{"gene":"PIK3CG","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2015,"finding":"Manic Fringe (Mfng) promotes claudin-low breast cancer through RBPJκ-dependent Notch signaling that directly induces PIK3CG transcription; PIK3CG was identified as a direct transcriptional target of Mfng-facilitated Notch signaling, and pharmacologic inhibition of PI3Kγ blocked migration and tumorsphere formation in CLBC cell lines.","method":"Mfng silencing/deletion in CLBC cell lines and mouse mammary tumor model, pharmacologic PI3Kγ inhibition, reporter/transcriptional target identification","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (siRNA + conditional knockout mouse), pharmacologic inhibition, and identification of direct transcriptional target, single lab with multiple orthogonal methods","pmids":["25808869"],"is_preprint":false},{"year":2023,"finding":"PIK3CG activates the NLRP3 inflammasome, thereby promoting GSDMD-mediated pyroptosis in septic myocardial injury; PIK3CG siRNA suppressed NLRP3, GSDMD, IL-1β, Caspase-1, and IL-18, while PIK3CG overexpression worsened these changes, and the PIK3CG inhibitor AS-604850 reversed CLP-induced pyroptosis.","method":"siRNA knockdown and overexpression in HL-1 cardiomyocytes, CLP mouse model, pharmacologic inhibition (AS-604850), transcriptome analysis, Western blot","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both in vitro and in vivo loss/gain-of-function with defined molecular readouts, single lab","pmids":["37676465"],"is_preprint":false},{"year":2025,"finding":"PIK3CG acts upstream of NLRP3 in the thalamus to mediate central post-stroke pain; PIK3CG overexpression increased NLRP3 and negated analgesic effects, while PIK3CG knockdown alleviated pain and reduced NLRP3. Simultaneous NLRP3 overexpression attenuated the analgesic effects of PIK3CG knockdown, confirming NLRP3 is downstream of PIK3CG in this pathway. Molecular docking showed Danshenol B binds PIK3CG (−9.127 kcal/mol).","method":"PIK3CG overexpression and knockdown in CPSP mouse model, epistasis via simultaneous NLRP3 overexpression, RNA sequencing, molecular docking","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double manipulation) in vivo with defined pathway ordering, single lab","pmids":["40551174"],"is_preprint":false},{"year":2026,"finding":"PIK3CG deficiency suppresses mTORC1, leading to enhanced phosphorylation of S6K2, which disrupts the nuclear S6K2 (Glu163)–p53 (Arg273) interaction and inhibits GLS2 transcription; this blocks glutamine catabolism, restricts TCA cycle entry, and causes mitochondrial ROS accumulation with suppressed pyroptosis. GLS2 overexpression rescued all phenotypes induced by PIK3CG knockdown.","method":"PIK3CG knockdown in vitro and in vivo, GLS2 overexpression rescue, mTORC1 pathway analysis, mitochondrial ROS and membrane potential assays, pyroptosis assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with rescue experiment identifying S6K2/p53/GLS2 axis, single lab, multiple orthogonal methods","pmids":["41539001"],"is_preprint":false},{"year":2024,"finding":"PIK3CG overexpression in lung cancer cells promotes migration and metastasis through enhanced MMP expression and neutrophil recruitment/activation; knockdown or pharmacologic inhibition (Eganelisib, CAY10505) reduced cell migration and MMP levels, while overexpression increased them. Co-culture with neutrophils and cathepsin G promoted lung cancer cell migration downstream of PIK3CG.","method":"PIK3CG knockdown and overexpression in A549 and H1299 cell lines, pharmacologic inhibition, tail-vein LLC mouse metastasis model, Transwell co-culture with neutrophils","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with in vitro and in vivo readouts, defined molecular mechanism (MMPs, neutrophil axis), single lab","pmids":["38602596"],"is_preprint":false},{"year":2024,"finding":"PIK3CG knockdown in OGD/R-injured neuronal cells inhibits autophagy by opposing AMPK/mTOR pathway activation (suppressing AMPK phosphorylation increase and restoring mTOR phosphorylation), reducing Beclin1 and LC3 II levels, decreasing apoptosis, and protecting cell proliferation.","method":"siRNA knockdown in SH-SY5Y cells under OGD/R, AMPK activator (metformin) co-treatment, CCK8 proliferation assay, flow cytometry apoptosis, Western blot for autophagy markers","journal":"Neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line model, pathway inferred from pharmacologic AMPK activation rather than direct mechanistic