{"gene":"SQLE","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1997,"finding":"Human SQLE was mapped to chromosome 8q24.1 by PCR on somatic cell hybrid panels and FISH, and was shown to be transcriptionally regulated by sterols and cholesterol synthesis inhibitors.","method":"PCR on somatic cell hybrid panel, radiation hybrid panel, fluorescence in situ hybridization (FISH), transcriptional regulation assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mapping methods (somatic cell hybrids, radiation hybrid, FISH); transcriptional regulation noted but mechanistic detail in abstract is limited","pmids":["9286711"],"is_preprint":false},{"year":2017,"finding":"The human SQLE promoter contains two sterol-regulatory elements (SREs) and two NF-Y binding sites that mediate SREBP-2-dependent transcriptional activation of SQLE in response to sterol deprivation.","method":"Luciferase reporter assays with SRE/NF-Y site mutants, electrophoretic mobility shift assay (EMSA), ChIP-PCR","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (luciferase mutagenesis screen, EMSA, ChIP-PCR) in a single rigorous study definitively mapping functional sites","pmids":["28342963"],"is_preprint":false},{"year":2018,"finding":"MARCH6 (an E3 ubiquitin ligase) promotes cholesterol-stimulated ubiquitylation and proteasomal degradation of SQLE, and UBE2J2 (not UBE2G2) is the primary E2 ubiquitin-conjugating enzyme required for this MARCH6-dependent SQLE degradation in mammalian cells, including hepatic cells.","method":"CRISPR/Cas9 screen of ERAD-associated E2 enzymes, protein stability assays, enzymatic activity-dependent rescue experiments in multiple human cell lines","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale CRISPR screen followed by targeted validation in multiple cell types with enzymatic activity mutant controls; single lab but multiple orthogonal methods","pmids":["30658189"],"is_preprint":false},{"year":2019,"finding":"Sensitivity to SQLE inhibition in a subset of neuroendocrine tumors (particularly small cell lung cancer) results from toxic accumulation of the SQLE substrate squalene, not from downstream cholesterol biosynthesis inhibition.","method":"Chemical biology screen, orthogonal metabolic and cell viability assays, squalene accumulation measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (chemical screen, metabolic tracing, cell biology) established the squalene-accumulation mechanism in a single rigorous study","pmids":["30626880"],"is_preprint":false},{"year":2019,"finding":"OSBPL2 deletion upregulates SQLE expression via suppression of the AMPK signaling pathway, which leads to increased SP1 and SREBF2 nuclear entry and binding to functional sites in the SQLE promoter, resulting in elevated intracellular cholesterol and cholesteryl ester.","method":"CRISPR/Cas9 OSBPL2 knockout HeLa cells, RNA-seq, dual-luciferase reporter assay, AMPK pathway inhibitor experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO combined with luciferase reporter and pathway inhibition; single lab, multiple methods","pmids":["31356817"],"is_preprint":false},{"year":2020,"finding":"MARCH6 promotes degradation of SQLE in endothelial cells to regulate cholesterol load; loss of MARCH6 increases SQLE protein and cholesterol, altering membrane order, disorganizing VE-cadherin-based adherens junctions, and impairing angiogenic sprouting.","method":"siRNA/shRNA knockdown of MARCHF6 and SQLE, cholesterol measurements, membrane order assays, barrier function assays, endothelial sprouting assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with multiple functional readouts (cholesterol, membrane order, barrier function, sprouting) establishing MARCH6-SQLE axis","pmids":["32755570"],"is_preprint":false},{"year":2021,"finding":"p53 directly represses SQLE transcription in a SREBP2-independent manner under normal sterol conditions, thereby reducing cholesterol production and suppressing tumor growth; SQLE inhibition reverses the increased cell proliferation caused by p53 deficiency.","method":"Transcriptional reporter assays, siRNA/shRNA knockdown, terbinafine inhibitor studies, in vivo mouse NAFLD tumorigenesis model with p53 KO","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KD, pharmacological inhibition, in vivo tumor model) establishing p53-SQLE axis with functional rescue experiments","pmids":["34459531"],"is_preprint":false},{"year":2021,"finding":"MYC directly transcriptionally upregulates SQLE, thereby increasing cholesterol biosynthesis and promoting tumor cell proliferation; SQLE overexpression restores cholesterol levels in MYC-knockdown cells, and enforced MYC expression has no effect on cholesterol in SQLE-depleted cells.","method":"MYC knockdown/overexpression, SQLE overexpression rescue, cholesterol measurements, epistasis experiments","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments (MYC KD + SQLE OE) with cholesterol readout; single lab, genetic approach with clear pathway placement","pmids":["33791309"],"is_preprint":false},{"year":2021,"finding":"miR-205 directly targets SQLE mRNA to repress its expression and inhibit de novo cholesterol biosynthesis in prostate cancer; inhibition of SQLE blocks AR pathway transactivation and suppresses tumor growth in vivo.","method":"miR-205 restoration, SQLE competitive inhibition with terbinafine, cholesterol biosynthesis assays, in vivo orthotopic tumor model, patient PSA measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic miRNA restoration, pharmacological SQLE inhibition, in vivo mouse model, human patient data) with consistent mechanistic findings","pmids":["34417456"],"is_preprint":false},{"year":2022,"finding":"Polyphyllin I (PPI) directly binds SQLE protein (not HMGCR), disrupting the SREBP-2/HMGCR/SQLE/lanosterol synthase cholesterol biosynthesis pathway and inducing hepatotoxicity.","method":"Pull-down assay, surface plasmon resonance (SPR), molecular docking, siRNA knockdown and overexpression of HMGCR and SQLE, proteomics/transcriptomics","journal":"Journal of pharmaceutical analysis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding confirmed by biophysical SPR and pull-down with functional pathway validation; single lab but multiple orthogonal biochemical methods","pmids":["36820075"],"is_preprint":false},{"year":2023,"finding":"SQLE inhibition in pancreatic cancer cells leads to squalene accumulation that inhibits CXCL1 transcription via the NF-κB/p65 pathway, reducing recruitment of MDSCs and TAMs and increasing CD8+ T cell infiltration in the tumor microenvironment.","method":"SQLE knockdown in immune-competent mouse model, squalene administration in vivo, flow cytometry of immune cells, RNA-sequencing, RT-PCR/Western blot for NF-κB pathway","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo immune-competent model with direct squalene administration and mechanistic NF-κB pathway analysis; single lab, multiple methods","pmids":["39763673"],"is_preprint":false},{"year":2023,"finding":"SQLE promotes pancreatic cancer growth through two mechanisms: (1) its inhibition causes squalene accumulation-induced ER stress and apoptosis; (2) SQLE-mediated cholesterol biosynthesis maintains lipid raft stability, activating the Src/PI3K/Akt signaling pathway.","method":"siRNA knockdown, SQLE inhibitors, ER stress markers, lipid raft fractionation, Src/PI3K/Akt pathway analysis, xenograft tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual mechanism tested by KD, lipid raft fractionation, and in vivo xenograft; single lab with multiple readouts","pmids":["37542052"],"is_preprint":false},{"year":2023,"finding":"p53 suppresses SQLE expression via induction of miR-205, which directly targets