gene":"HSP90AB1","stoichiometry":0.2},{"gene":"RPAP3","stoichiometry":0.2},{"gene":"SUGT1","stoichiometry":0.2},{"gene":"DNAJC17","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PPP5C","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000352","total_profiled":1310},"omim":[{"mim_id":"621413","title":"PHOSPHOLIPASE A2 INHIBITOR AND LY6/PLAUR DOMAIN-CONTAINING PROTEIN; PINLYP","url":"https://www.omim.org/entry/621413"},{"mim_id":"618372","title":"GASTROINTESTINAL ULCERATION, RECURRENT, WITH DYSFUNCTIONAL PLATELETS; GURDP","url":"https://www.omim.org/entry/618372"},{"mim_id":"606088","title":"PHOSPHOLIPASE A2, GROUP IVB; PLA2G4B","url":"https://www.omim.org/entry/606088"},{"mim_id":"601409","title":"LYSINE ACETYLTRANSFERASE 5; KAT5","url":"https://www.omim.org/entry/601409"},{"mim_id":"600722","title":"PALMITOYL-PROTEIN THIOESTERASE 1; PPT1","url":"https://www.omim.org/entry/600722"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":82.0},{"tissue":"seminal vesicle","ntpm":45.5}],"url":"https://www.proteinatlas.org/search/PLA2G4A"},"hgnc":{"alias_symbol":["cPLA2-alpha"],"prev_symbol":["PLA2G4"]},"alphafold":{"accession":"P47712","domains":[{"cath_id":"2.60.40.150","chopping":"19-139","consensus_level":"high","plddt":93.3853,"start":19,"end":139},{"cath_id":"3.40.1090.10","chopping":"153-408_461-502_536-722","consensus_level":"medium","plddt":90.431,"start":153,"end":722}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47712","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47712-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47712-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLA2G4A","jax_strain_url":"https://www.jax.org/strain/search?query=PLA2G4A"},"sequence":{"accession":"P47712","fasta_url":"https://rest.uniprot.org/uniprotkb/P47712.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47712/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47712"}},"corpus_meta":[{"pmid":"31238788","id":"PMC_31238788","title":"PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31238788","citation_count":147,"is_preprint":false},{"pmid":"28215748","id":"PMC_28215748","title":"Long non-coding RNA SNHG14 promotes microglia activation by regulating miR-145-5p/PLA2G4A in cerebral infarction.","date":"2017","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28215748","citation_count":121,"is_preprint":false},{"pmid":"12676927","id":"PMC_12676927","title":"Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid release.","date":"2003","source":"The Journal of biological 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amyloid-β-induced LMP in vitro.\",\n      \"method\": \"LC-MS/MS lysosomal membrane lipid profiling, pharmacological inhibition (AACOCF3), in vitro cell line and primary neuron assays, in vivo CCI mouse model with LC3/autophagy flux markers and neuronal death quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (lipidomics, pharmacological inhibition, genetic loss-of-function context, in vitro and in vivo models), replicated across cell lines, primary neurons, and mouse model\",\n      \"pmids\": [\"31238788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"cPLA2-alpha (PLA2G4A) is the primary enzyme responsible for arachidonic acid (AA) release in mesangial cells under oxidative stress; secretory PLA2s (group IIa and V) act as upstream regulators that depend on cPLA2-alpha activity and ERK1/2 and PKC signaling pathways to effect AA release.\",\n      \"method\": \"Genetic knockout mesangial cells (MC-/-) lacking cPLA2-alpha with recombinant adenovirus re-expression of specific PLA2 isoforms; pharmacological inhibition of MEK-1 (U0126), PKC (GF109203x), and calcium chelation (BAPTA-AM); AA release assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with isoform-specific re-expression and pharmacological pathway dissection, multiple orthogonal approaches\",\n      \"pmids\": [\"12676927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"cPLA2-alpha (PLA2G4A) is necessary for neutrophil arachidonate release and platelet-activating factor (PAF) biosynthesis, but not for NADPH oxidase activation, granule secretion, or phagocytosis; cPLA2-alpha is required for efficient bacterial killing in vitro (partially rescued by exogenous AA or PAF) and for pulmonary innate immune defense in vivo.