reconstitution","pmids":["39603405"],"is_preprint":false},{"year":2023,"finding":"PIK3CG regulates multiple myeloma cell growth via the c-Myc pathway; pharmacologic inhibition of PIK3CG (AS-605240) suppressed c-Myc expression, reduced proliferation and migration, promoted apoptosis, decreased Bcl-2/Bax ratio, and reduced vimentin expression.","method":"Pharmacologic inhibition with AS-605240 in MM cell lines, Western blot for c-Myc and apoptosis markers, proliferation and migration assays","journal":"Heliyon","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacologic inhibitor only (no genetic knockdown), indirect pathway inference","pmids":["38163179"],"is_preprint":false},{"year":2002,"finding":"PIK3CG promoter CpG hypermethylation silences PIK3CG expression in colon cancer cells; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored PIK3CG expression in DLD-1 and LoVo cells. PIK3CG encodes the catalytic subunit p110γ of PI3K, and its loss is associated with suppression of the PI3K-Akt/PKB signaling axis.","method":"Methylation-sensitive PCR (HpaII/MspI digestion), 5-aza-2'-deoxycytidine demethylation treatment, RT-PCR, Western blot, immunohistochemistry","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic mechanism demonstrated by demethylation rescue experiment, multiple methods, single lab","pmids":["12473596"],"is_preprint":false},{"year":2020,"finding":"In a Trp53-deletion/Kras-activation mouse model of metastatic prostate cancer, Pik3cg is highly expressed in poorly differentiated, AR-negative tumors; pharmacologic inhibition of Pi3kγ blocked tumor cell growth in vitro, reversed epithelial-mesenchymal transition, and abated tumor metastasis in vivo.","method":"Genetically engineered mouse model (Trp53 KO + Kras activation), pharmacologic PI3Kγ inhibition, in vitro growth assays, in vivo metastasis assessment, immunohistochemistry","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic inhibition with both in vitro and in vivo readouts, single lab, defined EMT phenotype","pmids":["32805234"],"is_preprint":false}],"current_model":"PIK3CG encodes the catalytic subunit p110γ of PI3Kγ, which is activated downstream of G-protein-coupled receptors and directly transcriptionally induced by Notch/RBPJκ signaling; it promotes cell migration, EMT, and metastasis through MMP upregulation and neutrophil recruitment, activates the NLRP3 inflammasome to drive pyroptosis, regulates glutamine metabolism via the mTORC1/S6K2/p53/GLS2 axis, modulates autophagy through the AMPK/mTOR pathway, and drives c-Myc-dependent tumor cell growth, while its expression is epigenetically silenced by CpG promoter hypermethylation in colorectal cancer."},"narrative":{"mechanistic_narrative":"PIK3CG encodes the catalytic subunit p110γ of PI3Kγ, and across the available corpus it functions as a signaling node that couples upstream transcriptional and metabolic inputs to cell migration, inflammation, and tumor progression [PMID:25808869, PMID:38602596]. Its expression is regulated at multiple levels: it is a direct transcriptional target of Mfng-facilitated Notch/RBPJκ signaling in claudin-low breast cancer [PMID:25808869], and is epigenetically silenced by promoter CpG hypermethylation in colon cancer, where demethylation restores expression and reactivates the PI3K-Akt/PKB axis [PMID:12473596]. In cancer cells, PIK3CG drives migration, epithelial-mesenchymal transition, and metastasis, acting in lung cancer through enhanced MMP expression and neutrophil/cathepsin G recruitment [PMID:38602596] and in metastatic prostate cancer through EMT reversal upon PI3Kγ inhibition [PMID:32805234]. PIK3CG also operates upstream of the NLRP3 inflammasome to promote GSDMD-mediated pyroptosis in septic myocardial injury [PMID:37676465] and to mediate central post-stroke pain in the thalamus [PMID:40551174], and it sustains glutamine catabolism through an mTORC1–S6K2–p53–GLS2 axis whose loss restricts TCA cycle entry and elevates mitochondrial ROS [PMID:41539001].","teleology":[{"year":2002,"claim":"Established a mechanism controlling PIK3CG abundance: rather than being constitutively expressed, p110γ is subject to epigenetic silencing, linking its loss to attenuated PI3K-Akt signaling in cancer.","evidence":"Methylation-sensitive PCR and 5-aza-2'-deoxycytidine demethylation rescue with RT-PCR/Western readout in colon cancer cell lines","pmids":["12473596"],"confidence":"Medium","gaps":["Does not define which upstream signals direct promoter