SQLE mRNA; c-MYC induces SQLE expression directly and via its transcriptional target AP4/TFAP4, which directly binds the SQLE promoter; loss of AP4 causes resistance to terbinafine.","method":"miR-205 target validation, AP4/TFAP4 transcriptional reporter assays, AP4 knockdown/overexpression, cholesterol measurements, terbinafine sensitivity assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (p53→miR-205→SQLE and MYC→AP4→SQLE) with luciferase validation and functional rescue; single lab","pmids":["37705742"],"is_preprint":false},{"year":2024,"finding":"Doa10/MARCH6 adopts a unique circular transmembrane structure with a lipid-binding scaffold and gated helical bundle; the RING domain is positioned over the membrane channel, and SQLE degradation requires interconnected channel, RING domain, and lipid-binding elements, revealing how metabolic signals, substrate binding, and E3 ligase activity are coupled.","method":"Cryo-EM structural analysis, AlphaFold predictions, structure-based mutagenesis campaign (95 MARCH6 variants), SQLE stability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with large-scale mutagenesis (95 variants) and functional SQLE degradation assays in a single rigorous study","pmids":["38195637"],"is_preprint":false},{"year":2024,"finding":"KDM4A histone demethylase demethylates H3K9me3 at the SQLE gene locus, opening chromatin to allow GABPA transcription factor binding and SQLE transcriptional activation; KDM4A inhibition downregulates SQLE, blocks cholesterol synthesis, causes squalene accumulation, suppresses JNK/c-Jun phosphorylation via ROS, and induces apoptosis in bladder cancer.","method":"KDM4A inhibitor (ML324) drug screening in tumor organoids, ChIP assays for H3K9me3 and GABPA, SQLE knockdown, ROS measurements, JNK/c-Jun pathway analysis, PDX models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating H3K9me3 demethylation and GABPA accessibility at SQLE promoter with functional pathway readout; single lab, multiple methods","pmids":["39461328"],"is_preprint":false},{"year":2024,"finding":"SQLE localizes to mitochondria and directly interacts with LONP1 (Lon peptidase 1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial ROS production in bladder cancer cells.","method":"Subcellular fractionation/localization studies, co-immunoprecipitation of SQLE-LONP1 interaction, TFAM stability assays, OXPHOS and mitochondrial ROS measurements, Sqle transgenic and knockout mouse models, Mito-TEMPO rescue experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct SQLE-LONP1 interaction by Co-IP, mitochondrial localization with functional consequence, transgenic/KO mouse models, and pharmacological rescue; single lab, multiple orthogonal methods","pmids":["41254141"],"is_preprint":false},{"year":2024,"finding":"SQLE-mediated removal of squalene promotes mitochondrial biogenesis via a non-cholesterol mechanism: squalene accumulation binds Sp1 protein and forms a tight Sp1-TFAP2E promoter complex, suppressing TFAP2E and downstream PGC-1α expression, thereby inhibiting mitochondrial metabolism and tumor formation.","method":"SQLE silencing, squalene direct administration in vivo, Sp1-DNA binding analysis (binding score calculation), TFAP2E/PGC-1α expression assays, xenograft tumor model, pharmacological squalene administration","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — squalene/Sp1/TFAP2E promoter complex characterized with in vivo rescue by squalene administration; single lab, functional in vivo validation","pmids":["40015662"],"is_preprint":false},{"year":2025,"finding":"H. pylori CagA upregulates SQLE expression, and elevated SQLE activity increases cellular palmitoyl-CoA levels, which enhances PD-L1 palmitoylation while decreasing its ubiquitination, thereby stabilizing PD-L1 and suppressing T cell activity to facilitate immune evasion.","method":"CagA overexpression, SQLE manipulation, palmitoyl-CoA measurement, PD-L1 palmitoylation and ubiquitination assays, T cell activity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain (CagA→SQLE→palmitoyl-CoA→PD-L1 palmitoylation) supported by biochemical PTM assays; single lab","pmids":["39809787"],"is_preprint":false},{"year":2025,"finding":"HDAC2-dependent delactylation of PD-L1 at K189 promotes vimentin-mediated nuclear translocation of PD-L1, which then upregulates SQLE transcription via the transcription factor YY1, thereby accelerating cholesterol production and liver cancer growth.","method":"PD-L1 lactylation site mapping, p300 acetyltransferase activity assays, HDAC2 deacylation assays, nuclear fractionation, YY1 ChIP/reporter assays for SQLE promoter, in vitro and in vivo tumor growth assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical PTM characterization (lactylation/delactylation) linked to nuclear PD-L1 transcriptional regulation of SQLE via YY1; single lab, multiple methods","pmids":["40614853"],"is_preprint":false},{"year":2025,"finding":"NSUN2 increases m5C modification of SQLE mRNA, stabilizing it and increasing SQLE expression in endothelial cells; elevated SQLE increases intracellular cholesterol, which promotes endothelial cell activation via the PI3K-AKT signaling pathway in diabetic retinopathy.","method":"NSUN2 knockdown/overexpression, m5C modification assays, SQLE mRNA stability measurements, cholesterol quantification, PI3K-AKT pathway analysis, tube formation and endothelial activation assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m5C modification experimentally linked to SQLE mRNA stability and downstream signaling; single lab, multiple orthogonal methods","pmids":["40536094"],"is_preprint":false},{"year":2025,"finding":"NAT10 acts as an upstream activator of SQLE-dependent cholesterol biosynthesis through two mechanisms: (1) activation of AKT/mTOR signaling leading to SQLE upregulation, and (2) ac4C modification of SQLE mRNA to enhance its stability.","method":"Multi-omics dataset analysis, AKT/mTOR pathway manipulation, ac4C mRNA modification assays, SQLE mRNA stability measurements, in vitro and in vivo cholesterol and tumor growth assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual mechanism (signaling pathway + RNA modification) supported by biochemical ac4C assays and functional in vivo data; single lab","pmids":["41550764"],"is_preprint":false},{"year":2025,"finding":"SP1 directly binds to the SQLE promoter and activates its transcription, as demonstrated in the context of SERPINH1/SENP3 signaling in hepatocellular carcinoma.","method":"ChIP-qPCR assay demonstrating SP1 binding to SQLE promoter, SP1 inhibitor (plicamycin) rescue experiments","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct SP1 occupancy at SQLE promoter demonstrated by ChIP-qPCR with functional inhibitor rescue; single lab","pmids":["39946769"],"is_preprint":false},{"year":2025,"finding":"SQLE-produced intermediate metabolite 2,3-oxidosqualene interacts with vinculin to enhance nuclear accumulation of YAP1, increasing YAP/TEAD-dependent gene expression and accelerating tumor growth and metastasis in esophageal squamous cell carcinoma.","method":"Whole genome sequencing of ESCC cohorts, metabolite-protein interaction studies (2,3-oxidosqualene/vinculin), YAP nuclear localization assays, in vivo 4-NQO mouse ESCC model with SQLE overexpression","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolite-protein interaction linked to YAP nuclear translocation with in vivo mouse model validation; single lab","pmids":["39924077"],"is_preprint":false},{"year":2025,"finding":"SQLE inhibition in hepatocellular carcinoma tumor cells suppresses oxysterol (27-hydroxycholesterol) secretion, overcoming cholesterol restrictions on CD8+ T cells via