\",\n      \"method\": \"Pharmacological inhibition (Pyrrolidine-1) in human neutrophils; cPLA2-alpha gene-disrupted mice; AA release assays, PAF biosynthesis assays, NADPH oxidase activation, bacterial killing assays, in vivo E. coli pulmonary infection model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse combined with pharmacological inhibition and multiple functional readouts across two biological systems\",\n      \"pmids\": [\"15475363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The C2 domain of cPLA2-alpha (PLA2G4A) binds to phospholipid monolayers in a Ca2+-dependent manner, with the calcium-binding loops CBL1 and CBL3 penetrating 2 Å into the lipid tail region; Ca2+-bound protein places its Ca2+ ions within 1 Å of the lipid phosphate group, and binding involves loss of headgroup-associated water molecules (entropic contribution) alongside electrostatic and hydrophobic interactions.\",\n      \"method\": \"X-ray reflectivity of cPLA2-alpha C2 domain adsorbed onto Langmuir monolayers of SOPC; domain mutants and calcium-free controls; crystallographic structure-based electron density profile analysis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural method with functional validation via mutants, single lab but multiple orthogonal analyses (X-ray reflectivity + structural fitting + mutagenesis controls)\",\n      \"pmids\": [\"15994899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In response to Ca2+ elevation, cPLA2-alpha (PLA2G4A) translocates from cytosol and nuclei to the trans-Golgi stack and trans-Golgi network in A549 lung epithelial cells, where it co-localizes specifically with cyclooxygenase-1 (COX-1) but not COX-2; this Golgi association was confirmed by sensitivity to brefeldin A.\",\n      \"method\": \"High-resolution confocal microscopy with Ca2+ ionophore A23187 stimulation; double staining with Golgi subcompartment markers and rhodamine-wheat germ agglutinin; brefeldin A disruption assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional perturbation (brefeldin A), co-localization with specific Golgi marker and COX-1, single lab\",\n      \"pmids\": [\"12711701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"cPLA2-alpha (PLA2G4A) is not required for PMA-stimulated NADPH oxidase activation or voltage-gated proton channel enhanced gating in human eosinophils or murine granulocytes; PKC activity (not cPLA2-alpha) is required for sustained activation of both proton channels and NADPH oxidase.\",\n      \"method\": \"cPLA2-alpha gene knockout mice; three specific cPLA2-alpha inhibitors (Wyeth-1, pyrrolidine-2, AACOCF3) in human eosinophils; perforated-patch electrophysiology; PKC inhibitors (GFX, staurosporine); okadaic acid phosphatase inhibition\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout replicated with three independent pharmacological inhibitors, electrophysiology as direct functional readout, replicated across species\",\n      \"pmids\": [\"17185330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTRF (Polymerase I and transcript release factor) stabilizes PLA2G4A protein by decreasing its proteasome-mediated degradation; PTRF overexpression enhances PLA2G4A activity and stability, promoting lipid metabolism reprogramming, mitochondrial bioenergetics changes, oxidative damage, autophagy, lipid peroxidation, and ferroptosis in neuronal cells after cerebral ischemia-reperfusion injury. HIF-1α and STAT3 regulate PTRF expression by binding its promoter.\",\n      \"method\": \"ChIP assay, luciferase assay, Co-IP, lentiviral-sgRNA knockout, AAV-shRNA knockdown in primary neurons and in vivo mouse I/R model; proteasome inhibition experiments; Western blot for PLA2G4A stability\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, genetic KO/KD in vitro and in vivo), single lab\",\n      \"pmids\": [\"35547748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF6α transcriptionally activates PLA2G4A expression (confirmed by ChIP), leading to increased AA release and PGE2 production; this ATF6α-PLA2G4A axis protects prostate cancer cells against ferroptosis, and inhibition of ATF6α reduces PLA2G4A-mediated AA/PGE2 signaling to promote ferroptotic cell death.\",\n      \"method\": \"ChIP assay, Western blot, qPCR, AA and PGE2 ELISA assays; genetic and pharmacological ATF6α inhibition; cell death assays in prostate cancer cell lines\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct transcriptional regulation, functional assays confirm downstream AA/PGE2 changes and ferroptosis outcome, single lab\",\n      \"pmids\": [\"35089606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PLA2G4A mRNA and protein expression is upregulated in bovine granulosa cells of ovulatory follicles in response to hCG via the adenylyl cyclase/cAMP pathway (confirmed by forskolin stimulation), implicating PLA2G4A in arachidonic acid release for prostaglandin biosynthesis during ovulation.