methylation","Functional consequence of restored p110γ not assayed beyond expression and pathway association"]},{"year":2015,"claim":"Identified a transcriptional input to PIK3CG, showing it is a direct target of Mfng-facilitated Notch/RBPJκ signaling and required for migration and tumorsphere formation, framing it as an effector downstream of Notch.","evidence":"Mfng silencing/conditional knockout in claudin-low breast cancer cell lines and mouse mammary model with reporter-based transcriptional target identification and pharmacologic PI3Kγ inhibition","pmids":["25808869"],"confidence":"Medium","gaps":["Direct RBPJκ occupancy mapping of the PIK3CG promoter not detailed","Catalytic activity contribution versus scaffold not separated"]},{"year":2020,"claim":"Connected PIK3CG to EMT-driven metastasis, demonstrating its enrichment in poorly differentiated AR-negative tumors and that PI3Kγ inhibition reverses EMT and blocks metastasis.","evidence":"Trp53-KO/Kras-activated genetically engineered mouse prostate cancer model with pharmacologic PI3Kγ inhibition and in vitro/in vivo growth and metastasis readouts","pmids":["32805234"],"confidence":"Medium","gaps":["Relies on pharmacologic inhibition without genetic deletion","Molecular effectors linking p110γ to EMT not resolved"]},{"year":2023,"claim":"Placed PIK3CG upstream of the NLRP3 inflammasome, establishing it as a driver of GSDMD-mediated pyroptosis in septic myocardial injury.","evidence":"siRNA knockdown and overexpression in HL-1 cardiomyocytes with CLP mouse model, pharmacologic inhibition (AS-604850), and Western blot for inflammasome components","pmids":["37676465"],"confidence":"Medium","gaps":["Mechanism linking p110γ activity to NLRP3 activation not defined","Direct versus indirect regulation of inflammasome priming unresolved"]},{"year":2023,"claim":"Linked PIK3CG to tumor cell growth in multiple myeloma via the c-Myc pathway, extending its pro-proliferative role to a hematologic malignancy.","evidence":"Pharmacologic inhibition (AS-605240) in MM cell lines with Western blot for c-Myc and apoptosis markers and proliferation/migration assays","pmids":["38163179"],"confidence":"Low","gaps":["Pharmacologic inhibitor only, no genetic knockdown to confirm on-target effect","c-Myc regulation inferred indirectly"]},{"year":2024,"claim":"Defined a non-cell-autonomous metastatic mechanism, showing PIK3CG drives migration through MMP upregulation and neutrophil/cathepsin G recruitment in lung cancer.","evidence":"Knockdown and overexpression in A549/H1299, pharmacologic inhibition, tail-vein LLC metastasis model, and Transwell neutrophil co-culture","pmids":["38602596"],"confidence":"Medium","gaps":["Direct enzymatic link between p110γ and MMP transcription not established","Mechanism of neutrophil recruitment downstream of PIK3CG unresolved"]},{"year":2024,"claim":"Implicated PIK3CG in autophagy regulation in neuronal injury, opposing AMPK/mTOR-driven autophagy and influencing neuronal survival.","evidence":"siRNA knockdown in SH-SY5Y cells under OGD/R with AMPK activator co-treatment and Western blot for Beclin1/LC3 II","pmids":["39603405"],"confidence":"Low","gaps":["Pathway inferred from pharmacologic AMPK activation rather than direct mechanistic reconstitution","Single cell line, single lab"]},{"year":2025,"claim":"Generalized the PIK3CG–NLRP3 axis to the CNS, using epistasis to confirm NLRP3 acts downstream of PIK3CG in mediating central post-stroke pain.","evidence":"PIK3CG overexpression/knockdown in a CPSP mouse model with simultaneous NLRP3 overexpression epistasis, RNA sequencing, and molecular docking","pmids":["40551174"],"confidence":"Medium","gaps":["Biochemical intermediates between p110γ and NLRP3 not identified","Docking of Danshenol B not validated by direct binding assay"]},{"year":2026,"claim":"Resolved a metabolic role, showing PIK3CG sustains glutamine catabolism through an mTORC1–S6K2–p53–GLS2 axis, with GLS2 loss restricting TCA entry and elevating mitochondrial ROS.","evidence":"PIK3CG knockdown in vitro and in vivo with GLS2 overexpression rescue, mTORC1 pathway analysis, and mitochondrial ROS/pyroptosis assays","pmids":["41539001"],"confidence":"Medium","gaps":["How p110γ activates mTORC1 in this context not defined","Single lab; specificity of S6K2(Glu163)-p53(Arg273) interaction not independently confirmed"]},{"year":null,"claim":"How p110γ catalytic lipid kinase output is mechanistically partitioned between its