oxysterol-SREBP2 signaling and enhancing antitumor immunity; terbinafine synergizes with anti-PD1 therapy in HCC mouse models.","method":"Pharmacological SQLE inhibition and genetic knockdown, co-culture experiments of tumor cells and T cells, untargeted metabolomics identifying 27-hydroxycholesterol, transcriptome analysis, murine HCC models with anti-PD1 combination therapy","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics identified oxysterol mechanism with co-culture functional validation and in vivo combination therapy; single lab","pmids":["41005980"],"is_preprint":false},{"year":2025,"finding":"Ginsenoside 20(S)-Rg3 upregulates SQLE expression by downregulating HIF-1α, and SQLE interacts with FDFT1 (farnesyl-diphosphate farnesyltransferase 1) as confirmed by co-immunoprecipitation.","method":"Co-immunoprecipitation of SQLE-FDFT1 interaction, HIF-1α/SQLE axis manipulation, transcriptomic and lipidomic analysis, SQLE silencing rescue experiments","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying SQLE-FDFT1 interaction without deeper mechanistic characterization of the interaction's functional consequence; single lab","pmids":["40792023"],"is_preprint":false}],"current_model":"SQLE (squalene epoxidase) is the second rate-limiting enzyme in cholesterol biosynthesis, catalyzing conversion of squalene to 2,3-oxidosqualene; its expression is transcriptionally activated by SREBP-2 via two promoter SREs, repressed by p53 (directly and via miR-205), and induced by MYC and its target AP4; post-translationally, SQLE is ubiquitylated by the MARCH6 E3 ligase (using UBE2J2 as its E2) and degraded via ERAD in response to cholesterol excess; beyond cholesterol synthesis, SQLE localizes to mitochondria where it stabilizes TFAM by interacting with LONP1 to drive oxidative phosphorylation, and its substrate squalene acts as a bioactive metabolite that suppresses immune cell infiltration via NF-κB/CXCL1, inhibits PGC-1α-mediated mitochondrial biogenesis via Sp1/TFAP2E, and SQLE's product 2,3-oxidosqualene activates YAP/TEAD signaling via vinculin."},"narrative":{"mechanistic_narrative":"SQLE (squalene epoxidase) is the second rate-limiting enzyme of cholesterol biosynthesis, converting squalene to 2,3-oxidosqualene, and its activity sits at a node where transcriptional control, substrate/product signaling, and protein turnover converge to govern sterol levels, membrane biology, and tumor growth [PMID:28342963, PMID:30626880]. Its transcription is activated upon sterol deprivation by SREBP-2 acting through two promoter sterol-regulatory elements with adjacent NF-Y sites [PMID:28342963], and is further controlled by an extensive regulatory network: MYC induces SQLE directly and through its target AP4/TFAP4 [PMID:33791309, PMID:37705742], SP1 binds and activates the promoter [PMID:39946769], and KDM4A-mediated H3K9me3 demethylation opens the locus to permit GABPA binding [PMID:39461328], while p53 represses SQLE both directly and via miR-205, which targets SQLE mRNA [PMID:34459531, PMID:34417456, PMID:37705742]. SQLE is also regulated at the RNA level through stabilizing m5C and ac4C modifications [PMID:40536094, PMID:41550764]. Post-translationally, SQLE is degraded by ERAD upon cholesterol excess through MARCH6-mediated ubiquitylation using UBE2J2 as its E2, a process governed by the circular transmembrane architecture of MARCH6 that couples lipid sensing, substrate channeling, and RING activity [PMID:30658189, PMID:32755570, PMID:38195637]. Beyond catalysis, SQLE drives oncogenic phenotypes through both its substrate and product: blocking the enzyme causes toxic squalene accumulation that triggers ER stress and apoptosis and reprograms the tumor microenvironment via NF-κB/CXCL1-dependent immune cell recruitment [PMID:30626880, PMID:37542052, PMID:39763673], whereas its product 2,3-oxidosqualene engages vinculin to promote YAP1 nuclear accumulation and YAP/TEAD signaling [PMID:39924077]. SQLE additionally localizes to mitochondria, where it interacts with LONP1 to stabilize TFAM and elevate oxidative phosphorylation [PMID:41254141]. Through these activities SQLE is broadly oncogenic and a tractable drug target, with the inhibitor terbinafine suppressing tumor growth and synergizing with anti-PD1 immunotherapy [PMID:34417456, PMID:41005980].","teleology":[{"year":1997,"claim":"Establishing the genomic location and sterol-responsiveness of human SQLE defined it as a regulated component of the cholesterol synthesis program, the foundation for all later regulatory work.","evidence":"PCR on somatic/radiation hybrid panels, FISH, and transcriptional regulation assays","pmids":["9286711"],"confidence":"Medium","gaps":["Promoter elements mediating sterol regulation not yet mapped","No mechanism for the regulation defined at this stage"]},{"year":2017,"claim":"Mapping two functional SREs and NF-Y sites in the SQLE promoter explained how sterol deprivation drives SQLE transcription through SREBP-2.","evidence":"Luciferase reporter mutagenesis, EMSA, and ChIP-PCR","pmids":["28342963"],"confidence":"High","gaps":["Does not address post-transcriptional or degradative control","Other transcription factors at the locus not examined"]},{"year":2019,"claim":"Identifying MARCH6 with UBE2J2 as the E3/E2 pair for cholesterol-stimulated SQLE degradation established post-translational, ERAD-dependent control as a second layer of SQLE regulation.","evidence":"CRISPR/Cas9 screen of ERAD E2 enzymes and protein stability/activity-rescue assays in multiple human cell lines","pmids":["30658189"],"confidence":"High","gaps":["Structural basis of MARCH6-SQLE recognition not resolved","Degron on SQLE not mapped here"]},{"year":2019,"claim":"Showing that SQLE inhibition kills certain neuroendocrine tumors through toxic squalene accumulation rather than cholesterol depletion redefined the enzyme's substrate as a context-dependent cytotoxic metabolite.","evidence":"Chemical biology screen with metabolic tracing, viability assays, and squalene measurements","pmids":["30626880"],"confidence":"High","gaps":["Molecular targets of accumulated squalene not identified","Why only a subset of tumors is sensitive not fully explained"]},{"year":2019,"claim":"Linking OSBPL2 loss to AMPK suppression and increased SP1/SREBF2 promoter occupancy connected upstream lipid-sensing signaling to SQLE transcriptional output.","evidence":"CRISPR knockout HeLa cells, RNA-seq, luciferase reporters, and AMPK inhibitor experiments","pmids":["31356817"],"confidence":"Medium","gaps":["Direct vs indirect SP1 contribution not separated from SREBF2","Generality beyond HeLa not tested"]},{"year":2020,"claim":"Demonstrating that the MARCH6-SQLE axis controls endothelial cholesterol load, membrane order, VE-cadherin junctions, and angiogenic sprouting extended SQLE regulation to a physiological cell-biological phenotype.","evidence":"siRNA/shRNA knockdown with cholesterol, membrane order, barrier, and sprouting assays in endothelial cells","pmids":["32755570"],"confidence":"High","gaps":["In vivo vascular relevance not established here","Which cholesterol pool drives junction effects unclear"]},{"year":2021,"claim":"Defining opposing transcriptional control by tumor-suppressive p53 (direct and via miR-205) and oncogenic MYC placed SQLE at a regulatory junction linking cell-state determinants to cholesterol output.","evidence":"Reporter assays, miRNA restoration, knockdown/overexpression epistasis, terbinafine studies, and in vivo p53-KO NAFLD tumor models","pmids":["34459531","33791309","34417456"],"confidence":"High","gaps":["Relative dominance of these regulators in different tissues unclear","Crosstalk with SREBP-2 control not fully