\",\n      \"method\": \"In vivo bovine model with timed hCG injection; quantitative RT-PCR; Western blot; immunohistochemistry; in vitro forskolin stimulation of granulosa cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct expression regulation confirmed by both in vivo and in vitro experiments with pathway perturbation (cAMP agonist), single lab\",\n      \"pmids\": [\"16510840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLA2G4A overexpression in colorectal cancer cells induces CD39+γδ Treg polarization through activation of the PLA2G4A/arachidonic acid metabolic pathway, which inhibits the anti-tumor immune response; this was demonstrated using in vitro co-culture and an orthotopic murine CRC model.\",\n      \"method\": \"Quantitative mass spectrometry, in vitro co-culture system, orthotopic murine CRC model with Pla2g4a-overexpressing CT26 cells, flow cytometry for CD39+γδ Treg quantification\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with defined cellular phenotype and pathway identification via mass spectrometry, single lab\",\n      \"pmids\": [\"34283812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CENPF interacts physically with PLA2G4A (confirmed by molecular docking and Co-IP), and this interaction promotes glioma cell growth via mTORC1 and NF-κB pathways; silencing CENPF combined with PLA2G4A inhibitor AACOCF3 induced glioma cell apoptosis synergistically.\",\n      \"method\": \"Molecular docking, Co-IP, CENPF silencing (siRNA/shRNA), Western blot for mTORC1/NF-κB pathway proteins, CCK-8 proliferation assay, flow cytometry for apoptosis/cell cycle\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP confirms interaction but mechanistic details of how PLA2G4A mediates downstream signaling are not deeply resolved\",\n      \"pmids\": [\"40025532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pirin (PIR) transcriptionally regulates PLA2G4A expression downstream of NRF2; PIR loss downregulates PLA2G4A (cPLA2α), increasing polyunsaturated fatty acid (PUFA)-containing phospholipids and shifting the lipidome toward a ferroptosis-permissive state. Restoration of PLA2G4A rescues ferroptosis resistance in PIR-deficient colorectal cancer cells, defining an NRF2-PIR-PLA2G4A circuit.\",\n      \"method\": \"NRF2 ChIP at PIR promoter, lipidomics, PIR genetic deletion (in vitro and intestinal epithelium-specific in vivo), PLA2G4A rescue experiments, pharmacological inhibition with AACOCF3, AOM/DSS tumorigenesis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, lipidomics, genetic rescue, in vivo model), single lab\",\n      \"pmids\": [\"41400081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANXA10 upregulates PLA2G4A expression, which increases PGE2 production and activates STAT3 signaling, thereby facilitating epithelial-mesenchymal transition (EMT) and promoting metastasis in perihilar cholangiocarcinoma.\",\n      \"method\": \"mRNA sequencing after ANXA10 manipulation, Western blot, ELISA for PGE2, in vitro migration/invasion assays, in vivo metastasis model, correlation analysis of ANXA10 and PLA2G4A expression\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — regulatory relationship between ANXA10 and PLA2G4A identified by mRNA sequencing, mechanistic detail of how PLA2G4A connects to STAT3/EMT relies on pathway inhibition rather than direct mechanistic dissection of PLA2G4A's role\",\n      \"pmids\": [\"31492557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GSK3β regulates PLA2G4A expression via an NF-κB-mediated transcriptional mechanism; pharmacological suppression of GSK3β with AS1842856 reduces NF-κB-driven PLA2G4A expression, restoring lysosomal membrane integrity and enhancing lysosomal degradation of amyloid-β in Alzheimer's disease models. Knockdown experiments established that GSK3β (but not GSK3α) specifically suppresses PLA2G4A.\",\n      \"method\": \"AS1842856 treatment in APP/PS1 mice and N2a-sw cells; GSK3α/β and PLA2G4A knockdown experiments; lysosomal integrity assays; cognitive function testing; Western blot for pathway proteins\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (knockdown) and pharmacological dissection of pathway, in vivo and in vitro confirmation, single lab\",\n      \"pmids\": [\"42047940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The lncRNA PACERR interacts with an enhancer element affecting cPLA2/PLA2G4A transcriptional activation and escorts the cPLA2 protein to the nuclear membrane in response to HDL, where PLA2G4A releases arachidonic acid to further activate COX-2 and limit LXR/RXR-dependent ABCA1/ABCG1 transcription.