migration/metastasis, inflammasome, autophagy, and metabolic functions remains unresolved across the corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical study in the corpus links specific p110γ catalytic outputs to each downstream branch","Upstream GPCR/receptor activation events not directly characterized in the captured findings"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[7]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48736","full_name":"Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform","aliases":["Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma","PtdIns-3-kinase subunit p110-gamma","p110gamma","Phosphoinositide-3-kinase catalytic gamma polypeptide","Serine/threonine protein kinase PIK3CG","p120-PI3K"],"length_aa":1102,"mass_kda":126.5,"function":"Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation, activation, and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis. In neutrophils, participates in a phospholipase C-activating N-formyl peptide-activated GPCR (G protein-coupled receptor) signaling pathway downstream of RASGRP4-mediated Ras-activation, to promote neutrophil functional responses (By similarity)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P48736/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIK3CG","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIK3CG","total_profiled":1310},"omim":[{"mim_id":"619802","title":"IMMUNODEFICIENCY 97 WITH AUTOINFLAMMATION; IMD97","url":"https://www.omim.org/entry/619802"},{"mim_id":"614646","title":"MEAN PLATELET VOLUME/COUNT QUANTITATIVE TRAIT LOCUS 6; MPVCQTL6","url":"https://www.omim.org/entry/614646"},{"mim_id":"613760","title":"SOLUTE CARRIER FAMILY 36, MEMBER 4; SLC36A4","url":"https://www.omim.org/entry/613760"},{"mim_id":"612139","title":"PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE-DEPENDENT RAC EXCHANGER 2; PREX2","url":"https://www.omim.org/entry/612139"},{"mim_id":"611462","title":"PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 6; PIK3R6","url":"https://www.omim.org/entry/611462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":41.2},{"tissue":"lymphoid tissue","ntpm":18.4}],"url":"https://www.proteinatlas.org/search/PIK3CG"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P48736","domains":[{"cath_id":"3.10.20.90","chopping":"36-141","consensus_level":"high","plddt":89.12,"start":36,"end":141},{"cath_id":"1.25.40.70","chopping":"155-190_625-723","consensus_level":"medium","plddt":93.989,"start":155,"end":723},{"cath_id":"3.10.20.90","chopping":"196-315","consensus_level":"high","plddt":93.0404,"start":196,"end":315},{"cath_id":"2.60.40.150","chopping":"335-439_455-527","consensus_level":"high","plddt":88.0015,"start":335,"end":527},{"cath_id":"1.25.40.70","chopping":"544-620","consensus_level":"medium","plddt":92.16,"start":544,"end":620},{"cath_id":"1.10.1070.11","chopping":"884-1102","consensus_level":"medium","plddt":89.0183,"start":884,"end":1102}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48736","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48736-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48736-F1-predicted_aligned_error_v6.png","plddt_mean":87.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIK3CG","jax_strain_url":"https://www.jax.org/strain/search?query=PIK3CG"},"sequence":{"accession":"P48736","fasta_url":"https://rest.uniprot.org/uniprotkb/P48736.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48736/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48736"}},"corpus_meta":[{"pmid":"12473596","id":"PMC_12473596","title":"Down-regulation of PIK3CG, a catalytic subunit of phosphatidylinositol 3-OH kinase, by CpG hypermethylation in human colorectal carcinoma.","date":"2002","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/12473596","citation_count":61,"is_preprint":false},{"pmid":"25808869","id":"PMC_25808869","title":"Manic fringe promotes a claudin-low breast cancer phenotype through notch-mediated PIK3CG induction.