{"gene":"LPCAT1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2006,"finding":"Mouse LPCAT1 encodes a 60 kDa enzyme with three putative transmembrane domains that catalyzes Ca2+-independent acyltransferase activity (pH optimum 7.4–10), with a clear preference for saturated fatty acyl-CoAs (palmitoyl-CoA) and 1-palmitoyl-LPC as substrate, converting LPC to PC. The enzyme is predominantly expressed in lung alveolar type II cells.","method":"cDNA cloning, heterologous expression in CHO cells, in vitro acyltransferase activity assay, tissue expression profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic characterization with defined substrates, heterologous expression, replicated by multiple subsequent studies","pmids":["16704971"],"is_preprint":false},{"year":2010,"finding":"LPCAT1 is required for surfactant phosphatidylcholine (SatPC) homeostasis in vivo. Hypomorphic Lpcat1GT/GT mice showed reduced LPCAT1 mRNA levels that directly correlated with SatPC content, LPCAT1 activity, and survival. Newborn Lpcat1GT/GT mice died from respiratory failure with atelectasis and hyaline membranes, and their surfactant failed to reduce minimum surface tension to wild-type levels.","method":"Gene-trap hypomorphic mouse model, biochemical assay of SatPC content and LPCAT1 activity, surfactant function measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in vivo with multiple biochemical readouts; directly demonstrates LPCAT1 is required for SatPC synthesis and lung function","pmids":["20407208"],"is_preprint":false},{"year":2008,"finding":"Overexpressed LPCAT1 localizes to the endoplasmic reticulum and mitochondria in COS7 cells, increases LPCAT1-specific acyltransferase activity 38-fold, and enhances incorporation of [14C]palmitate into phosphatidylcholine.","method":"Overexpression in COS7 cells, subcellular fractionation/localization, radiolabeled palmitate incorporation assay, enzymatic activity measurement","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization and enzymatic activity assay, single lab, two orthogonal methods","pmids":["18974965"],"is_preprint":false},{"year":2009,"finding":"LPCAT1 catalyzes two reactions in the retina: (1) conversion of LPC to PC (anti-inflammatory) and (2) synthesis of alkyl-PC (an inactivated form of PAF) from lyso-PAF and acyl-CoA, thereby inactivating PAF. LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain of diabetic mice (Ins2Akita and db/db models), while rosiglitazone treatment restored LPCAT1 activity.","method":"Acyltransferase activity assay with lyso-PAF and LPC substrates, qPCR, diabetic mouse models (Ins2Akita, db/db), pharmacological treatment","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay with defined substrates in two mouse disease models, single lab","pmids":["19773578"],"is_preprint":false},{"year":2011,"finding":"LPCAT1 translocates from the cytosol to the nucleus in lung epithelia in response to exogenous Ca2+, where it directly binds histone H4 and catalyzes O-palmitoylation of histone H4 at Ser47. This nuclear LPCAT1-mediated histone H4 palmitoylation regulates global mRNA synthesis, as LPCAT1 knockdown or expression of a H4-S47A mutant decreased cellular mRNA synthesis.","method":"Subcellular fractionation, co-immunoprecipitation, site-directed mutagenesis (H4-S47A), LPCAT1 knockdown, nuclear translocation imaging, mRNA synthesis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical identification of protein substrate, mutagenesis of acceptor site, subcellular localization with functional consequence, single lab with multiple orthogonal methods","pmids":["21685381"],"is_preprint":false},{"year":2010,"finding":"LPS triggers proteasomal degradation of LPCAT1 via the SCF-β-TrCP E3 ubiquitin ligase. GSK-3β phosphorylates LPCAT1 at Ser178 within a phosphodegron, enabling β-TrCP docking and subsequent polyubiquitination at Lys221. Substitution of K221R abolished polyubiquitination. siRNA to β-TrCP or GSK-3β rescued LPCAT1 levels and lung surfactant mechanics impaired by LPS.","method":"Co-immunoprecipitation, site-directed mutagenesis (S178, K221), ubiquitination assay, siRNA knockdown, surfactant function assay, LPS treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution of ubiquitination pathway, mutagenesis of phosphodegron and ubiquitin acceptor site, functional rescue experiments","pmids":["21068446"],"is_preprint":false},{"year":2012,"finding":"LPCAT1 acyltransferase activity is negatively regulated by Ca2+ binding through an EF-hand motif (EFh-1) in its C-terminal domain; residues Asp392 and Glu403 define the Ca2+-binding loop. Substitution of D392A/E403A rendered the enzyme insensitive to Ca2+ inhibition, establishing that Ca2+ binding to the C-terminal domain negatively regulates the N-terminal acyltransferase activity. Additionally, an active cysteine mutant was identified that is resistant to sulfhydryl-alkylating and sulfhydryl-oxidizing agents, placing PC synthesis under control of both Ca2+ and the cellular redox status.","method":"Site-directed mutagenesis, in vitro acyltransferase activity assay, Ca2+ titration, sulfhydryl modifier treatment","journal":"BMC biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus in vitro enzyme assay, mechanistic dissection of regulatory domains, single lab","pmids":["22676268"],"is_preprint":false},{"year":2014,"finding":"Lpcat1 mutation (spontaneous insertion in rd11 mice) causes photoreceptor degeneration. AAV8(Y733F)-mediated subretinal delivery of Lpcat1 cDNA preserved the outer nuclear layer, restored rod and cone opsin expression, rescued ERG responses, and recovered visually-guided behavior, establishing that LPCAT1 loss of function is the direct cause of rd11 retinal degeneration.","method":"AAV gene replacement therapy, ERG, SD-OCT, immunohistochemistry, visually-guided behavior assay","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue by gene therapy with multiple functional readouts directly links LPCAT1 loss to photoreceptor degeneration","pmids":["24557352"],"is_preprint":false},{"year":2015,"finding":"LPCAT1 directly and specifically interacts with the phospholipid transfer protein StarD10 in alveolar type II cells; amino acids 79–271 of LPCAT1 and the START domain of StarD10 are sufficient for this interaction. StarD10 knockdown significantly reduced phospholipid transport to lamellar bodies, placing LPCAT1-StarD10 interaction at the step of SatPC trafficking from ER to lamellar bodies.","method":"Co-immunoprecipitation, pulldown with truncation/deletion mutants, StarD10 siRNA knockdown, phospholipid trafficking assay to lamellar bodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown with domain mapping and functional consequence (StarD10 KD reducing lipid trafficking), single lab with multiple orthogonal methods","pmids":["26048993"],"is_preprint":false},{"year":2019,"finding":"LPCAT1 promotes lung adenocarcinoma brain metastasis at least partially through the PI3K/AKT signaling pathway by targeting MYC transcription. shRNA-mediated LPCAT1 depletion abrogated cell proliferation, migration, and invasion in vitro and arrested tumor growth and brain metastases in vivo.","method":"shRNA knockdown, in vitro proliferation/migration/invasion assays, in vivo xenograft and brain metastasis model, RNA sequencing, PI3K/AKT pathway activator rescue","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with in vivo validation and pathway rescue, single lab","pmids":["30791942"],"is_preprint":false},{"year":2020,"finding":"LPCAT1 drives CRPC progression via two mechanisms: (1) nuclear re-localization and histone H4 palmitoylation in an androgen-dependent fashion, increasing mRNA synthesis rates; (2) production of PAF, which enhances cancer cell invasion through the PAF receptor (reversed by PAF-AH and PAF receptor antagonist ABT-491). Exogenous PAF rescued invasion in LPCAT1 knockdown cells.","method":"Cell transfection, siRNA knockdown, pulse-chase RNA labeling, migration/invasion assays, exogenous PAF rescue, PAF-AH and ABT-491 inhibition, xenograft model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic rescue experiments with PAF and receptor antagonist, functional nuclear localization with mRNA synthesis measurement, single lab","pmids":["33137125"],"is_preprint":false},{"year":2021,"finding":"LPCAT1 directly interacts with and suppresses STAT1 protein expression in hepatocellular carcinoma cells. High LPCAT1 leads to decreased STAT1, upregulation of CyclinD1, CyclinE, CDK4, MMP-9, and decreased p27kip1, promoting cell cycle progression and metastasis. Conversely, LPCAT1 knockdown caused opposite changes and arrested HCC cells at G0/G1.","method":"Co-immunoprecipitation, knockdown/overexpression, Western blot, cell cycle analysis, in vitro and in vivo tumor assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct protein-protein interaction by co-IP with functional downstream pathway changes, single lab","pmids":["34178664"],"is_preprint":false},{"year":2021,"finding":"LPCAT1 reprograms cholesterol metabolism in esophageal squamous cell carcinoma by activating PI3K to promote SP1/SREBPF2 nuclear entry (upregulating cholesterol synthesis enzyme SQLE) and by activating EGFR to downregulate INSIG-1, facilitating SREBP-1 nuclear entry and cholesterol synthesis.","method":"LPCAT1 knockdown/overexpression, Western blot for PI3K, EGFR, SREBP-1, INSIG-1, SQLE, SP1/SREBPF2 nuclear fractionation, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway components assessed by Western blot and subcellular fractionation, single lab","pmids":["34518524"],"is_preprint":false},{"year":2021,"finding":"LPCAT1 is identified as a transcriptional target of nuclear respiratory factor 1 (NRF1) in hepatocellular carcinoma. NRF1 transactivates LPCAT1, which in turn activates ERK1/2-CREB signaling, and activated CREB then further upregulates NRF1, forming a positive feedback loop that promotes HCC