integrated"]},{"year":2022,"claim":"Identifying SQLE as the direct binding target of polyphyllin I established the enzyme as a small-molecule-druggable node within the SREBP-2/HMGCR/SQLE pathway and a mediator of hepatotoxicity.","evidence":"Pull-down, SPR, molecular docking, and knockdown/overexpression of HMGCR and SQLE","pmids":["36820075"],"confidence":"High","gaps":["Binding site on SQLE not mapped at residue level","Selectivity over related enzymes not fully characterized"]},{"year":2023,"claim":"Resolving dual cancer-promoting mechanisms — squalene-driven ER stress/apoptosis on inhibition and lipid-raft-dependent Src/PI3K/Akt activation — clarified how SQLE both maintains and, when blocked, kills tumor cells.","evidence":"siRNA knockdown, inhibitors, ER stress markers, lipid raft fractionation, pathway analysis, and xenografts in pancreatic cancer","pmids":["37542052"],"confidence":"Medium","gaps":["Direct effector of raft-dependent signaling not isolated","Balance between the two mechanisms in vivo unclear"]},{"year":2023,"claim":"Showing that SQLE inhibition raises squalene to repress NF-κB/CXCL1 and remodel immune infiltration revealed a non-cholesterol, microenvironmental function for the SQLE substrate.","evidence":"SQLE knockdown and squalene administration in immune-competent mice with flow cytometry, RNA-seq, and NF-κB pathway analysis","pmids":["39763673"],"confidence":"Medium","gaps":["Direct molecular target of squalene upstream of NF-κB not defined","Single tumor model"]},{"year":2023,"claim":"Extending the MYC and p53 networks to the AP4/TFAP4 effector and miR-205 axis, and linking AP4 loss to terbinafine resistance, refined the transcriptional logic governing SQLE-targeted therapy response.","evidence":"miR-205 target validation, AP4 reporter assays, AP4 knockdown/overexpression, and terbinafine sensitivity assays","pmids":["37705742"],"confidence":"Medium","gaps":["Whether AP4 status predicts clinical drug response untested","Interaction with degradation control not addressed"]},{"year":2024,"claim":"The cryo-EM structure of MARCH6 with large-scale mutagenesis explained mechanistically how lipid sensing, a transmembrane channel, and RING activity are coupled to drive SQLE degradation.","evidence":"Cryo-EM, AlphaFold modeling, 95-variant mutagenesis, and SQLE stability assays","pmids":["38195637"],"confidence":"High","gaps":["Atomic detail of the SQLE substrate engagement not captured","Dynamics of channel gating during turnover not resolved"]},{"year":2024,"claim":"Defining KDM4A/GABPA chromatin-level activation of SQLE and downstream ROS-JNK/c-Jun signaling added an epigenetic layer to SQLE control with therapeutic implications in bladder cancer.","evidence":"KDM4A inhibitor organoid screening, H3K9me3 and GABPA ChIP, knockdown, ROS measurements, and PDX models","pmids":["39461328"],"confidence":"Medium","gaps":["Generality of KDM4A-SQLE control across tumor types unknown","Direct GABPA dependence vs cofactors not dissected"]},{"year":2024,"claim":"Discovering mitochondrial SQLE that binds LONP1 to stabilize TFAM and boost OXPHOS established a moonlighting, catalysis-independent role outside the ER cholesterol pathway.","evidence":"Subcellular fractionation, SQLE-LONP1 Co-IP, TFAM stability and OXPHOS/ROS assays, transgenic/KO mice, and Mito-TEMPO rescue","pmids":["41254141"],"confidence":"High","gaps":["How SQLE is targeted to mitochondria not defined","Whether enzymatic activity is required for TFAM stabilization unclear"]},{"year":2024,"claim":"Showing that accumulated squalene binds Sp1 to form an Sp1-TFAP2E promoter complex suppressing PGC-1α revealed a second non-cholesterol mechanism by which SQLE substrate restrains mitochondrial biogenesis.","evidence":"SQLE silencing, in vivo squalene administration, Sp1-DNA binding analysis, and TFAP2E/PGC-1α expression assays in xenografts","pmids":["40015662"],"confidence":"Medium","gaps":["Direct squalene-Sp1 binding biophysics not shown","Reconciliation with mitochondrial OXPHOS-promoting role of SQLE not addressed"]},{"year":2025,"claim":"Connecting SQLE activity to palmitoyl-CoA-driven PD-L1 palmitoylation downstream of H. pylori CagA linked the enzyme's lipid metabolism to immune-checkpoint stabilization and immune evasion.","evidence":"CagA overexpression, SQLE manipulation, palmitoyl-CoA measurement, and PD-L1 palmitoylation/ubiquitination and T-cell assays","pmids":["39809787"],"confidence":"Medium","gaps":["Enzymatic route from SQLE to palmitoyl-CoA pools not fully traced","In vivo relevance to infection-associated cancer untested here"]},{"year":2025,"claim":"Identifying RNA modifications (m5C by NSUN2, ac4C by NAT10) and additional transcription factors (YY1, SP1) as SQLE regulators expanded the regulatory network to mRNA stability and further signaling inputs across disease contexts.","evidence":"NSUN2/NAT10 manipulation with m5C/ac4C and mRNA stability assays; YY1 and SP1 ChIP/reporter assays with PI3K-AKT and AKT/mTOR pathway analysis","pmids":["40536094","41550764","40614853","39946769"],"confidence":"Medium","gaps":["Relative quantitative contribution of each input not benchmarked","Crosstalk among RNA modifications and transcriptional control not integrated"]},{"year":2025,"claim":"Showing that the SQLE product 2,3-oxidosqualene binds vinculin to drive YAP1 nuclear accumulation identified a product-based signaling output coupling SQLE to YAP/TEAD oncogenic transcription.","evidence":"ESCC cohort sequencing, 2,3-oxidosqualene/vinculin interaction studies, YAP localization assays, and in vivo 4-NQO ESCC mouse model","pmids":["39924077"],"confidence":"Medium","gaps":["Structural basis of 2,3-oxidosqualene-vinculin binding not resolved","Generality beyond ESCC unknown"]},{"year":2025,"claim":"Demonstrating that SQLE inhibition reduces tumor 27-hydroxycholesterol secretion to relieve cholesterol restriction on CD8+ T cells positioned SQLE blockade, including terbinafine plus anti-PD1, as an immunotherapy-sensitizing strategy.","evidence":"Pharmacological and genetic SQLE inhibition, tumor-T cell co-culture, untargeted metabolomics, and murine HCC anti-PD1 combination models","pmids":["41005980"],"confidence":"Medium","gaps":["Human clinical efficacy of the combination not established","Direct vs indirect oxysterol effects on T cells not fully separated"]},{"year":null,"claim":"It remains unresolved how SQLE's enzymatic and non-enzymatic (mitochondrial LONP1/TFAM-stabilizing) roles, its substrate- and product-based signaling outputs, and its layered transcriptional/RNA/degradative regulation are integrated and prioritized within a single cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling ER catalysis, mitochondrial moonlighting, and metabolite signaling","Mechanism of SQLE mitochondrial targeting unknown","Direct molecular targets of squalene and 2,3-oxidosqualene incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,17,23]}],"complexes":[],"partners":["MARCH6","UBE2J2","LONP1","FDFT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14534","full_name":"Squalene monooxygenase","aliases":["Squalene epoxidase","SE"],"length_aa":574,"mass_kda":63.9,"function":"Catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, and is considered to be a rate-limiting enzyme in steroid biosynthesis","subcellular_location":"Microsome membrane; Endoplasmic reticulum 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regulation assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mapping methods (somatic cell hybrids, radiation hybrid, FISH); transcriptional regulation noted but mechanistic detail in abstract is limited\",\n      \"pmids\": [\"9286711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The human SQLE promoter contains two sterol-regulatory elements (SREs) and two NF-Y binding sites that mediate SREBP-2-dependent transcriptional activation of SQLE in response to sterol deprivation.