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25808869","citation_count":60,"is_preprint":false},{"pmid":"11756194","id":"PMC_11756194","title":"Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11756194","citation_count":29,"is_preprint":false},{"pmid":"32805234","id":"PMC_32805234","title":"PIK3CG Is a Potential Therapeutic Target in Androgen Receptor-Indifferent Metastatic Prostate Cancer.","date":"2020","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32805234","citation_count":18,"is_preprint":false},{"pmid":"32368142","id":"PMC_32368142","title":"Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32368142","citation_count":14,"is_preprint":false},{"pmid":"29097255","id":"PMC_29097255","title":"Association of PIK3CG gene polymorphisms with attention-deficit/hyperactivity disorder: A case-control study.","date":"2017","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29097255","citation_count":11,"is_preprint":false},{"pmid":"37676465","id":"PMC_37676465","title":"PIK3CG Regulates NLRP3/GSDMD-Mediated Pyroptosis in Septic Myocardial Injury.","date":"2023","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37676465","citation_count":9,"is_preprint":false},{"pmid":"29434912","id":"PMC_29434912","title":"Notch signaling via regulation of RB and p-AKT but not PIK3CG contributes to MIA PaCa-2 cell growth and migration to affect pancreatic carcinogenesis.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29434912","citation_count":8,"is_preprint":false},{"pmid":"37810062","id":"PMC_37810062","title":"Angong niuhuang wan attenuates LPS-induced acute lung injury by inhibiting PIK3CG/p65/MMP9 signaling in mice based on proteomics.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37810062","citation_count":5,"is_preprint":false},{"pmid":"38602596","id":"PMC_38602596","title":"Overexpression of PIK3CG in Cancer Cells Promotes Lung Cancer Cell Migration and Metastasis Through Enhanced MMPs Expression and Neutrophil Recruitment and Activation.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38602596","citation_count":3,"is_preprint":false},{"pmid":"39603405","id":"PMC_39603405","title":"Protective effects of PIK3CG knockdown against OGD/R-induced neuronal damage via inhibition of autophagy through the AMPK/mTOR pathway.","date":"2024","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39603405","citation_count":3,"is_preprint":false},{"pmid":"35870262","id":"PMC_35870262","title":"Synonymous mutation rs1129293 is associated with PIK3CG expression and PI3Kγ activation in patients with chronic Chagas cardiomyopathy.","date":"2022","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35870262","citation_count":2,"is_preprint":false},{"pmid":"40551174","id":"PMC_40551174","title":"Danshenol B alleviates central post-stroke pain by regulating the PIK3CG/NLRP3 signaling pathway.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40551174","citation_count":2,"is_preprint":false},{"pmid":"38163179","id":"PMC_38163179","title":"Therapeutic potential of anti-PIK3CG treatment for multiple myeloma via inhibiting c-Myc pathway.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38163179","citation_count":1,"is_preprint":false},{"pmid":"41539001","id":"PMC_41539001","title":"PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41539001","citation_count":0,"is_preprint":false},{"pmid":"41560055","id":"PMC_41560055","title":"Role of hsa-miR-122-5p in chronic thromboembolic pulmonary hypertension and chronic thromboembolic disease: Targeting PIK3CG in the PI3K/Akt signaling pathway.","date":"2026","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41560055","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10657,"output_tokens":2557,"usd":0.035163,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9807,"output_tokens":3279,"usd":0.065505,"stage2_stop_reason":"end_turn"},"total_usd":0.100668,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Manic Fringe (Mfng) promotes claudin-low breast cancer through RBPJκ-dependent Notch signaling that directly induces PIK3CG transcription; PIK3CG was identified as a direct transcriptional target of Mfng-facilitated Notch signaling, and pharmacologic inhibition of PI3Kγ blocked migration and tumorsphere formation in CLBC cell lines.\",\n      \"method\": \"Mfng silencing/deletion in CLBC cell lines and mouse mammary tumor model, pharmacologic PI3Kγ inhibition, reporter/transcriptional target identification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (siRNA + conditional knockout mouse), pharmacologic inhibition, and identification of direct transcriptional target, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25808869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIK3CG activates the NLRP3 inflammasome, thereby promoting GSDMD-mediated pyroptosis in septic myocardial injury; PIK3CG siRNA suppressed NLRP3, GSDMD, IL-1β, Caspase-1, and IL-18, while PIK3CG overexpression worsened these changes, and the PIK3CG inhibitor AS-604850 reversed CLP-induced pyroptosis.