cell cycle progression and EMT.","method":"ChIP/luciferase reporter assay for NRF1-LPCAT1 transcriptional activation, Western blot for ERK1/2-CREB, knockdown/overexpression, in vitro and in vivo assays","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation validated by ChIP and reporter, pathway activation by Western blot, single lab","pmids":["37875967"],"is_preprint":false},{"year":2022,"finding":"LPCAT1 forms a positive feedback loop with EGFR in lung adenocarcinoma: LPCAT1 upregulation activates EGFR/PI3K/AKT signaling, and EGFR activation in turn further increases LPCAT1 expression, conferring gefitinib resistance.","method":"LPCAT1 knockdown/overexpression, gefitinib resistance assay, Western blot for EGFR/PI3K/AKT, in vivo and in vitro functional assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — positive feedback loop demonstrated by gain/loss-of-function with pathway markers, single lab","pmids":["35399731"],"is_preprint":false},{"year":2022,"finding":"LPCAT1 regulates cervical cancer progression through the JAK2/STAT3 signaling pathway. LPCAT1 knockdown decreased IL-6, p-JAK2, and p-STAT3 levels, and exogenous IL-6 addition abolished the anti-proliferative and pro-apoptotic effects of LPCAT1 knockdown, establishing IL-6/JAK2/STAT3 as downstream of LPCAT1.","method":"siRNA knockdown, RNA-seq, Western blot for p-JAK2/p-STAT3/IL-6, exogenous IL-6 rescue, xenograft and lung metastasis model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IL-6 rescue experiment establishes pathway placement; RNA-seq plus Western blot, single lab","pmids":["36122769"],"is_preprint":false},{"year":2022,"finding":"FOXA1 transcriptionally regulates LPCAT1 in breast cancer, as demonstrated by luciferase reporter and chromatin immunoprecipitation assays. FOXA1 overexpression attenuated the effects of LPCAT1 knockdown on cell proliferation, colony formation, migration, invasion, and paclitaxel resistance.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), LPCAT1 knockdown, FOXA1 overexpression rescue","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with functional rescue, single lab","pmids":["36909375"],"is_preprint":false},{"year":2022,"finding":"LPCAT1 overexpression changes phospholipid composition (PE, PC, TG) in endometrial cancer cells and promotes stemness and metastasis through activation of the TGF-β/Smad2/3 signaling pathway, upregulating stem cell transcription factors and EMT-related proteins. The LPCAT1 inhibitor TSI-01 restrained EC cell proliferation and promoted apoptosis.","method":"LPCAT1 knockdown/overexpression, lipidomics, RNA sequencing, Western blot for Smad2/3, TSI-01 pharmacological inhibition","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipidomics plus RNA-seq and Western blot with pharmacological inhibition, single lab","pmids":["35880567"],"is_preprint":false},{"year":2021,"finding":"HECTD2, a HECT-domain E3 ubiquitin ligase, co-immunoprecipitates with ubiquitinated LPCAT1 and drives LPCAT1 polyubiquitination and degradation. LPCAT1 overexpression rescued CRC cell proliferation impaired by HECTD2 overexpression, placing HECTD2 as an upstream negative regulator of LPCAT1.","method":"Co-immunoprecipitation, ubiquitination assay, HECTD2 and LPCAT1 overexpression, cell proliferation rescue assay","journal":"Molekuliarnaia biologiia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP/ubiquitination assay, single lab, limited mechanistic follow-up","pmids":["35964314"],"is_preprint":false},{"year":2021,"finding":"miR-205 directly targets LPCAT1 in multiple cancer cell lines (LIHC, HNSCC, LUSC), and LPCAT1 is required for sustained cancer cell proliferation downstream of miR-205 suppression.","method":"miR-205 stable overexpression, luciferase/target validation (implied), cell proliferation assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — miRNA-target relationship and proliferation assay, single lab, limited mechanistic detail in abstract","pmids":["32334831"],"is_preprint":false},{"year":2021,"finding":"ROBO4 deletion reduces LPCAT1 (and LPCAT2) protein levels in macrophages without affecting mRNA levels, by decreasing ribosome abundance and ATP levels, which impairs LPCAT1/LPCAT2 mRNA translation efficiency (shown by polyribosome assay). This reduces PAF synthesis and PAF-mediated skin inflammation.","method":"ROBO4 knockout mouse model, polyribosome assay, Western blot, HPLC for ATP, RNA expression profiling","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polyribosome assay directly demonstrates translational regulation; multiple orthogonal methods, single lab","pmids":["32140075"],"is_preprint":false},{"year":2021,"finding":"MNRR1 (mitochondrial nuclear retrograde regulator 1), a bi-organellar transcription regulator, transcriptionally activates LPCAT1. Dexamethasone (antenatal corticosteroids) upregulates LPCAT1 at least in part through an MNRR1-dependent pathway; in MNRR1 knockout cells, the response of LPCAT1 to dexamethasone is significantly blunted.","method":"MNRR1 knockout cells, dexamethasone treatment, Western blot for LPCAT1, hypoxia treatment (4% O2), placental cell line (HTR-8/SVneo)","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MNRR1 KO rescue experiment demonstrates transcriptional dependence; single lab, single model","pmids":["33618181"],"is_preprint":false},{"year":2024,"finding":"LPCAT1 increases membrane phospholipid saturation via the Lands cycle, reducing membrane polyunsaturated fatty acid (PUFA) levels, thereby protecting cells from phospholipid peroxidation-induced membrane damage and enabling ferroptosis resistance. LPCAT1 inhibition combined with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumor growth in vivo.","method":"LPCAT1 gain/loss-of-function, lipidomics for membrane PUFA content, ferroptosis induction assays, in vivo tumor growth assay, combination treatment","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic lipidomics demonstrating PUFA reduction through Lands cycle, multiple functional assays in vitro and in vivo, published in high-quality journal","pmids":["38671262"],"is_preprint":false},{"year":2024,"finding":"HIF-2α directly binds to the LPCAT1 promoter and transcriptionally activates LPCAT1 in ccRCC. LPCAT1 knockdown activates NF-κB signaling, which upregulates FBXW7 (an E3 ubiquitin ligase); FBXW7 then promotes ubiquitination and degradation of ACLY, lowering fatty acid production and reducing lipid content. RNA-seq and lipidomics confirmed that LPCAT1 knockdown significantly reduced triglyceride production.","method":"ChIP/promoter binding assay for HIF-2α-LPCAT1, RNA-seq, lipidomics, NF-κB pathway Western blot, FBXW7-ACLY co-immunoprecipitation and ubiquitination assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, lipidomics, and Co-IP for downstream ubiquitination, single lab, multiple orthogonal methods","pmids":["39781455"],"is_preprint":false},{"year":2025,"finding":"LRRK2 inhibits RBX1-mediated proteasomal degradation of LPCAT1, thereby stabilizing LPCAT1 protein in ccRCC. LRRK2/LPCAT1 upregulation promotes IL-1β expression through AKT and by activating the inflammasome, reducing sensitivity to TKI and PD-1 blockade.","method":"Protein degradation assay, co-immunoprecipitation with RBX1, Western blot for LPCAT1 stability, AKT/inflammasome pathway analysis, PROTAC targeting","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP with degradation mechanism and pathway assays, single lab","pmids":["40121376"],"is_preprint":false},{"year":2021,"finding":"ppGalNAc-T18 (GALNT18) retains in the ER through its luminal stem region and catalytic domain interacting with ER resident proteins including LPCAT1, as shown by co-immunoprecipitation. This identifies LPCAT1 as an ER-resident protein involved in ER retention interactions.","method":"Co-immunoprecipitation with truncation mutants of ppGalNAc-T18, flow cytometry for O-glycosylation","journal":"Glycobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP showing LPCAT1 as ER-resident binding partner; not the primary focus, limited mechanistic follow-up for LPCAT1 itself","pmids":["33909026"],"is_preprint":false},{"year":2025,"finding":"LPCAT1 promotes OPC differentiation into oligodendrocytes by activating mTOR phosphorylation (not through increased PC production per se). LPCAT1 upregulates the transcription factor ZBTB20, which regulates mTOR phosphorylation. In vivo, conditional knockout of LPCAT1 in oligodendrocyte lineage cells caused complex myelin tomacula but no obvious myelin thickness abnormalities.","method":"LPCAT1 overexpression and siRNA knockdown in OPC cultures, RNA sequencing, Western blot for p-mTOR, in vivo conditional knockout, OPC differentiation assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus Western blot for mTOR with in vivo KO phenotype; single lab, mechanistic pathway partially established","pmids":["39878319"],"is_preprint":false},{"year":2024,"finding":"LPCAT1 promotes keratinocyte hyperproliferation and skin inflammation in psoriasis by activating AKT/NF-κB and STAT3 signaling, which in turn upregulates glucose transporter GLUT3. GLUT3 deficiency impaired proliferation and inflammation of psoriatic keratinocytes, establishing GLUT3 as a critical downstream effector of LPCAT1.","method":"LPCAT1 gain/loss-of-function, siRNA for GLUT3, NF-κB and STAT3 pathway inhibition, imiquimod mouse model, cytokine ELISA, GLUT3 rescue assay","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments with GLUT3 KD and signaling pathway inhibitors, in vivo mouse model, single lab","pmids":["38246582"],"is_preprint":false},{"year":2021,"finding":"SOX2 transcriptionally activates LPCAT1 in osteosarcoma (validated by dual-luciferase reporter and ChIP assays). LPCAT1 overexpression promoted cholesterol metabolism reprogramming (free cholesterol/total cholesterol levels, SREBP1/INSIG1), proliferation, migration and invasion; LPCAT1 knockdown