\",\n      \"method\": \"Luciferase reporter assays with SRE/NF-Y site mutants, electrophoretic mobility shift assay (EMSA), ChIP-PCR\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (luciferase mutagenesis screen, EMSA, ChIP-PCR) in a single rigorous study definitively mapping functional sites\",\n      \"pmids\": [\"28342963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MARCH6 (an E3 ubiquitin ligase) promotes cholesterol-stimulated ubiquitylation and proteasomal degradation of SQLE, and UBE2J2 (not UBE2G2) is the primary E2 ubiquitin-conjugating enzyme required for this MARCH6-dependent SQLE degradation in mammalian cells, including hepatic cells.\",\n      \"method\": \"CRISPR/Cas9 screen of ERAD-associated E2 enzymes, protein stability assays, enzymatic activity-dependent rescue experiments in multiple human cell lines\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale CRISPR screen followed by targeted validation in multiple cell types with enzymatic activity mutant controls; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30658189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sensitivity to SQLE inhibition in a subset of neuroendocrine tumors (particularly small cell lung cancer) results from toxic accumulation of the SQLE substrate squalene, not from downstream cholesterol biosynthesis inhibition.\",\n      \"method\": \"Chemical biology screen, orthogonal metabolic and cell viability assays, squalene accumulation measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (chemical screen, metabolic tracing, cell biology) established the squalene-accumulation mechanism in a single rigorous study\",\n      \"pmids\": [\"30626880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OSBPL2 deletion upregulates SQLE expression via suppression of the AMPK signaling pathway, which leads to increased SP1 and SREBF2 nuclear entry and binding to functional sites in the SQLE promoter, resulting in elevated intracellular cholesterol and cholesteryl ester.\",\n      \"method\": \"CRISPR/Cas9 OSBPL2 knockout HeLa cells, RNA-seq, dual-luciferase reporter assay, AMPK pathway inhibitor experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO combined with luciferase reporter and pathway inhibition; single lab, multiple methods\",\n      \"pmids\": [\"31356817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MARCH6 promotes degradation of SQLE in endothelial cells to regulate cholesterol load; loss of MARCH6 increases SQLE protein and cholesterol, altering membrane order, disorganizing VE-cadherin-based adherens junctions, and impairing angiogenic sprouting.\",\n      \"method\": \"siRNA/shRNA knockdown of MARCHF6 and SQLE, cholesterol measurements, membrane order assays, barrier function assays, endothelial sprouting assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with multiple functional readouts (cholesterol, membrane order, barrier function, sprouting) establishing MARCH6-SQLE axis\",\n      \"pmids\": [\"32755570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"p53 directly represses SQLE transcription in a SREBP2-independent manner under normal sterol conditions, thereby reducing cholesterol production and suppressing tumor growth; SQLE inhibition reverses the increased cell proliferation caused by p53 deficiency.\",\n      \"method\": \"Transcriptional reporter assays, siRNA/shRNA knockdown, terbinafine inhibitor studies, in vivo mouse NAFLD tumorigenesis model with p53 KO\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KD, pharmacological inhibition, in vivo tumor model) establishing p53-SQLE axis with functional rescue experiments\",\n      \"pmids\": [\"34459531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYC directly transcriptionally upregulates SQLE, thereby increasing cholesterol biosynthesis and promoting tumor cell proliferation; SQLE overexpression restores cholesterol levels in MYC-knockdown cells, and enforced MYC expression has no effect on cholesterol in SQLE-depleted cells.\",\n      \"method\": \"MYC knockdown/overexpression, SQLE overexpression rescue, cholesterol measurements, epistasis experiments\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments (MYC KD + SQLE OE) with cholesterol readout; single lab, genetic approach with clear pathway placement\",\n      \"pmids\": [\"33791309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-205 directly targets SQLE mRNA to repress its expression and inhibit de novo cholesterol biosynthesis in prostate cancer; inhibition of SQLE blocks AR pathway transactivation and suppresses tumor growth in vivo.\",\n      \"method\": \"miR-205 restoration, SQLE competitive inhibition with terbinafine, cholesterol biosynthesis assays, in vivo orthotopic tumor model, patient PSA measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic miRNA restoration, pharmacological SQLE inhibition, in vivo mouse model, human patient data) with consistent mechanistic findings\",\n      \"pmids\": [\"34417456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Polyphyllin I (PPI) directly binds SQLE protein (not HMGCR), disrupting the SREBP-2/HMGCR/SQLE/lanosterol synthase cholesterol biosynthesis pathway and inducing hepatotoxicity.\",\n      \"method\": \"Pull-down assay, surface plasmon resonance (SPR), molecular docking, siRNA knockdown and overexpression of HMGCR and SQLE, proteomics/transcriptomics\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding confirmed by biophysical SPR and pull-down with functional pathway validation; single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"36820075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SQLE inhibition in pancreatic cancer cells leads to squalene accumulation that inhibits CXCL1 transcription via the NF-κB/p65 pathway, reducing recruitment of MDSCs and TAMs and increasing CD8+ T cell infiltration in the tumor microenvironment.\",\n      \"method\": \"SQLE knockdown in immune-competent mouse model, squalene administration in vivo, flow cytometry of immune cells, RNA-sequencing, RT-PCR/Western blot for NF-κB pathway\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo immune-competent model with direct squalene administration and mechanistic NF-κB pathway analysis; single lab, multiple methods\",\n      \"pmids\": [\"39763673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SQLE promotes pancreatic cancer growth through two mechanisms: (1) its inhibition causes squalene accumulation-induced ER stress and apoptosis; (2) SQLE-mediated cholesterol biosynthesis maintains lipid raft stability, activating the Src/PI3K/Akt signaling pathway.\",\n      \"method\": \"siRNA knockdown, SQLE inhibitors, ER stress markers, lipid raft fractionation, Src/PI3K/Akt pathway analysis, xenograft tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual mechanism tested by KD, lipid raft fractionation, and in vivo xenograft; single lab with multiple readouts\",\n      \"pmids\": [\"37542052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p53 suppresses SQLE expression via induction of miR-205, which directly targets SQLE mRNA; c-MYC induces SQLE expression directly and via its transcriptional target AP4/TFAP4, which directly binds the SQLE promoter; loss of AP4 causes resistance to terbinafine.