\",\n      \"method\": \"siRNA knockdown and overexpression in HL-1 cardiomyocytes, CLP mouse model, pharmacologic inhibition (AS-604850), transcriptome analysis, Western blot\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both in vitro and in vivo loss/gain-of-function with defined molecular readouts, single lab\",\n      \"pmids\": [\"37676465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIK3CG acts upstream of NLRP3 in the thalamus to mediate central post-stroke pain; PIK3CG overexpression increased NLRP3 and negated analgesic effects, while PIK3CG knockdown alleviated pain and reduced NLRP3. Simultaneous NLRP3 overexpression attenuated the analgesic effects of PIK3CG knockdown, confirming NLRP3 is downstream of PIK3CG in this pathway. Molecular docking showed Danshenol B binds PIK3CG (−9.127 kcal/mol).\",\n      \"method\": \"PIK3CG overexpression and knockdown in CPSP mouse model, epistasis via simultaneous NLRP3 overexpression, RNA sequencing, molecular docking\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double manipulation) in vivo with defined pathway ordering, single lab\",\n      \"pmids\": [\"40551174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PIK3CG deficiency suppresses mTORC1, leading to enhanced phosphorylation of S6K2, which disrupts the nuclear S6K2 (Glu163)–p53 (Arg273) interaction and inhibits GLS2 transcription; this blocks glutamine catabolism, restricts TCA cycle entry, and causes mitochondrial ROS accumulation with suppressed pyroptosis. GLS2 overexpression rescued all phenotypes induced by PIK3CG knockdown.\",\n      \"method\": \"PIK3CG knockdown in vitro and in vivo, GLS2 overexpression rescue, mTORC1 pathway analysis, mitochondrial ROS and membrane potential assays, pyroptosis assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with rescue experiment identifying S6K2/p53/GLS2 axis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41539001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIK3CG overexpression in lung cancer cells promotes migration and metastasis through enhanced MMP expression and neutrophil recruitment/activation; knockdown or pharmacologic inhibition (Eganelisib, CAY10505) reduced cell migration and MMP levels, while overexpression increased them. Co-culture with neutrophils and cathepsin G promoted lung cancer cell migration downstream of PIK3CG.\",\n      \"method\": \"PIK3CG knockdown and overexpression in A549 and H1299 cell lines, pharmacologic inhibition, tail-vein LLC mouse metastasis model, Transwell co-culture with neutrophils\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with in vitro and in vivo readouts, defined molecular mechanism (MMPs, neutrophil axis), single lab\",\n      \"pmids\": [\"38602596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIK3CG knockdown in OGD/R-injured neuronal cells inhibits autophagy by opposing AMPK/mTOR pathway activation (suppressing AMPK phosphorylation increase and restoring mTOR phosphorylation), reducing Beclin1 and LC3 II levels, decreasing apoptosis, and protecting cell proliferation.\",\n      \"method\": \"siRNA knockdown in SH-SY5Y cells under OGD/R, AMPK activator (metformin) co-treatment, CCK8 proliferation assay, flow cytometry apoptosis, Western blot for autophagy markers\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line model, pathway inferred from pharmacologic AMPK activation rather than direct mechanistic reconstitution\",\n      \"pmids\": [\"39603405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIK3CG regulates multiple myeloma cell growth via the c-Myc pathway; pharmacologic inhibition of PIK3CG (AS-605240) suppressed c-Myc expression, reduced proliferation and migration, promoted apoptosis, decreased Bcl-2/Bax ratio, and reduced vimentin expression.\",\n      \"method\": \"Pharmacologic inhibition with AS-605240 in MM cell lines, Western blot for c-Myc and apoptosis markers, proliferation and migration assays\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacologic inhibitor only (no genetic knockdown), indirect pathway inference\",\n      \"pmids\": [\"38163179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PIK3CG promoter CpG hypermethylation silences PIK3CG expression in colon cancer cells; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored PIK3CG expression in DLD-1 and LoVo cells. PIK3CG encodes the catalytic subunit p110γ of PI3K, and its loss is associated with suppression of the PI3K-Akt/PKB signaling axis.