attenuated SOX2-driven oncogenicity in vitro and in vivo.","method":"Dual-luciferase reporter, ChIP, LPCAT1 and SOX2 overexpression/knockdown, cholesterol measurement, xenograft and lung metastasis model","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter for transcriptional regulation plus functional epistasis, single lab","pmids":["41358198"],"is_preprint":false},{"year":2026,"finding":"TRIM33 directly interacts with LPCAT1 and promotes its ubiquitination and proteasomal degradation. TRIM33 overexpression inhibited LPCAT1-driven PI3K/AKT activation and glycolysis, reversing cisplatin resistance in NSCLC cells in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM33 and LPCAT1 overexpression/knockdown, PI3K/AKT Western blot, glycolysis assay, xenograft model","journal":"World journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with ubiquitination assay and pathway/functional rescue; single lab, multiple orthogonal methods","pmids":["42147264"],"is_preprint":false},{"year":2026,"finding":"ATF2, activated by the p38 MAPK pathway in response to cholesterol loading, transcriptionally upregulates LPCAT1. LPCAT1 in turn promotes acetylation of PKM2 at K433, exacerbating cholesterol-induced metabolic disorders and inflammation in macrophages. K433 mutations ameliorated these effects, establishing the p38-ATF2-LPCAT1-PKM2 axis.","method":"p38 MAPK inhibition, ATF2 knockdown, LPCAT1 knockdown, PKM2-K433 mutagenesis, metabolic and inflammatory assays in cholesterol-loaded macrophages","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of PKM2 acceptor site and genetic epistasis across pathway, single lab","pmids":["41740546"],"is_preprint":false},{"year":2025,"finding":"AT2 cell-specific Lpcat1 deletion in mice resulted in reduced AT2 cell renewal, spontaneous lung fibrosis, and heightened susceptibility to bleomycin-induced fibrosis in vivo. Pharmacologically, artesunate and PLA2 inhibitor ONO-RS-082 increased LPCAT1 mRNA expression, promoted AT2 renewal, and attenuated bleomycin-induced fibrosis, confirming that LPCAT1 is required for AT2 progenitor renewal through PC metabolism.","method":"AT2 cell-specific conditional knockout, 3D organoid AT2 renewal assay, bleomycin fibrosis model, pharmacological LPCAT1 upregulation, LPCAT1 knock-in cell line drug screening","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with organoid and in vivo functional readouts; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Microbiota-derived lithocholic acid (LCA) directly activates LPCAT1, upregulating its expression. LPCAT1 overexpression leads to intestinal barrier dysfunction and promotes colonic inflammation via activation of MMP1. LPCAT1 inhibition ameliorated intestinal barrier dysfunction, diarrhea symptoms, and colonic inflammation in LCA-treated mice and experimental colitis models.","method":"LCA treatment in mice and cell culture, LPCAT1 knockdown/overexpression, MMP1 pathway analysis, in vivo intestinal barrier assays, colitis mouse model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — mechanism of LCA-LPCAT1-MMP1 axis stated but mechanistic detail (e.g., direct binding) is limited in abstract; preprint only","pmids":[],"is_preprint":true}],"current_model":"LPCAT1 is an endoplasmic reticulum-resident acyltransferase that catalyzes Ca2+-independent, palmitate-preferring reacylation of lysophosphatidylcholine to phosphatidylcholine (and lyso-PAF to alkyl-PC) in the Lands cycle, with activity negatively regulated by Ca2+ binding to a C-terminal EF-hand motif and by cellular redox status; in lung alveolar type II cells it forms a complex with StarD10 to traffic saturated PC to lamellar bodies for surfactant production, and its protein stability is controlled by GSK-3β-mediated phosphorylation at Ser178 and subsequent β-TrCP/proteasomal degradation; in addition, LPCAT1 translocates to the nucleus in response to Ca2+ to catalyze O-palmitoylation of histone H4 at Ser47, thereby regulating global mRNA synthesis, and its transcription is activated by HIF-2α, NRF1, SOX2, FOXA1, and MNRR1, while HECTD2, TRIM33, and RBX1 (countered by LRRK2) promote its ubiquitination and degradation; through membrane phospholipid saturation via the Lands cycle, LPCAT1 reduces polyunsaturated fatty acid content and confers ferroptosis resistance in cancer cells."},"narrative":{"mechanistic_narrative":"LPCAT1 is an endoplasmic reticulum-resident, Ca2+-independent acyltransferase that drives the reacylation arm of the Lands cycle, converting lysophosphatidylcholine to phosphatidylcholine with a strong preference for saturated palmitoyl-CoA and additionally producing alkyl-PC from lyso-PAF [PMID:16704971, PMID:18974965, PMID:19773578]. Its catalytic output is governed by an N-terminal acyltransferase activity that is negatively regulated by Ca2+ binding to a C-terminal EF-hand (residues Asp392/Glu403) and by the cellular redox state of an active-site cysteine [PMID:22676268]. In lung alveolar type II cells LPCAT1 is required for synthesis of surfactant saturated PC, and its loss causes neonatal respiratory failure with atelectasis and surfactant dysfunction [PMID:20407208]; the enzyme partners with the phospholipid transfer protein StarD10 (via LPCAT1 residues 79–271 and the START domain) to traffic saturated PC from the ER to lamellar bodies, and AT2-specific deletion impairs progenitor renewal and predisposes to lung fibrosis [PMID:26048993]. Beyond bulk lipid synthesis, LPCAT1 translocates to the nucleus in response to Ca2+, where it binds histone H4 and catalyzes O-palmitoylation at Ser47 to control global mRNA synthesis [PMID:21685381]. LPCAT1 abundance is set post-translationally by ubiquitin-dependent degradation: GSK-3β phosphorylates a Ser178 phosphodegron to license SCF-β-TrCP-mediated polyubiquitination at Lys221 [PMID:21068446]. Through these activities LPCAT1 acts broadly in disease, and genetically its loss directly causes rd11 photoreceptor degeneration, rescued by AAV-mediated cDNA delivery [PMID:24557352]. In cancer, LPCAT1 increases membrane phospholipid saturation to deplete polyunsaturated fatty acids and confer ferroptosis resistance [PMID:38671262], and across multiple tumor types it activates PI3K/AKT and downstream growth and metabolic programs [PMID:30791942, PMID:34518524, PMID:38671262].","teleology":[{"year":2006,"claim":"Established the core biochemical identity of LPCAT1 — what reaction it catalyzes and with what substrate selectivity — defining it as the Lands-cycle reacylation enzyme.","evidence":"cDNA cloning and heterologous expression in CHO cells with in vitro acyltransferase assay and tissue profiling","pmids":["16704971"],"confidence":"High","gaps":["No structural model of the catalytic site","Did not address regulation or in vivo requirement"]},{"year":2008,"claim":"Localized LPCAT1 activity to the ER (and mitochondria) and confirmed it drives palmitate incorporation into PC in cells, anchoring the enzyme to a membrane compartment.","evidence":"Overexpression in COS7 with subcellular fractionation and radiolabeled palmitate incorporation","pmids":["18974965"],"confidence":"Medium","gaps":["Mitochondrial localization not independently confirmed","Overexpression artifact possible"]},{"year":2009,"claim":"Extended LPCAT1 substrate scope to lyso-PAF, showing it both generates anti-inflammatory PC and inactivates the pro-inflammatory lipid mediator PAF.","evidence":"Acyltransferase assays with lyso-PAF/LPC and diabetic mouse retina/brain models","pmids":["19773578"],"confidence":"Medium","gaps":["Causal role of LPCAT1 loss in diabetic neuropathy not tested by genetic LOF"]},{"year":2010,"claim":"Demonstrated the physiological requirement for LPCAT1 in surfactant PC homeostasis and identified its post-translational control by ubiquitin-dependent degradation.","evidence":"Hypomorphic gene-trap mice with surfactant assays; co-IP, phosphodegron/ubiquitin-site mutagenesis (S178, K221) and rescue by GSK-3β/β-TrCP knockdown","pmids":["20407208","21068446"],"confidence":"High","gaps":["Other E3 ligases not yet defined","Trigger linking inflammation to GSK-3β activation incompletely mapped"]},{"year":2011,"claim":"Revealed an unexpected nuclear, chromatin-modifying function: Ca2+-triggered nuclear LPCAT1 palmitoylates histone H4 at Ser47 to regulate global mRNA synthesis.","evidence":"Subcellular fractionation, co-IP with H4, H4-S47A mutagenesis, knockdown and mRNA synthesis assay","pmids":["21685381"],"confidence":"High","gaps":["How a lipid acyltransferase reads/writes a serine residue mechanistically unresolved","Genome-wide consequences not mapped"]},{"year":2012,"claim":"Defined the regulatory architecture of the enzyme — a C-terminal EF-hand confers Ca2+ inhibition of the N-terminal catalytic domain, and a cysteine confers redox sensitivity.","evidence":"Site-directed mutagenesis (D392A/E403A), Ca2+ titration and sulfhydryl-modifier assays in vitro","pmids":["22676268"],"confidence":"High","gaps":["Physiological Ca2+ concentrations triggering inhibition not established","No crystal structure of the regulated enzyme"]},{"year":2014,"claim":"Provided causal genetic proof that LPCAT1 loss of function drives photoreceptor degeneration, distinct from its lung role.","evidence":"AAV8-mediated Lpcat1 cDNA rescue in rd11 mice with ERG, OCT, IHC and behavioral readouts","pmids":["24557352"],"confidence":"High","gaps":["Specific retinal lipid species rescued not defined","Human retinal disease relevance untested"]},{"year":2015,"claim":"Identified the trafficking partner that couples LPCAT1 PC synthesis to surfactant delivery, placing it at the ER-to-lamellar-body step.","evidence":"Reciprocal co-IP/pulldown with domain mapping (LPCAT1 79–271, StarD10 START) and StarD10 knockdown trafficking assay","pmids":["26048993"],"confidence":"High","gaps":["Whether interaction directly hands off lipid vs. co-localizes not resolved","Stoichiometry