\",\n      \"method\": \"PACERR antisense oligonucleotide silencing, humanized mouse model, RNA-protein interaction assays, ChIP/enhancer analysis, COX-2 and cholesterol efflux functional readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic details for PLA2G4A specifically are part of a larger study; direct evidence for PLA2G4A nuclear membrane localization by PACERR is not independently validated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLA2G4A (cPLA2-alpha) is a Ca2+-dependent cytosolic phospholipase that translocates to intracellular membranes (including the Golgi apparatus and lysosomal membranes) via its C2 domain in a calcium-dependent manner, where it cleaves arachidonic acid from membrane phospholipids; this AA release fuels eicosanoid (prostaglandins, PAF, leukotrienes) biosynthesis through coupling with COX-1 and downstream enzymes, and PLA2G4A activity is regulated upstream by secretory PLA2s (requiring cPLA2-alpha for their effect), by ERK1/2 and PKC signaling, and transcriptionally by ATF6α, NRF2-PIR, GSK3β/NF-κB, and STAT3/HIF-1α/PTRF axes; at the lysosome, excess PLA2G4A activity causes lysosomal membrane permeabilization, blocking autophagy and promoting neurodegeneration, while in cancer cells PLA2G4A-mediated AA/PGE2 production suppresses ferroptosis and modulates immune responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLA2G4A (cytosolic phospholipase A2-alpha, cPLA2-alpha) is the principal Ca2+-dependent enzyme that liberates arachidonic acid (AA) from membrane phospholipids to fuel eicosanoid biosynthesis across inflammation, immune defense, reproduction, and cancer [#1, #2]. Calcium elevation drives its C2 domain to insert into lipid membranes, with the calcium-binding loops CBL1 and CBL3 penetrating the phospholipid tail region and positioning bound Ca2+ ions adjacent to the headgroup phosphate [#3]; this Ca2+-triggered translocation relocates cPLA2-alpha to the trans-Golgi where it co-localizes specifically with COX-1 to couple AA release to prostaglandin synthesis [#4]. In innate immunity, cPLA2-alpha is required for neutrophil AA release, PAF biosynthesis, and efficient bacterial killing and pulmonary defense, while being dispensable for NADPH oxidase activation, granule secretion, and phagocytosis [#2, #5]. PLA2G4A expression and activity are controlled at multiple levels: transcriptionally by ATF6alpha, the NRF2-PIR circuit, and GSK3beta/NF-kappaB, and post-translationally by PTRF, which stabilizes the protein against proteasomal degradation [#6, #7, #11, #13]. Through these inputs, cPLA2-alpha-mediated AA/PGE2 production suppresses ferroptosis in prostate and colorectal cancer and reprograms the tumor immune microenvironment by polarizing CD39+ gamma-delta Tregs [#7, #9, #11]. In the nervous system, excessive cPLA2-alpha activity causes lysosomal membrane permeabilization that blocks autophagy flux and drives neuronal death following traumatic brain injury and in Alzheimer's models [#0, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing which phospholipase carries out stimulus-coupled arachidonic acid release resolved cPLA2-alpha as the obligate effector downstream of secretory PLA2s and ERK/PKC signaling.\",\n      \"evidence\": \"cPLA2-alpha-knockout mesangial cells with isoform-specific adenoviral re-expression and pharmacological MEK/PKC/Ca2+ blockade, AA release assays\",\n      \"pmids\": [\"12676927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how sPLA2 activity mechanistically depends on cPLA2-alpha\", \"Restricted to mesangial cells under oxidative stress\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining where the activated enzyme acts showed that Ca2+ drives cPLA2-alpha to the trans-Golgi to co-localize with COX-1, providing a spatial basis for AA-to-prostaglandin coupling.\",\n      \"evidence\": \"Confocal microscopy after Ca2+ ionophore stimulation with Golgi-subcompartment and COX markers, brefeldin A perturbation in A549 cells\",\n      \"pmids\": [\"12711701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"Did not establish the targeting determinant for trans-Golgi versus other membranes\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Dissecting cPLA2-alpha's immune role showed it is specifically required for neutrophil AA/PAF generation and antibacterial defense but not for the oxidative burst, separating lipid signaling from other effector functions.\",\n      \"evidence\": \"Gene-disrupted mice plus pharmacological inhibition in human neutrophils, AA/PAF assays, bacterial killing, in vivo E. coli pulmonary infection\",\n      \"pmids\": [\"15475363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partial rescue by exogenous AA/PAF left other contributing pathways unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Determining how cPLA2-alpha engages membranes showed the C2 domain inserts CBL loops into the lipid tail region with Ca2+ ions at the phosphate, explaining the calcium dependence of translocation.