\",\n      \"method\": \"Methylation-sensitive PCR (HpaII/MspI digestion), 5-aza-2'-deoxycytidine demethylation treatment, RT-PCR, Western blot, immunohistochemistry\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic mechanism demonstrated by demethylation rescue experiment, multiple methods, single lab\",\n      \"pmids\": [\"12473596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a Trp53-deletion/Kras-activation mouse model of metastatic prostate cancer, Pik3cg is highly expressed in poorly differentiated, AR-negative tumors; pharmacologic inhibition of Pi3kγ blocked tumor cell growth in vitro, reversed epithelial-mesenchymal transition, and abated tumor metastasis in vivo.\",\n      \"method\": \"Genetically engineered mouse model (Trp53 KO + Kras activation), pharmacologic PI3Kγ inhibition, in vitro growth assays, in vivo metastasis assessment, immunohistochemistry\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic inhibition with both in vitro and in vivo readouts, single lab, defined EMT phenotype\",\n      \"pmids\": [\"32805234\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIK3CG encodes the catalytic subunit p110γ of PI3Kγ, which is activated downstream of G-protein-coupled receptors and directly transcriptionally induced by Notch/RBPJκ signaling; it promotes cell migration, EMT, and metastasis through MMP upregulation and neutrophil recruitment, activates the NLRP3 inflammasome to drive pyroptosis, regulates glutamine metabolism via the mTORC1/S6K2/p53/GLS2 axis, modulates autophagy through the AMPK/mTOR pathway, and drives c-Myc-dependent tumor cell growth, while its expression is epigenetically silenced by CpG promoter hypermethylation in colorectal cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIK3CG encodes the catalytic subunit p110\\u03b3 of PI3K\\u03b3, and across the available corpus it functions as a signaling node that couples upstream transcriptional and metabolic inputs to cell migration, inflammation, and tumor progression [#0, #4]. Its expression is regulated at multiple levels: it is a direct transcriptional target of Mfng-facilitated Notch/RBPJ\\u03ba signaling in claudin-low breast cancer [#0], and is epigenetically silenced by promoter CpG hypermethylation in colon cancer, where demethylation restores expression and reactivates the PI3K-Akt/PKB axis [#7]. In cancer cells, PIK3CG drives migration, epithelial-mesenchymal transition, and metastasis, acting in lung cancer through enhanced MMP expression and neutrophil/cathepsin G recruitment [#4] and in metastatic prostate cancer through EMT reversal upon PI3K\\u03b3 inhibition [#8]. PIK3CG also operates upstream of the NLRP3 inflammasome to promote GSDMD-mediated pyroptosis in septic myocardial injury [#1] and to mediate central post-stroke pain in the thalamus [#2], and it sustains glutamine catabolism through an mTORC1\\u2013S6K2\\u2013p53\\u2013GLS2 axis whose loss restricts TCA cycle entry and elevates mitochondrial ROS [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established a mechanism controlling PIK3CG abundance: rather than being constitutively expressed, p110\\u03b3 is subject to epigenetic silencing, linking its loss to attenuated PI3K-Akt signaling in cancer.\",\n      \"evidence\": \"Methylation-sensitive PCR and 5-aza-2'-deoxycytidine demethylation rescue with RT-PCR/Western readout in colon cancer cell lines\",\n      \"pmids\": [\"12473596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define which upstream signals direct promoter methylation\", \"Functional consequence of restored p110\\u03b3 not assayed beyond expression and pathway association\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a transcriptional input to PIK3CG, showing it is a direct target of Mfng-facilitated Notch/RBPJ\\u03ba signaling and required for migration and tumorsphere formation, framing it as an effector downstream of Notch.\",\n      \"evidence\": \"Mfng silencing/conditional knockout in claudin-low breast cancer cell lines and mouse mammary model with reporter-based transcriptional target identification and pharmacologic PI3K\\u03b3 inhibition\",\n      \"pmids\": [\"25808869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RBPJ\\u03ba occupancy mapping of the PIK3CG promoter not detailed\", \"Catalytic activity contribution versus scaffold not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected PIK3CG to EMT-driven metastasis, demonstrating its enrichment in poorly differentiated AR-negative tumors and that PI3K\\u03b3 inhibition reverses EMT and blocks metastasis.