of complex unknown"]},{"year":2019,"claim":"Initiated the body of evidence that LPCAT1 acts as an oncogenic driver through PI3K/AKT signaling and downstream transcriptional targets.","evidence":"shRNA depletion with in vitro and in vivo brain-metastasis models, RNA-seq and pathway-activator rescue","pmids":["30791942"],"confidence":"Medium","gaps":["Whether catalytic activity is required for PI3K/AKT effect not separated from scaffolding","Direct link from lipid output to MYC unclear"]},{"year":2021,"claim":"Mapped a dense transcriptional and post-translational regulatory network controlling LPCAT1 levels across tissues, and linked LPCAT1 to multiple cancer signaling pathways.","evidence":"ChIP/reporter (NRF1, SOX2, MNRR1), translational control (ROBO4 polyribosome assay), E3 ligase co-IP/ubiquitination (HECTD2), miR-205 targeting, and STAT/PI3K pathway assays across HCC, OS, macrophage and other models","pmids":["34178664","34518524","37875967","35964314","32334831","32140075","33618181","41358198","33909026"],"confidence":"Medium","gaps":["Many regulators tested in single cell types only","HECTD2 and miR-205 links rest on limited mechanistic follow-up"]},{"year":2022,"claim":"Broadened LPCAT1's disease reach to additional cancers and tissues via shared PI3K/AKT, STAT3, and TGF-β effector programs and drug-resistance phenotypes.","evidence":"Gain/loss-of-function with pathway markers, lipidomics, IL-6 and EGFR rescue, FOXA1 ChIP, and pharmacological inhibition (TSI-01) across LUAD, cervical, breast, endometrial models","pmids":["35399731","36122769","36909375","35880567"],"confidence":"Medium","gaps":["Tissue-specific effectors (GLUT3, JAK2, Smad) reported in isolation","Catalytic vs. non-catalytic contribution often untested"]},{"year":2024,"claim":"Unified LPCAT1's lipid biochemistry with a major cancer phenotype by showing it depletes membrane PUFAs to confer ferroptosis resistance, and added a hypoxia-driven transcriptional/metabolic axis.","evidence":"Gain/loss-of-function with membrane lipidomics, ferroptosis induction and combination therapy in vivo; HIF-2α ChIP with RNA-seq, lipidomics and FBXW7-ACLY ubiquitination assays","pmids":["38671262","39781455"],"confidence":"High","gaps":["Whether the EF-hand/redox regulation modulates ferroptosis output untested","FBXW7-ACLY arm characterized in single model"]},{"year":2025,"claim":"Demonstrated tissue-progenitor and stability-regulation roles — AT2 renewal, oligodendrocyte differentiation, and LRRK2/RBX1 control of LPCAT1 protein stability.","evidence":"Conditional knockouts and organoid assays (lung AT2, oligodendrocyte lineage), ZBTB20/mTOR Western blot, and RBX1 co-IP/degradation assays with PROTAC targeting","pmids":["39878319","40121376"],"confidence":"Medium","gaps":["AT2 fibrosis finding is preprint and not peer-reviewed","Oligodendrocyte effect reported as PC-independent, leaving the mediating activity unclear"]},{"year":2026,"claim":"Added further substrate/effector relationships — TRIM33-mediated degradation and an ATF2-LPCAT1-PKM2 acetylation axis — expanding LPCAT1's regulatory inputs and metabolic outputs.","evidence":"Co-IP/ubiquitination (TRIM33), PKM2-K433 mutagenesis and epistasis in cholesterol-loaded macrophages, with pathway and xenograft assays","pmids":["42147264","41740546"],"confidence":"Medium","gaps":["Mechanism by which an acyltransferase promotes PKM2 acetylation unresolved","Single-lab findings without independent replication"]},{"year":null,"claim":"How LPCAT1's distinct activities — ER bulk PC synthesis, nuclear histone palmitoylation, and PUFA-depleting ferroptosis resistance — are coordinated within a cell, and whether its catalytic activity is required for the many reported PI3K/AKT signaling effects, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length human LPCAT1","Catalytic vs. scaffolding requirement for oncogenic signaling not systematically dissected","Mechanism switching cytosolic vs. nuclear localization beyond Ca2+ unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,8,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,22,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5]}],"complexes":["LPCAT1-StarD10 complex"],"partners":["STARD10","GSK3B","BTRC","HIST1H4 (HISTONE H4)","STAT1","HECTD2","TRIM33","RBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NF37","full_name":"Lysophosphatidylcholine acyltransferase 1","aliases":["1-acylglycerol-3-phosphate O-acyltransferase","1-acylglycerophosphocholine O-acyltransferase","1-alkenylglycerophosphocholine O-acyltransferase","1-alkylglycerophosphocholine O-acetyltransferase","Acetyl-CoA:lyso-platelet-activating factor acetyltransferase","Acetyl-CoA:lyso-PAF acetyltransferase","Lyso-PAF acetyltransferase","LysoPAFAT","Acyltransferase-like 2","Phosphonoformate immuno-associated protein 3"],"length_aa":534,"mass_kda":59.2,"function":"Exhibits acyltransferase activity (PubMed:18156367, PubMed:21498505). Exhibits acetyltransferase activity (By similarity). Activity is calcium-independent (By similarity). Catalyzes the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) (PubMed:18156367, PubMed:21498505). Catalyzes the conversion 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (By similarity). Displays a clear preference for saturated fatty acyl-CoAs, and 1-myristoyl or 1-palmitoyl LPC as acyl donors and acceptors, respectively (By similarity). Involved in platelet-activating factor (PAF) biosynthesis by catalyzing the conversion of the PAF precursor, 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) into 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) (By similarity). May synthesize phosphatidylcholine in pulmonary surfactant, thereby playing a pivotal role in respiratory physiology (By similarity). Involved in the regulation of lipid droplet number and size (PubMed:25491198)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Cell membrane; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/Q8NF37/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LPCAT1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000153395","cell_line_id":"CID000333","localizations":[{"compartment":"er","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"GLB1","stoichiometry":0.2},{"gene":"ACBD4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000333","total_profiled":1310},"omim":[{"mim_id":"612040","title":"LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE 2; LPCAT2","url":"https://www.omim.org/entry/612040"},{"mim_id":"610472","title":"LPC ACYLTRANSFERASE 1; LPCAT1","url":"https://www.omim.org/entry/610472"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Lipid droplets","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":53.5},{"tissue":"lymphoid tissue","ntpm":35.5}],"url":"https://www.proteinatlas.org/search/LPCAT1"},"hgnc":{"alias_symbol":["FLJ12443","AGPAT9","AGPAT10","LPLAT8"],"prev_symbol":["AYTL2"]},"alphafold":{"accession":"Q8NF37","domains":[{"cath_id":"-","chopping":"41-311","consensus_level":"high","plddt":90.7205,"start":41,"end":311},{"cath_id":"-","chopping":"320-496","consensus_level":"high","plddt":87.9286,"start":320,"end":496}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NF37","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NF37-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NF37-F1-predicted_aligned_error_v6.png","plddt_mean":82.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LPCAT1","jax_strain_url":"https://www.jax.org/strain/search?query=LPCAT1"},"sequence":{"accession":"Q8NF37","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NF37.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NF37/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NF37"}},"corpus_meta":[{"pmid":"16704971","id":"PMC_16704971","title":"Cloning and characterization of mouse lung-type acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1). 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Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40343577","citation_count":3,"is_preprint":false},{"pmid":"35964314","id":"PMC_35964314","title":"[HECTD2 Represses Cell Proliferation in Colorectal Cancer through Driving Ubiquitination and Degradation of LPCAT1].","date":"2022","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/35964314","citation_count":2,"is_preprint":false},{"pmid":"39878319","id":"PMC_39878319","title":"LPCAT1, the Enzyme Responsible for Converting LPC to PC, Promotes OPC Differentiation In Vitro.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39878319","citation_count":2,"is_preprint":false},{"pmid":"38703867","id":"PMC_38703867","title":"Identification of LPCAT1 as a key biomarker for Crohn's disease based on bioinformatics and machine learnings and experimental verification.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38703867","citation_count":2,"is_preprint":false},{"pmid":"37300846","id":"PMC_37300846","title":"LncRNA AC012360.1 facilitates growth and metastasis by regulating the miR-139-5p/LPCAT1 axis in hepatocellular carcinoma.","date":"2023","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37300846","citation_count":2,"is_preprint":false},{"pmid":"39837174","id":"PMC_39837174","title":"LPCAT1 reduces inflammatory response, apoptosis and barrier damage of nasal mucosal epithelial cells caused by allergic rhinitis through endoplasmic reticulum stress.","date":"2024","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/39837174","citation_count":1,"is_preprint":false},{"pmid":"41007798","id":"PMC_41007798","title":"Association of LPCAT1*rs9728 Variant with Reduced Susceptibility to Neonatal Respiratory Distress Syndrome.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41007798","citation_count":1,"is_preprint":false},{"pmid":"37079124","id":"PMC_37079124","title":"The validation and clinical significance of LPCAT1 down-regulation in acute myeloid leukemia.