\",\n      \"method\": \"miR-205 target validation, AP4/TFAP4 transcriptional reporter assays, AP4 knockdown/overexpression, cholesterol measurements, terbinafine sensitivity assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (p53→miR-205→SQLE and MYC→AP4→SQLE) with luciferase validation and functional rescue; single lab\",\n      \"pmids\": [\"37705742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Doa10/MARCH6 adopts a unique circular transmembrane structure with a lipid-binding scaffold and gated helical bundle; the RING domain is positioned over the membrane channel, and SQLE degradation requires interconnected channel, RING domain, and lipid-binding elements, revealing how metabolic signals, substrate binding, and E3 ligase activity are coupled.\",\n      \"method\": \"Cryo-EM structural analysis, AlphaFold predictions, structure-based mutagenesis campaign (95 MARCH6 variants), SQLE stability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with large-scale mutagenesis (95 variants) and functional SQLE degradation assays in a single rigorous study\",\n      \"pmids\": [\"38195637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4A histone demethylase demethylates H3K9me3 at the SQLE gene locus, opening chromatin to allow GABPA transcription factor binding and SQLE transcriptional activation; KDM4A inhibition downregulates SQLE, blocks cholesterol synthesis, causes squalene accumulation, suppresses JNK/c-Jun phosphorylation via ROS, and induces apoptosis in bladder cancer.\",\n      \"method\": \"KDM4A inhibitor (ML324) drug screening in tumor organoids, ChIP assays for H3K9me3 and GABPA, SQLE knockdown, ROS measurements, JNK/c-Jun pathway analysis, PDX models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating H3K9me3 demethylation and GABPA accessibility at SQLE promoter with functional pathway readout; single lab, multiple methods\",\n      \"pmids\": [\"39461328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SQLE localizes to mitochondria and directly interacts with LONP1 (Lon peptidase 1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial ROS production in bladder cancer cells.\",\n      \"method\": \"Subcellular fractionation/localization studies, co-immunoprecipitation of SQLE-LONP1 interaction, TFAM stability assays, OXPHOS and mitochondrial ROS measurements, Sqle transgenic and knockout mouse models, Mito-TEMPO rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct SQLE-LONP1 interaction by Co-IP, mitochondrial localization with functional consequence, transgenic/KO mouse models, and pharmacological rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41254141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SQLE-mediated removal of squalene promotes mitochondrial biogenesis via a non-cholesterol mechanism: squalene accumulation binds Sp1 protein and forms a tight Sp1-TFAP2E promoter complex, suppressing TFAP2E and downstream PGC-1α expression, thereby inhibiting mitochondrial metabolism and tumor formation.\",\n      \"method\": \"SQLE silencing, squalene direct administration in vivo, Sp1-DNA binding analysis (binding score calculation), TFAP2E/PGC-1α expression assays, xenograft tumor model, pharmacological squalene administration\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — squalene/Sp1/TFAP2E promoter complex characterized with in vivo rescue by squalene administration; single lab, functional in vivo validation\",\n      \"pmids\": [\"40015662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H. pylori CagA upregulates SQLE expression, and elevated SQLE activity increases cellular palmitoyl-CoA levels, which enhances PD-L1 palmitoylation while decreasing its ubiquitination, thereby stabilizing PD-L1 and suppressing T cell activity to facilitate immune evasion.\",\n      \"method\": \"CagA overexpression, SQLE manipulation, palmitoyl-CoA measurement, PD-L1 palmitoylation and ubiquitination assays, T cell activity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain (CagA→SQLE→palmitoyl-CoA→PD-L1 palmitoylation) supported by biochemical PTM assays; single lab\",\n      \"pmids\": [\"39809787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC2-dependent delactylation of PD-L1 at K189 promotes vimentin-mediated nuclear translocation of PD-L1, which then upregulates SQLE transcription via the transcription factor YY1, thereby accelerating cholesterol production and liver cancer growth.\",\n      \"method\": \"PD-L1 lactylation site mapping, p300 acetyltransferase activity assays, HDAC2 deacylation assays, nuclear fractionation, YY1 ChIP/reporter assays for SQLE promoter, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical PTM characterization (lactylation/delactylation) linked to nuclear PD-L1 transcriptional regulation of SQLE via YY1; single lab, multiple methods\",\n      \"pmids\": [\"40614853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NSUN2 increases m5C modification of SQLE mRNA, stabilizing it and increasing SQLE expression in endothelial cells; elevated SQLE increases intracellular cholesterol, which promotes endothelial cell activation via the PI3K-AKT signaling pathway in diabetic retinopathy.\",\n      \"method\": \"NSUN2 knockdown/overexpression, m5C modification assays, SQLE mRNA stability measurements, cholesterol quantification, PI3K-AKT pathway analysis, tube formation and endothelial activation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m5C modification experimentally linked to SQLE mRNA stability and downstream signaling; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40536094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10 acts as an upstream activator of SQLE-dependent cholesterol biosynthesis through two mechanisms: (1) activation of AKT/mTOR signaling leading to SQLE upregulation, and (2) ac4C modification of SQLE mRNA to enhance its stability.\",\n      \"method\": \"Multi-omics dataset analysis, AKT/mTOR pathway manipulation, ac4C mRNA modification assays, SQLE mRNA stability measurements, in vitro and in vivo cholesterol and tumor growth assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual mechanism (signaling pathway + RNA modification) supported by biochemical ac4C assays and functional in vivo data; single lab\",\n      \"pmids\": [\"41550764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SP1 directly binds to the SQLE promoter and activates its transcription, as demonstrated in the context of SERPINH1/SENP3 signaling in hepatocellular carcinoma.\",\n      \"method\": \"ChIP-qPCR assay demonstrating SP1 binding to SQLE promoter, SP1 inhibitor (plicamycin) rescue experiments\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct SP1 occupancy at SQLE promoter demonstrated by ChIP-qPCR with functional inhibitor rescue; single lab\",\n      \"pmids\": [\"39946769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SQLE-produced intermediate metabolite 2,3-oxidosqualene interacts with vinculin to enhance nuclear accumulation of YAP1, increasing YAP/TEAD-dependent gene expression and accelerating tumor growth and metastasis in esophageal squamous cell carcinoma.\",\n      \"method\": \"Whole genome sequencing of ESCC cohorts, metabolite-protein interaction studies (2,3-oxidosqualene/vinculin), YAP nuclear localization assays, in vivo 4-NQO mouse ESCC model with SQLE overexpression\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolite-protein interaction linked to YAP nuclear translocation with in vivo mouse model validation; single lab\",\n      \"pmids\": [\"39924077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SQLE inhibition in hepatocellular carcinoma tumor cells suppresses oxysterol (27-hydroxycholesterol) secretion, overcoming cholesterol restrictions on CD8+ T cells via oxysterol-SREBP2 signaling and enhancing antitumor immunity; terbinafine synergizes with anti-PD1 therapy in HCC mouse models.