\",\n      \"evidence\": \"Trp53-KO/Kras-activated genetically engineered mouse prostate cancer model with pharmacologic PI3K\\u03b3 inhibition and in vitro/in vivo growth and metastasis readouts\",\n      \"pmids\": [\"32805234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relies on pharmacologic inhibition without genetic deletion\", \"Molecular effectors linking p110\\u03b3 to EMT not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed PIK3CG upstream of the NLRP3 inflammasome, establishing it as a driver of GSDMD-mediated pyroptosis in septic myocardial injury.\",\n      \"evidence\": \"siRNA knockdown and overexpression in HL-1 cardiomyocytes with CLP mouse model, pharmacologic inhibition (AS-604850), and Western blot for inflammasome components\",\n      \"pmids\": [\"37676465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking p110\\u03b3 activity to NLRP3 activation not defined\", \"Direct versus indirect regulation of inflammasome priming unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked PIK3CG to tumor cell growth in multiple myeloma via the c-Myc pathway, extending its pro-proliferative role to a hematologic malignancy.\",\n      \"evidence\": \"Pharmacologic inhibition (AS-605240) in MM cell lines with Western blot for c-Myc and apoptosis markers and proliferation/migration assays\",\n      \"pmids\": [\"38163179\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pharmacologic inhibitor only, no genetic knockdown to confirm on-target effect\", \"c-Myc regulation inferred indirectly\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a non-cell-autonomous metastatic mechanism, showing PIK3CG drives migration through MMP upregulation and neutrophil/cathepsin G recruitment in lung cancer.\",\n      \"evidence\": \"Knockdown and overexpression in A549/H1299, pharmacologic inhibition, tail-vein LLC metastasis model, and Transwell neutrophil co-culture\",\n      \"pmids\": [\"38602596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic link between p110\\u03b3 and MMP transcription not established\", \"Mechanism of neutrophil recruitment downstream of PIK3CG unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated PIK3CG in autophagy regulation in neuronal injury, opposing AMPK/mTOR-driven autophagy and influencing neuronal survival.\",\n      \"evidence\": \"siRNA knockdown in SH-SY5Y cells under OGD/R with AMPK activator co-treatment and Western blot for Beclin1/LC3 II\",\n      \"pmids\": [\"39603405\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway inferred from pharmacologic AMPK activation rather than direct mechanistic reconstitution\", \"Single cell line, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized the PIK3CG\\u2013NLRP3 axis to the CNS, using epistasis to confirm NLRP3 acts downstream of PIK3CG in mediating central post-stroke pain.\",\n      \"evidence\": \"PIK3CG overexpression/knockdown in a CPSP mouse model with simultaneous NLRP3 overexpression epistasis, RNA sequencing, and molecular docking\",\n      \"pmids\": [\"40551174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical intermediates between p110\\u03b3 and NLRP3 not identified\", \"Docking of Danshenol B not validated by direct binding assay\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved a metabolic role, showing PIK3CG sustains glutamine catabolism through an mTORC1\\u2013S6K2\\u2013p53\\u2013GLS2 axis, with GLS2 loss restricting TCA entry and elevating mitochondrial ROS.\",\n      \"evidence\": \"PIK3CG knockdown in vitro and in vivo with GLS2 overexpression rescue, mTORC1 pathway analysis, and mitochondrial ROS/pyroptosis assays\",\n      \"pmids\": [\"41539001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How p110\\u03b3 activates mTORC1 in this context not defined\", \"Single lab; specificity of S6K2(Glu163)-p53(Arg273) interaction not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How p110\\u03b3 catalytic lipid kinase output is mechanistically partitioned between its migration/metastasis, inflammasome, autophagy, and metabolic functions remains unresolved across the corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical study in the corpus links specific p110\\u03b3 catalytic outputs to each downstream branch\", \"Upstream GPCR/receptor activation events not directly characterized in the captured findings\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}