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37079124","citation_count":0,"is_preprint":false},{"pmid":"41549297","id":"PMC_41549297","title":"Lysolecithin reprogramming via LPCAT1 modulation restores endothelial function and prevents diabetes-associated dysmetabolism.","date":"2026","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/41549297","citation_count":0,"is_preprint":false},{"pmid":"37146534","id":"PMC_37146534","title":"LPCAT1 levels in the placenta, the maternal plasma and the fetal plasma do not predict fetal lung responses to glucocorticoids in a sheep model of pregnancy.","date":"2023","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/37146534","citation_count":0,"is_preprint":false},{"pmid":"41358198","id":"PMC_41358198","title":"SOX2 induces LPCAT1 expression to promote cholesterol metabolic reprogramming-mediated invasion and metastasis in osteosarcoma.","date":"2025","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/41358198","citation_count":0,"is_preprint":false},{"pmid":"38042217","id":"PMC_38042217","title":"Molecular cloning, tissue expression pattern, responses to different fatty acids and potential functions of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in large yellow croaker (Larimichthys crocea).","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38042217","citation_count":0,"is_preprint":false},{"pmid":"41986490","id":"PMC_41986490","title":"LPCAT1 depletion inhibits colorectal cancer tumorigenesis and is associated with the ECM-receptor-interaction signaling pathway.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41986490","citation_count":0,"is_preprint":false},{"pmid":"41711314","id":"PMC_41711314","title":"Oncogenic LPCAT1 Accelerates Intrahepatic Cholangiocarcinoma Development Through PI3K/Akt Signaling-Dependent Cell Cycle Regulation.","date":"2026","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/41711314","citation_count":0,"is_preprint":false},{"pmid":"39871194","id":"PMC_39871194","title":"Association of LPCAT1-rs8352 genetic variant with susceptibility and severity of pediatric bronchial asthma: a case-control study.","date":"2025","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/39871194","citation_count":0,"is_preprint":false},{"pmid":"41740546","id":"PMC_41740546","title":"ATF2-LPCAT1-mediated PKM2 acetylation links cholesterol stress to macrophage metabolic reprogramming and functional remodeling.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41740546","citation_count":0,"is_preprint":false},{"pmid":"42147264","id":"PMC_42147264","title":"TRIM33 Reverses Cisplatin Resistance in Non-Small Cell Lung Cancer by Regulating the PI3K/AKT Pathway via Ubiquitination-Mediated Degradation of LPCAT1.","date":"2026","source":"World journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42147264","citation_count":0,"is_preprint":false},{"pmid":"41859820","id":"PMC_41859820","title":"Reduction in Synaptic Vesicle Protein Abundance but Increased Amounts of Nsg2 and Lpcat1 in Cerebral Cortices Without the Endosomal SNARE Proteins Vti1a and Vti1b.","date":"2026","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/41859820","citation_count":0,"is_preprint":false},{"pmid":"41928265","id":"PMC_41928265","title":"KL-6 assisted subtyping of ARDS: from subtype-specific metabolomics to LPCAT1 as a pathogenic target.","date":"2026","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/41928265","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.26.678894","title":"Phosphatidylcholine Metabolism Controls Alveolar Progenitor Renewal and Pulmonary Fibrosis","date":"2025-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.26.678894","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.13.25320445","title":"Gut microbiota-derived lithocholic acid leads to intestinal barrier dysfunction via LPCAT1 in irritable bowel syndrome","date":"2025-01-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.13.25320445","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36993,"output_tokens":8736,"usd":0.12101,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18888,"output_tokens":4982,"usd":0.109495,"stage2_stop_reason":"end_turn"},"total_usd":0.230505,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Mouse LPCAT1 encodes a 60 kDa enzyme with three putative transmembrane domains that catalyzes Ca2+-independent acyltransferase activity (pH optimum 7.4–10), with a clear preference for saturated fatty acyl-CoAs (palmitoyl-CoA) and 1-palmitoyl-LPC as substrate, converting LPC to PC. The enzyme is predominantly expressed in lung alveolar type II cells.\",\n      \"method\": \"cDNA cloning, heterologous expression in CHO cells, in vitro acyltransferase activity assay, tissue expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic characterization with defined substrates, heterologous expression, replicated by multiple subsequent studies\",\n      \"pmids\": [\"16704971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPCAT1 is required for surfactant phosphatidylcholine (SatPC) homeostasis in vivo. Hypomorphic Lpcat1GT/GT mice showed reduced LPCAT1 mRNA levels that directly correlated with SatPC content, LPCAT1 activity, and survival. Newborn Lpcat1GT/GT mice died from respiratory failure with atelectasis and hyaline membranes, and their surfactant failed to reduce minimum surface tension to wild-type levels.\",\n      \"method\": \"Gene-trap hypomorphic mouse model, biochemical assay of SatPC content and LPCAT1 activity, surfactant function measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in vivo with multiple biochemical readouts; directly demonstrates LPCAT1 is required for SatPC synthesis and lung function\",\n      \"pmids\": [\"20407208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Overexpressed LPCAT1 localizes to the endoplasmic reticulum and mitochondria in COS7 cells, increases LPCAT1-specific acyltransferase activity 38-fold, and enhances incorporation of [14C]palmitate into phosphatidylcholine.\",\n      \"method\": \"Overexpression in COS7 cells, subcellular fractionation/localization, radiolabeled palmitate incorporation assay, enzymatic activity measurement\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization and enzymatic activity assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"18974965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPCAT1 catalyzes two reactions in the retina: (1) conversion of LPC to PC (anti-inflammatory) and (2) synthesis of alkyl-PC (an inactivated form of PAF) from lyso-PAF and acyl-CoA, thereby inactivating PAF. LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain of diabetic mice (Ins2Akita and db/db models), while rosiglitazone treatment restored LPCAT1 activity.\",\n      \"method\": \"Acyltransferase activity assay with lyso-PAF and LPC substrates, qPCR, diabetic mouse models (Ins2Akita, db/db), pharmacological treatment\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay with defined substrates in two mouse disease models, single lab\",\n      \"pmids\": [\"19773578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LPCAT1 translocates from the cytosol to the nucleus in lung epithelia in response to exogenous Ca2+, where it directly binds histone H4 and catalyzes O-palmitoylation of histone H4 at Ser47. This nuclear LPCAT1-mediated histone H4 palmitoylation regulates global mRNA synthesis, as LPCAT1 knockdown or expression of a H4-S47A mutant decreased cellular mRNA synthesis.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, site-directed mutagenesis (H4-S47A), LPCAT1 knockdown, nuclear translocation imaging, mRNA synthesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical identification of protein substrate, mutagenesis of acceptor site, subcellular localization with functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21685381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPS triggers proteasomal degradation of LPCAT1 via the SCF-β-TrCP E3 ubiquitin ligase. GSK-3β phosphorylates LPCAT1 at Ser178 within a phosphodegron, enabling β-TrCP docking and subsequent polyubiquitination at Lys221. Substitution of K221R abolished polyubiquitination. siRNA to β-TrCP or GSK-3β rescued LPCAT1 levels and lung surfactant mechanics impaired by LPS.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (S178, K221), ubiquitination assay, siRNA knockdown, surfactant function assay, LPS treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution of ubiquitination pathway, mutagenesis of phosphodegron and ubiquitin acceptor site, functional rescue experiments\",\n      \"pmids\": [\"21068446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LPCAT1 acyltransferase activity is negatively regulated by Ca2+ binding through an EF-hand motif (EFh-1) in its C-terminal domain; residues Asp392 and Glu403 define the Ca2+-binding loop. Substitution of D392A/E403A rendered the enzyme insensitive to Ca2+ inhibition, establishing that Ca2+ binding to the C-terminal domain negatively regulates the N-terminal acyltransferase activity. Additionally, an active cysteine mutant was identified that is resistant to sulfhydryl-alkylating and sulfhydryl-oxidizing agents, placing PC synthesis under control of both Ca2+ and the cellular redox status.\",\n      \"method\": \"Site-directed mutagenesis, in vitro acyltransferase activity assay, Ca2+ titration, sulfhydryl modifier treatment\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus in vitro enzyme assay, mechanistic dissection of regulatory domains, single lab\",\n      \"pmids\": [\"22676268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Lpcat1 mutation (spontaneous insertion in rd11 mice) causes photoreceptor degeneration. AAV8(Y733F)-mediated subretinal delivery of Lpcat1 cDNA preserved the outer nuclear layer, restored rod and cone opsin expression, rescued ERG responses, and recovered visually-guided behavior, establishing that LPCAT1 loss of function is the direct cause of rd11 retinal degeneration.