\",\n      \"method\": \"Pharmacological SQLE inhibition and genetic knockdown, co-culture experiments of tumor cells and T cells, untargeted metabolomics identifying 27-hydroxycholesterol, transcriptome analysis, murine HCC models with anti-PD1 combination therapy\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics identified oxysterol mechanism with co-culture functional validation and in vivo combination therapy; single lab\",\n      \"pmids\": [\"41005980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ginsenoside 20(S)-Rg3 upregulates SQLE expression by downregulating HIF-1α, and SQLE interacts with FDFT1 (farnesyl-diphosphate farnesyltransferase 1) as confirmed by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation of SQLE-FDFT1 interaction, HIF-1α/SQLE axis manipulation, transcriptomic and lipidomic analysis, SQLE silencing rescue experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying SQLE-FDFT1 interaction without deeper mechanistic characterization of the interaction's functional consequence; single lab\",\n      \"pmids\": [\"40792023\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SQLE (squalene epoxidase) is the second rate-limiting enzyme in cholesterol biosynthesis, catalyzing conversion of squalene to 2,3-oxidosqualene; its expression is transcriptionally activated by SREBP-2 via two promoter SREs, repressed by p53 (directly and via miR-205), and induced by MYC and its target AP4; post-translationally, SQLE is ubiquitylated by the MARCH6 E3 ligase (using UBE2J2 as its E2) and degraded via ERAD in response to cholesterol excess; beyond cholesterol synthesis, SQLE localizes to mitochondria where it stabilizes TFAM by interacting with LONP1 to drive oxidative phosphorylation, and its substrate squalene acts as a bioactive metabolite that suppresses immune cell infiltration via NF-κB/CXCL1, inhibits PGC-1α-mediated mitochondrial biogenesis via Sp1/TFAP2E, and SQLE's product 2,3-oxidosqualene activates YAP/TEAD signaling via vinculin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SQLE (squalene epoxidase) is the second rate-limiting enzyme of cholesterol biosynthesis, converting squalene to 2,3-oxidosqualene, and its activity sits at a node where transcriptional control, substrate/product signaling, and protein turnover converge to govern sterol levels, membrane biology, and tumor growth [#1, #3]. Its transcription is activated upon sterol deprivation by SREBP-2 acting through two promoter sterol-regulatory elements with adjacent NF-Y sites [#1], and is further controlled by an extensive regulatory network: MYC induces SQLE directly and through its target AP4/TFAP4 [#7, #12], SP1 binds and activates the promoter [#21], and KDM4A-mediated H3K9me3 demethylation opens the locus to permit GABPA binding [#14], while p53 represses SQLE both directly and via miR-205, which targets SQLE mRNA [#6, #8, #12]. SQLE is also regulated at the RNA level through stabilizing m5C and ac4C modifications [#19, #20]. Post-translationally, SQLE is degraded by ERAD upon cholesterol excess through MARCH6-mediated ubiquitylation using UBE2J2 as its E2, a process governed by the circular transmembrane architecture of MARCH6 that couples lipid sensing, substrate channeling, and RING activity [#2, #5, #13]. Beyond catalysis, SQLE drives oncogenic phenotypes through both its substrate and product: blocking the enzyme causes toxic squalene accumulation that triggers ER stress and apoptosis and reprograms the tumor microenvironment via NF-κB/CXCL1-dependent immune cell recruitment [#3, #11, #10], whereas its product 2,3-oxidosqualene engages vinculin to promote YAP1 nuclear accumulation and YAP/TEAD signaling [#22]. SQLE additionally localizes to mitochondria, where it interacts with LONP1 to stabilize TFAM and elevate oxidative phosphorylation [#15]. Through these activities SQLE is broadly oncogenic and a tractable drug target, with the inhibitor terbinafine suppressing tumor growth and synergizing with anti-PD1 immunotherapy [#8, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the genomic location and sterol-responsiveness of human SQLE defined it as a regulated component of the cholesterol synthesis program, the foundation for all later regulatory work.\",\n      \"evidence\": \"PCR on somatic/radiation hybrid panels, FISH, and transcriptional regulation assays\",\n      \"pmids\": [\"9286711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter elements mediating sterol regulation not yet mapped\", \"No mechanism for the regulation defined at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping two functional SREs and NF-Y sites in the SQLE promoter explained how sterol deprivation drives SQLE transcription through SREBP-2.\",\n      \"evidence\": \"Luciferase reporter mutagenesis, EMSA, and ChIP-PCR\",\n      \"pmids\": [\"28342963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address post-transcriptional or degradative control\", \"Other transcription factors at the locus not examined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying MARCH6 with UBE2J2 as the E3/E2 pair for cholesterol-stimulated SQLE degradation established post-translational, ERAD-dependent control as a second layer of SQLE regulation.\",\n      \"evidence\": \"CRISPR/Cas9 screen of ERAD E2 enzymes and protein stability/activity-rescue assays in multiple human cell lines\",\n      \"pmids\": [\"30658189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MARCH6-SQLE recognition not resolved\", \"Degron on SQLE not mapped here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that SQLE inhibition kills certain neuroendocrine tumors through toxic squalene accumulation rather than cholesterol depletion redefined the enzyme's substrate as a context-dependent cytotoxic metabolite.\",\n      \"evidence\": \"Chemical biology screen with metabolic tracing, viability assays, and squalene measurements\",\n      \"pmids\": [\"30626880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets of accumulated squalene not identified\", \"Why only a subset of tumors is sensitive not fully explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking OSBPL2 loss to AMPK suppression and increased SP1/SREBF2 promoter occupancy connected upstream lipid-sensing signaling to SQLE transcriptional output.\",\n      \"evidence\": \"CRISPR knockout HeLa cells, RNA-seq, luciferase reporters, and AMPK inhibitor experiments\",\n      \"pmids\": [\"31356817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect SP1 contribution not separated from SREBF2\", \"Generality beyond HeLa not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that the MARCH6-SQLE axis controls endothelial cholesterol load, membrane order, VE-cadherin junctions, and angiogenic sprouting extended SQLE regulation to a physiological cell-biological phenotype.\",\n      \"evidence\": \"siRNA/shRNA knockdown with cholesterol, membrane order, barrier, and sprouting assays in endothelial cells\",\n      \"pmids\": [\"32755570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo vascular relevance not established here\", \"Which cholesterol pool drives junction effects unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining opposing transcriptional control by tumor-suppressive p53 (direct and via miR-205) and oncogenic MYC placed SQLE at a regulatory junction linking cell-state determinants to cholesterol output.\",\n      \"evidence\": \"Reporter assays, miRNA restoration, knockdown/overexpression epistasis, terbinafine studies, and in vivo p53-KO NAFLD tumor models\",\n      \"pmids\": [\"34459531\", \"33791309\", \"34417456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative dominance of these regulators in different tissues unclear\", \"Crosstalk with SREBP-2 control not fully integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying SQLE as the direct binding target of polyphyllin I established the enzyme as a small-molecule-druggable node within the SREBP-2/HMGCR/SQLE pathway and a mediator of hepatotoxicity.