\",\n      \"evidence\": \"X-ray reflectivity of the C2 domain on lipid monolayers with domain mutants and Ca2+-free controls\",\n      \"pmids\": [\"15994899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isolated C2 domain rather than full-length enzyme\", \"Model membrane rather than native bilayer\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Testing functional specificity confirmed PKC, not cPLA2-alpha, drives NADPH oxidase and proton channel gating, sharpening the boundary of cPLA2-alpha's effector functions.\",\n      \"evidence\": \"Knockout mice and three independent inhibitors in eosinophils/granulocytes with perforated-patch electrophysiology\",\n      \"pmids\": [\"17185330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative result for a specific pathway; does not address other granulocyte functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking cPLA2-alpha to reproduction showed hCG induces its expression via cAMP signaling in ovulatory granulosa cells, implicating it in prostaglandin production during ovulation.\",\n      \"evidence\": \"Timed hCG injection in bovine model, RT-PCR/Western/IHC, in vitro forskolin stimulation\",\n      \"pmids\": [\"16510840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative expression; did not demonstrate functional requirement in ovulation\", \"Single species\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying a pathological consequence of excess activity showed cPLA2-alpha drives lysosomal membrane permeabilization that blocks autophagy and kills neurons after brain injury.\",\n      \"evidence\": \"Lysosomal lipidomics, AACOCF3 inhibition, in vitro neuron assays, in vivo CCI mouse model with autophagy/neuronal-death readouts\",\n      \"pmids\": [\"31238788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Used pharmacological rather than genetic loss-of-function in vivo\", \"Mechanism linking AA release to LMP not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connecting cPLA2-alpha to tumor immunity showed its AA pathway polarizes CD39+ gamma-delta Tregs to suppress anti-tumor responses in colorectal cancer.\",\n      \"evidence\": \"Quantitative mass spectrometry, co-culture, orthotopic murine CRC model with Pla2g4a overexpression, flow cytometry\",\n      \"pmids\": [\"34283812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relied on overexpression\", \"Downstream AA metabolite mediating Treg polarization not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining upstream control identified two regulatory layers: PTRF stabilizes cPLA2-alpha protein against proteasomal degradation, and ATF6alpha transcriptionally activates it, with both axes feeding AA/ferroptosis outcomes.\",\n      \"evidence\": \"ChIP, Co-IP, luciferase, proteasome inhibition, genetic KO/KD in neurons and prostate cancer cells with AA/PGE2 ELISA and in vivo models\",\n      \"pmids\": [\"35547748\", \"35089606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs for each axis\", \"How PTRF binding physically blocks degradation unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending transcriptional regulation, the NRF2-PIR circuit and GSK3beta/NF-kappaB were shown to set PLA2G4A levels that tune the cellular lipidome toward or away from ferroptosis and govern lysosomal integrity in neurodegeneration.\",\n      \"evidence\": \"NRF2/PIR ChIP, lipidomics, genetic deletion and PLA2G4A rescue in CRC and AOM/DSS models; GSK3alpha/beta and PLA2G4A knockdown plus AS1842856 in APP/PS1 mice and N2a cells\",\n      \"pmids\": [\"41400081\", \"42047940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each regulatory axis from a single lab\", \"Whether these inputs converge on the same enzyme pool unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple transcriptional and post-translational inputs are integrated to direct cPLA2-alpha between protective and pathological (e.g., Golgi-COX coupling versus lysosomal permeabilization) membrane targets remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking specific upstream regulators to subcellular targeting outcomes\", \"Structural basis for differential membrane targeting beyond the C2 domain not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005544\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTRF\", \"CENPF\", \"COX-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}