\",\n      \"method\": \"AAV gene replacement therapy, ERG, SD-OCT, immunohistochemistry, visually-guided behavior assay\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue by gene therapy with multiple functional readouts directly links LPCAT1 loss to photoreceptor degeneration\",\n      \"pmids\": [\"24557352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LPCAT1 directly and specifically interacts with the phospholipid transfer protein StarD10 in alveolar type II cells; amino acids 79–271 of LPCAT1 and the START domain of StarD10 are sufficient for this interaction. StarD10 knockdown significantly reduced phospholipid transport to lamellar bodies, placing LPCAT1-StarD10 interaction at the step of SatPC trafficking from ER to lamellar bodies.\",\n      \"method\": \"Co-immunoprecipitation, pulldown with truncation/deletion mutants, StarD10 siRNA knockdown, phospholipid trafficking assay to lamellar bodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown with domain mapping and functional consequence (StarD10 KD reducing lipid trafficking), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26048993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LPCAT1 promotes lung adenocarcinoma brain metastasis at least partially through the PI3K/AKT signaling pathway by targeting MYC transcription. shRNA-mediated LPCAT1 depletion abrogated cell proliferation, migration, and invasion in vitro and arrested tumor growth and brain metastases in vivo.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation/migration/invasion assays, in vivo xenograft and brain metastasis model, RNA sequencing, PI3K/AKT pathway activator rescue\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with in vivo validation and pathway rescue, single lab\",\n      \"pmids\": [\"30791942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LPCAT1 drives CRPC progression via two mechanisms: (1) nuclear re-localization and histone H4 palmitoylation in an androgen-dependent fashion, increasing mRNA synthesis rates; (2) production of PAF, which enhances cancer cell invasion through the PAF receptor (reversed by PAF-AH and PAF receptor antagonist ABT-491). Exogenous PAF rescued invasion in LPCAT1 knockdown cells.\",\n      \"method\": \"Cell transfection, siRNA knockdown, pulse-chase RNA labeling, migration/invasion assays, exogenous PAF rescue, PAF-AH and ABT-491 inhibition, xenograft model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic rescue experiments with PAF and receptor antagonist, functional nuclear localization with mRNA synthesis measurement, single lab\",\n      \"pmids\": [\"33137125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LPCAT1 directly interacts with and suppresses STAT1 protein expression in hepatocellular carcinoma cells. High LPCAT1 leads to decreased STAT1, upregulation of CyclinD1, CyclinE, CDK4, MMP-9, and decreased p27kip1, promoting cell cycle progression and metastasis. Conversely, LPCAT1 knockdown caused opposite changes and arrested HCC cells at G0/G1.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, Western blot, cell cycle analysis, in vitro and in vivo tumor assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct protein-protein interaction by co-IP with functional downstream pathway changes, single lab\",\n      \"pmids\": [\"34178664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LPCAT1 reprograms cholesterol metabolism in esophageal squamous cell carcinoma by activating PI3K to promote SP1/SREBPF2 nuclear entry (upregulating cholesterol synthesis enzyme SQLE) and by activating EGFR to downregulate INSIG-1, facilitating SREBP-1 nuclear entry and cholesterol synthesis.\",\n      \"method\": \"LPCAT1 knockdown/overexpression, Western blot for PI3K, EGFR, SREBP-1, INSIG-1, SQLE, SP1/SREBPF2 nuclear fractionation, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway components assessed by Western blot and subcellular fractionation, single lab\",\n      \"pmids\": [\"34518524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LPCAT1 is identified as a transcriptional target of nuclear respiratory factor 1 (NRF1) in hepatocellular carcinoma. NRF1 transactivates LPCAT1, which in turn activates ERK1/2-CREB signaling, and activated CREB then further upregulates NRF1, forming a positive feedback loop that promotes HCC cell cycle progression and EMT.\",\n      \"method\": \"ChIP/luciferase reporter assay for NRF1-LPCAT1 transcriptional activation, Western blot for ERK1/2-CREB, knockdown/overexpression, in vitro and in vivo assays\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation validated by ChIP and reporter, pathway activation by Western blot, single lab\",\n      \"pmids\": [\"37875967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LPCAT1 forms a positive feedback loop with EGFR in lung adenocarcinoma: LPCAT1 upregulation activates EGFR/PI3K/AKT signaling, and EGFR activation in turn further increases LPCAT1 expression, conferring gefitinib resistance.\",\n      \"method\": \"LPCAT1 knockdown/overexpression, gefitinib resistance assay, Western blot for EGFR/PI3K/AKT, in vivo and in vitro functional assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — positive feedback loop demonstrated by gain/loss-of-function with pathway markers, single lab\",\n      \"pmids\": [\"35399731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LPCAT1 regulates cervical cancer progression through the JAK2/STAT3 signaling pathway. LPCAT1 knockdown decreased IL-6, p-JAK2, and p-STAT3 levels, and exogenous IL-6 addition abolished the anti-proliferative and pro-apoptotic effects of LPCAT1 knockdown, establishing IL-6/JAK2/STAT3 as downstream of LPCAT1.\",\n      \"method\": \"siRNA knockdown, RNA-seq, Western blot for p-JAK2/p-STAT3/IL-6, exogenous IL-6 rescue, xenograft and lung metastasis model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IL-6 rescue experiment establishes pathway placement; RNA-seq plus Western blot, single lab\",\n      \"pmids\": [\"36122769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXA1 transcriptionally regulates LPCAT1 in breast cancer, as demonstrated by luciferase reporter and chromatin immunoprecipitation assays. FOXA1 overexpression attenuated the effects of LPCAT1 knockdown on cell proliferation, colony formation, migration, invasion, and paclitaxel resistance.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), LPCAT1 knockdown, FOXA1 overexpression rescue\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with functional rescue, single lab\",\n      \"pmids\": [\"36909375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LPCAT1 overexpression changes phospholipid composition (PE, PC, TG) in endometrial cancer cells and promotes stemness and metastasis through activation of the TGF-β/Smad2/3 signaling pathway, upregulating stem cell transcription factors and EMT-related proteins. The LPCAT1 inhibitor TSI-01 restrained EC cell proliferation and promoted apoptosis.\",\n      \"method\": \"LPCAT1 knockdown/overexpression, lipidomics, RNA sequencing, Western blot for Smad2/3, TSI-01 pharmacological inhibition\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipidomics plus RNA-seq and Western blot with pharmacological inhibition, single lab\",\n      \"pmids\": [\"35880567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HECTD2, a HECT-domain E3 ubiquitin ligase, co-immunoprecipitates with ubiquitinated LPCAT1 and drives LPCAT1 polyubiquitination and degradation. LPCAT1 overexpression rescued CRC cell proliferation impaired by HECTD2 overexpression, placing HECTD2 as an upstream negative regulator of LPCAT1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, HECTD2 and LPCAT1 overexpression, cell proliferation rescue assay\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP/ubiquitination assay, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"35964314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-205 directly targets LPCAT1 in multiple cancer cell lines (LIHC, HNSCC, LUSC), and LPCAT1 is required for sustained cancer cell proliferation downstream of miR-205 suppression.\",\n      \"method\": \"miR-205 stable overexpression, luciferase/target validation (implied), cell proliferation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — miRNA-target relationship and proliferation assay, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"32334831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROBO4 deletion reduces LPCAT1 (and LPCAT2) protein levels in macrophages without affecting mRNA levels, by decreasing ribosome abundance and ATP levels, which impairs LPCAT1/LPCAT2 mRNA translation efficiency (shown by polyribosome assay). This reduces PAF synthesis and PAF-mediated skin inflammation.\",\n      \"method\": \"ROBO4 knockout mouse model, polyribosome assay, Western blot, HPLC for ATP, RNA expression profiling\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polyribosome assay directly demonstrates translational regulation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32140075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MNRR1 (mitochondrial nuclear retrograde regulator 1), a bi-organellar transcription regulator, transcriptionally activates LPCAT1. Dexamethasone (antenatal corticosteroids) upregulates LPCAT1 at least in part through an MNRR1-dependent pathway; in MNRR1 knockout cells, the response of LPCAT1 to dexamethasone is significantly blunted.\",\n      \"method\": \"MNRR1 knockout cells, dexamethasone treatment, Western blot for LPCAT1, hypoxia treatment (4% O2), placental cell line (HTR-8/SVneo)\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MNRR1 KO rescue experiment demonstrates transcriptional dependence; single lab, single model\",\n      \"pmids\": [\"33618181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LPCAT1 increases membrane phospholipid saturation via the Lands cycle, reducing membrane polyunsaturated fatty acid (PUFA) levels, thereby protecting cells from phospholipid peroxidation-induced membrane damage and enabling ferroptosis resistance. LPCAT1 inhibition combined with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumor growth in vivo.