\",\n      \"evidence\": \"Pull-down, SPR, molecular docking, and knockdown/overexpression of HMGCR and SQLE\",\n      \"pmids\": [\"36820075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site on SQLE not mapped at residue level\", \"Selectivity over related enzymes not fully characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolving dual cancer-promoting mechanisms — squalene-driven ER stress/apoptosis on inhibition and lipid-raft-dependent Src/PI3K/Akt activation — clarified how SQLE both maintains and, when blocked, kills tumor cells.\",\n      \"evidence\": \"siRNA knockdown, inhibitors, ER stress markers, lipid raft fractionation, pathway analysis, and xenografts in pancreatic cancer\",\n      \"pmids\": [\"37542052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effector of raft-dependent signaling not isolated\", \"Balance between the two mechanisms in vivo unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that SQLE inhibition raises squalene to repress NF-κB/CXCL1 and remodel immune infiltration revealed a non-cholesterol, microenvironmental function for the SQLE substrate.\",\n      \"evidence\": \"SQLE knockdown and squalene administration in immune-competent mice with flow cytometry, RNA-seq, and NF-κB pathway analysis\",\n      \"pmids\": [\"39763673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of squalene upstream of NF-κB not defined\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending the MYC and p53 networks to the AP4/TFAP4 effector and miR-205 axis, and linking AP4 loss to terbinafine resistance, refined the transcriptional logic governing SQLE-targeted therapy response.\",\n      \"evidence\": \"miR-205 target validation, AP4 reporter assays, AP4 knockdown/overexpression, and terbinafine sensitivity assays\",\n      \"pmids\": [\"37705742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AP4 status predicts clinical drug response untested\", \"Interaction with degradation control not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The cryo-EM structure of MARCH6 with large-scale mutagenesis explained mechanistically how lipid sensing, a transmembrane channel, and RING activity are coupled to drive SQLE degradation.\",\n      \"evidence\": \"Cryo-EM, AlphaFold modeling, 95-variant mutagenesis, and SQLE stability assays\",\n      \"pmids\": [\"38195637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic detail of the SQLE substrate engagement not captured\", \"Dynamics of channel gating during turnover not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining KDM4A/GABPA chromatin-level activation of SQLE and downstream ROS-JNK/c-Jun signaling added an epigenetic layer to SQLE control with therapeutic implications in bladder cancer.\",\n      \"evidence\": \"KDM4A inhibitor organoid screening, H3K9me3 and GABPA ChIP, knockdown, ROS measurements, and PDX models\",\n      \"pmids\": [\"39461328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of KDM4A-SQLE control across tumor types unknown\", \"Direct GABPA dependence vs cofactors not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering mitochondrial SQLE that binds LONP1 to stabilize TFAM and boost OXPHOS established a moonlighting, catalysis-independent role outside the ER cholesterol pathway.\",\n      \"evidence\": \"Subcellular fractionation, SQLE-LONP1 Co-IP, TFAM stability and OXPHOS/ROS assays, transgenic/KO mice, and Mito-TEMPO rescue\",\n      \"pmids\": [\"41254141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SQLE is targeted to mitochondria not defined\", \"Whether enzymatic activity is required for TFAM stabilization unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that accumulated squalene binds Sp1 to form an Sp1-TFAP2E promoter complex suppressing PGC-1α revealed a second non-cholesterol mechanism by which SQLE substrate restrains mitochondrial biogenesis.\",\n      \"evidence\": \"SQLE silencing, in vivo squalene administration, Sp1-DNA binding analysis, and TFAP2E/PGC-1α expression assays in xenografts\",\n      \"pmids\": [\"40015662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct squalene-Sp1 binding biophysics not shown\", \"Reconciliation with mitochondrial OXPHOS-promoting role of SQLE not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connecting SQLE activity to palmitoyl-CoA-driven PD-L1 palmitoylation downstream of H. pylori CagA linked the enzyme's lipid metabolism to immune-checkpoint stabilization and immune evasion.\",\n      \"evidence\": \"CagA overexpression, SQLE manipulation, palmitoyl-CoA measurement, and PD-L1 palmitoylation/ubiquitination and T-cell assays\",\n      \"pmids\": [\"39809787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic route from SQLE to palmitoyl-CoA pools not fully traced\", \"In vivo relevance to infection-associated cancer untested here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying RNA modifications (m5C by NSUN2, ac4C by NAT10) and additional transcription factors (YY1, SP1) as SQLE regulators expanded the regulatory network to mRNA stability and further signaling inputs across disease contexts.\",\n      \"evidence\": \"NSUN2/NAT10 manipulation with m5C/ac4C and mRNA stability assays; YY1 and SP1 ChIP/reporter assays with PI3K-AKT and AKT/mTOR pathway analysis\",\n      \"pmids\": [\"40536094\", \"41550764\", \"40614853\", \"39946769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative quantitative contribution of each input not benchmarked\", \"Crosstalk among RNA modifications and transcriptional control not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that the SQLE product 2,3-oxidosqualene binds vinculin to drive YAP1 nuclear accumulation identified a product-based signaling output coupling SQLE to YAP/TEAD oncogenic transcription.\",\n      \"evidence\": \"ESCC cohort sequencing, 2,3-oxidosqualene/vinculin interaction studies, YAP localization assays, and in vivo 4-NQO ESCC mouse model\",\n      \"pmids\": [\"39924077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of 2,3-oxidosqualene-vinculin binding not resolved\", \"Generality beyond ESCC unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that SQLE inhibition reduces tumor 27-hydroxycholesterol secretion to relieve cholesterol restriction on CD8+ T cells positioned SQLE blockade, including terbinafine plus anti-PD1, as an immunotherapy-sensitizing strategy.\",\n      \"evidence\": \"Pharmacological and genetic SQLE inhibition, tumor-T cell co-culture, untargeted metabolomics, and murine HCC anti-PD1 combination models\",\n      \"pmids\": [\"41005980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human clinical efficacy of the combination not established\", \"Direct vs indirect oxysterol effects on T cells not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SQLE's enzymatic and non-enzymatic (mitochondrial LONP1/TFAM-stabilizing) roles, its substrate- and product-based signaling outputs, and its layered transcriptional/RNA/degradative regulation are integrated and prioritized within a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling ER catalysis, mitochondrial moonlighting, and metabolite signaling\", \"Mechanism of SQLE mitochondrial targeting unknown\", \"Direct molecular targets of squalene and 2,3-oxidosqualene incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 17, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MARCH6\", \"UBE2J2\", \"LONP1\", \"FDFT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}