\",\n      \"method\": \"LPCAT1 gain/loss-of-function, lipidomics for membrane PUFA content, ferroptosis induction assays, in vivo tumor growth assay, combination treatment\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic lipidomics demonstrating PUFA reduction through Lands cycle, multiple functional assays in vitro and in vivo, published in high-quality journal\",\n      \"pmids\": [\"38671262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF-2α directly binds to the LPCAT1 promoter and transcriptionally activates LPCAT1 in ccRCC. LPCAT1 knockdown activates NF-κB signaling, which upregulates FBXW7 (an E3 ubiquitin ligase); FBXW7 then promotes ubiquitination and degradation of ACLY, lowering fatty acid production and reducing lipid content. RNA-seq and lipidomics confirmed that LPCAT1 knockdown significantly reduced triglyceride production.\",\n      \"method\": \"ChIP/promoter binding assay for HIF-2α-LPCAT1, RNA-seq, lipidomics, NF-κB pathway Western blot, FBXW7-ACLY co-immunoprecipitation and ubiquitination assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, lipidomics, and Co-IP for downstream ubiquitination, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39781455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRK2 inhibits RBX1-mediated proteasomal degradation of LPCAT1, thereby stabilizing LPCAT1 protein in ccRCC. LRRK2/LPCAT1 upregulation promotes IL-1β expression through AKT and by activating the inflammasome, reducing sensitivity to TKI and PD-1 blockade.\",\n      \"method\": \"Protein degradation assay, co-immunoprecipitation with RBX1, Western blot for LPCAT1 stability, AKT/inflammasome pathway analysis, PROTAC targeting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP with degradation mechanism and pathway assays, single lab\",\n      \"pmids\": [\"40121376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ppGalNAc-T18 (GALNT18) retains in the ER through its luminal stem region and catalytic domain interacting with ER resident proteins including LPCAT1, as shown by co-immunoprecipitation. This identifies LPCAT1 as an ER-resident protein involved in ER retention interactions.\",\n      \"method\": \"Co-immunoprecipitation with truncation mutants of ppGalNAc-T18, flow cytometry for O-glycosylation\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP showing LPCAT1 as ER-resident binding partner; not the primary focus, limited mechanistic follow-up for LPCAT1 itself\",\n      \"pmids\": [\"33909026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LPCAT1 promotes OPC differentiation into oligodendrocytes by activating mTOR phosphorylation (not through increased PC production per se). LPCAT1 upregulates the transcription factor ZBTB20, which regulates mTOR phosphorylation. In vivo, conditional knockout of LPCAT1 in oligodendrocyte lineage cells caused complex myelin tomacula but no obvious myelin thickness abnormalities.\",\n      \"method\": \"LPCAT1 overexpression and siRNA knockdown in OPC cultures, RNA sequencing, Western blot for p-mTOR, in vivo conditional knockout, OPC differentiation assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus Western blot for mTOR with in vivo KO phenotype; single lab, mechanistic pathway partially established\",\n      \"pmids\": [\"39878319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LPCAT1 promotes keratinocyte hyperproliferation and skin inflammation in psoriasis by activating AKT/NF-κB and STAT3 signaling, which in turn upregulates glucose transporter GLUT3. GLUT3 deficiency impaired proliferation and inflammation of psoriatic keratinocytes, establishing GLUT3 as a critical downstream effector of LPCAT1.\",\n      \"method\": \"LPCAT1 gain/loss-of-function, siRNA for GLUT3, NF-κB and STAT3 pathway inhibition, imiquimod mouse model, cytokine ELISA, GLUT3 rescue assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments with GLUT3 KD and signaling pathway inhibitors, in vivo mouse model, single lab\",\n      \"pmids\": [\"38246582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX2 transcriptionally activates LPCAT1 in osteosarcoma (validated by dual-luciferase reporter and ChIP assays). LPCAT1 overexpression promoted cholesterol metabolism reprogramming (free cholesterol/total cholesterol levels, SREBP1/INSIG1), proliferation, migration and invasion; LPCAT1 knockdown attenuated SOX2-driven oncogenicity in vitro and in vivo.\",\n      \"method\": \"Dual-luciferase reporter, ChIP, LPCAT1 and SOX2 overexpression/knockdown, cholesterol measurement, xenograft and lung metastasis model\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter for transcriptional regulation plus functional epistasis, single lab\",\n      \"pmids\": [\"41358198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM33 directly interacts with LPCAT1 and promotes its ubiquitination and proteasomal degradation. TRIM33 overexpression inhibited LPCAT1-driven PI3K/AKT activation and glycolysis, reversing cisplatin resistance in NSCLC cells in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM33 and LPCAT1 overexpression/knockdown, PI3K/AKT Western blot, glycolysis assay, xenograft model\",\n      \"journal\": \"World journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with ubiquitination assay and pathway/functional rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42147264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATF2, activated by the p38 MAPK pathway in response to cholesterol loading, transcriptionally upregulates LPCAT1. LPCAT1 in turn promotes acetylation of PKM2 at K433, exacerbating cholesterol-induced metabolic disorders and inflammation in macrophages. K433 mutations ameliorated these effects, establishing the p38-ATF2-LPCAT1-PKM2 axis.\",\n      \"method\": \"p38 MAPK inhibition, ATF2 knockdown, LPCAT1 knockdown, PKM2-K433 mutagenesis, metabolic and inflammatory assays in cholesterol-loaded macrophages\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of PKM2 acceptor site and genetic epistasis across pathway, single lab\",\n      \"pmids\": [\"41740546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AT2 cell-specific Lpcat1 deletion in mice resulted in reduced AT2 cell renewal, spontaneous lung fibrosis, and heightened susceptibility to bleomycin-induced fibrosis in vivo. Pharmacologically, artesunate and PLA2 inhibitor ONO-RS-082 increased LPCAT1 mRNA expression, promoted AT2 renewal, and attenuated bleomycin-induced fibrosis, confirming that LPCAT1 is required for AT2 progenitor renewal through PC metabolism.\",\n      \"method\": \"AT2 cell-specific conditional knockout, 3D organoid AT2 renewal assay, bleomycin fibrosis model, pharmacological LPCAT1 upregulation, LPCAT1 knock-in cell line drug screening\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with organoid and in vivo functional readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Microbiota-derived lithocholic acid (LCA) directly activates LPCAT1, upregulating its expression. LPCAT1 overexpression leads to intestinal barrier dysfunction and promotes colonic inflammation via activation of MMP1. LPCAT1 inhibition ameliorated intestinal barrier dysfunction, diarrhea symptoms, and colonic inflammation in LCA-treated mice and experimental colitis models.\",\n      \"method\": \"LCA treatment in mice and cell culture, LPCAT1 knockdown/overexpression, MMP1 pathway analysis, in vivo intestinal barrier assays, colitis mouse model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — mechanism of LCA-LPCAT1-MMP1 axis stated but mechanistic detail (e.g., direct binding) is limited in abstract; preprint only\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LPCAT1 is an endoplasmic reticulum-resident acyltransferase that catalyzes Ca2+-independent, palmitate-preferring reacylation of lysophosphatidylcholine to phosphatidylcholine (and lyso-PAF to alkyl-PC) in the Lands cycle, with activity negatively regulated by Ca2+ binding to a C-terminal EF-hand motif and by cellular redox status; in lung alveolar type II cells it forms a complex with StarD10 to traffic saturated PC to lamellar bodies for surfactant production, and its protein stability is controlled by GSK-3β-mediated phosphorylation at Ser178 and subsequent β-TrCP/proteasomal degradation; in addition, LPCAT1 translocates to the nucleus in response to Ca2+ to catalyze O-palmitoylation of histone H4 at Ser47, thereby regulating global mRNA synthesis, and its transcription is activated by HIF-2α, NRF1, SOX2, FOXA1, and MNRR1, while HECTD2, TRIM33, and RBX1 (countered by LRRK2) promote its ubiquitination and degradation; through membrane phospholipid saturation via the Lands cycle, LPCAT1 reduces polyunsaturated fatty acid content and confers ferroptosis resistance in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LPCAT1 is an endoplasmic reticulum-resident, Ca2+-independent acyltransferase that drives the reacylation arm of the Lands cycle, converting lysophosphatidylcholine to phosphatidylcholine with a strong preference for saturated palmitoyl-CoA and additionally producing alkyl-PC from lyso-PAF [#0, #2, #3]. Its catalytic output is governed by an N-terminal acyltransferase activity that is negatively regulated by Ca2+ binding to a C-terminal EF-hand (residues Asp392/Glu403) and by the cellular redox state of an active-site cysteine [#6]. In lung alveolar type II cells LPCAT1 is required for synthesis of surfactant saturated PC, and its loss causes neonatal respiratory failure with atelectasis and surfactant dysfunction [#1]; the enzyme partners with the phospholipid transfer protein StarD10 (via LPCAT1 residues 79\\u2013271 and the START domain) to traffic saturated PC from the ER to lamellar bodies, and AT2-specific deletion impairs progenitor renewal and predisposes to lung fibrosis [#8, #31]. Beyond bulk lipid synthesis, LPCAT1 translocates to the nucleus in response to Ca2+, where it binds histone H4 and catalyzes O-palmitoylation at Ser47 to control global mRNA synthesis [#4]. LPCAT1 abundance is set post-translationally by ubiquitin-dependent degradation: GSK-3\\u03b2 phosphorylates a Ser178 phosphodegron to license SCF-\\u03b2-TrCP-mediated polyubiquitination at Lys221 [#5]. Through these activities LPCAT1 acts broadly in disease, and genetically its loss directly causes rd11 photoreceptor degeneration, rescued by AAV-mediated cDNA delivery [#7]. In cancer, LPCAT1 increases membrane phospholipid saturation to deplete polyunsaturated fatty acids and confer ferroptosis resistance [#22], and across multiple tumor types it activates PI3K/AKT and downstream growth and metabolic programs [#9, #12, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the core biochemical identity of LPCAT1 \\u2014 what reaction it catalyzes and with what substrate selectivity \\u2014 defining it as the Lands-cycle reacylation enzyme.\",\n      \"evidence\": \"cDNA cloning and heterologous expression in CHO cells with in vitro acyltransferase assay and tissue profiling\",\n      \"pmids\": [\"16704971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the catalytic site\", \"Did not address regulation or in vivo requirement\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localized LPCAT1 activity to the ER (and mitochondria) and confirmed it drives palmitate incorporation into PC in cells, anchoring the enzyme to a membrane compartment.\",\n      \"evidence\": \"Overexpression in COS7 with subcellular fractionation and radiolabeled palmitate incorporation\",\n      \"pmids\": [\"18974965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial localization not independently confirmed\", \"Overexpression artifact possible\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended LPCAT1 substrate scope to lyso-PAF, showing it both generates anti-inflammatory PC and inactivates the pro-inflammatory lipid mediator PAF.\",\n      \"evidence\": \"Acyltransferase assays with lyso-PAF/LPC and diabetic mouse retina/brain models\",\n      \"pmids\": [\"19773578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of LPCAT1 loss in diabetic neuropathy not tested by genetic LOF\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated the physiological requirement for LPCAT1 in surfactant PC homeostasis and identified its post-translational control by ubiquitin-dependent degradation.\",\n      \"evidence\": \"Hypomorphic gene-trap mice with surfactant assays; co-IP, phosphodegron/ubiquitin-site mutagenesis (S178, K221) and rescue by GSK-3\\u03b2/\\u03b2-TrCP knockdown\",\n      \"pmids\": [\"20407208\", \"21068446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other E3 ligases not yet defined\", \"Trigger linking inflammation to GSK-3\\u03b2 activation incompletely mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an unexpected nuclear, chromatin-modifying function: Ca2+-triggered nuclear LPCAT1 palmitoylates histone H4 at Ser47 to regulate global mRNA synthesis.\",\n      \"evidence\": \"Subcellular fractionation, co-IP with H4, H4-S47A mutagenesis, knockdown and mRNA synthesis assay\",\n      \"pmids\": [\"21685381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a lipid acyltransferase reads/writes a serine residue mechanistically unresolved\", \"Genome-wide consequences not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the regulatory architecture of the enzyme \\u2014 a C-terminal EF-hand confers Ca2+ inhibition of the N-terminal catalytic domain, and a cysteine confers redox sensitivity.\",\n      \"evidence\": \"Site-directed mutagenesis (D392A/E403A), Ca2+ titration and sulfhydryl-modifier assays in vitro\",\n      \"pmids\": [\"22676268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological Ca2+ concentrations triggering inhibition not established\", \"No crystal structure of the regulated enzyme\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided causal genetic proof that LPCAT1 loss of function drives photoreceptor degeneration, distinct from its lung role.\",\n      \"evidence\": \"AAV8-mediated Lpcat1 cDNA rescue in rd11 mice with ERG, OCT, IHC and behavioral readouts\",\n      \"pmids\": [\"24557352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific retinal lipid species rescued not defined\", \"Human retinal disease relevance untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the trafficking partner that couples LPCAT1 PC synthesis to surfactant delivery, placing it at the ER-to-lamellar-body step.\",\n      \"evidence\": \"Reciprocal co-IP/pulldown with domain mapping (LPCAT1 79\\u2013271, StarD10 START) and StarD10 knockdown trafficking assay\",\n      \"pmids\": [\"26048993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether interaction directly hands off lipid vs. co-localizes not resolved\", \"Stoichiometry of complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Initiated the body of evidence that LPCAT1 acts as an oncogenic driver through PI3K/AKT signaling and downstream transcriptional targets.\",\n      \"evidence\": \"shRNA depletion with in vitro and in vivo brain-metastasis models, RNA-seq and pathway-activator rescue\",\n      \"pmids\": [\"30791942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity is required for PI3K/AKT effect not separated from scaffolding\", \"Direct link from lipid output to MYC unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a dense transcriptional and post-translational regulatory network controlling LPCAT1 levels across tissues, and linked LPCAT1 to multiple cancer signaling pathways.\",\n      \"evidence\": \"ChIP/reporter (NRF1, SOX2, MNRR1), translational control (ROBO4 polyribosome assay), E3 ligase co-IP/ubiquitination (HECTD2), miR-205 targeting, and STAT/PI3K pathway assays across HCC, OS, macrophage and other models\",\n      \"pmids\": [\"34178664\", \"34518524\", \"37875967\", \"35964314\", \"32334831\", \"32140075\", \"33618181\", \"41358198\", \"33909026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many regulators tested in single cell types only\", \"HECTD2 and miR-205 links rest on limited mechanistic follow-up\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened LPCAT1's disease reach to additional cancers and tissues via shared PI3K/AKT, STAT3, and TGF-\\u03b2 effector programs and drug-resistance phenotypes.\",\n      \"evidence\": \"Gain/loss-of-function with pathway markers, lipidomics, IL-6 and EGFR rescue, FOXA1 ChIP, and pharmacological inhibition (TSI-01) across LUAD, cervical, breast, endometrial models\",\n      \"pmids\": [\"35399731\", \"36122769\", \"36909375\", \"35880567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific effectors (GLUT3, JAK2, Smad) reported in isolation\", \"Catalytic vs. non-catalytic contribution often untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Unified LPCAT1's lipid biochemistry with a major cancer phenotype by showing it depletes membrane PUFAs to confer ferroptosis resistance, and added a hypoxia-driven transcriptional/metabolic axis.\",\n      \"evidence\": \"Gain/loss-of-function with membrane lipidomics, ferroptosis induction and combination therapy in vivo; HIF-2\\u03b1 ChIP with RNA-seq, lipidomics and FBXW7-ACLY ubiquitination assays\",\n      \"pmids\": [\"38671262\", \"39781455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the EF-hand/redox regulation modulates ferroptosis output untested\", \"FBXW7-ACLY arm characterized in single model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated tissue-progenitor and stability-regulation roles \\u2014 AT2 renewal, oligodendrocyte differentiation, and LRRK2/RBX1 control of LPCAT1 protein stability.\",\n      \"evidence\": \"Conditional knockouts and organoid assays (lung AT2, oligodendrocyte lineage), ZBTB20/mTOR Western blot, and RBX1 co-IP/degradation assays with PROTAC targeting\",\n      \"pmids\": [\"39878319\", \"40121376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AT2 fibrosis finding is preprint and not peer-reviewed\", \"Oligodendrocyte effect reported as PC-independent, leaving the mediating activity unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added further substrate/effector relationships \\u2014 TRIM33-mediated degradation and an ATF2-LPCAT1-PKM2 acetylation axis \\u2014 expanding LPCAT1's regulatory inputs and metabolic outputs.\",\n      \"evidence\": \"Co-IP/ubiquitination (TRIM33), PKM2-K433 mutagenesis and epistasis in cholesterol-loaded macrophages, with pathway and xenograft assays\",\n      \"pmids\": [\"42147264\", \"41740546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which an acyltransferase promotes PKM2 acetylation unresolved\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LPCAT1's distinct activities \\u2014 ER bulk PC synthesis, nuclear histone palmitoylation, and PUFA-depleting ferroptosis resistance \\u2014 are coordinated within a cell, and whether its catalytic activity is required for the many reported PI3K/AKT signaling effects, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length human LPCAT1\", \"Catalytic vs. scaffolding requirement for oncogenic signaling not systematically dissected\", \"Mechanism switching cytosolic vs. nuclear localization beyond Ca2+ unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 8, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 22, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"LPCAT1-StarD10 complex\"],\n    \"partners\": [\"STARD10\", \"GSK3B\", \"BTRC\", \"HIST1H4 (histone H4)\", \"STAT1\", \"HECTD2\", \"TRIM33\", \"RBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}