{"gene":"SELENOP","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2012,"finding":"Hepatocyte-specific deletion of Sepp1 lowered plasma Sepp1 to ~10% of controls, increased urinary selenium excretion, and reduced selenium in extra-hepatic tissues, establishing that hepatocyte-produced Sepp1 is central to retaining selenium in the organism and distributing it from liver to peripheral tissues.","method":"Conditional knockout mouse (hepatocyte-specific Sepp1 deletion via alb-cre), selenium measurements in plasma/urine/tissues, mRNA quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined tissue-level phenotype, quantitative selenium tracking, replicated concept across multiple tissues and dietary conditions","pmids":["23038251"],"is_preprint":false},{"year":2008,"finding":"Transgenic hepatocyte-specific expression of human SELENOP in Sepp-/- mice restored selenium content and selenoenzyme activities in serum, kidney, testis, and brain, rescued male fertility and neurological defects under selenium-adequate diet, demonstrating that liver-derived circulating SePP is the main transport form supplying selenium to peripheral tissues including testis and brain.","method":"Transgenic rescue in Sepp-/- mice (hepatocyte-specific transthyretin promoter driving human SEPP1), selenium measurements, selenoenzyme activity assays, behavioral assessment","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic rescue experiment with multiple orthogonal readouts (selenium levels, enzyme activity, fertility, neurological behavior), consistent with conditional KO data","pmids":["17961124"],"is_preprint":false},{"year":2012,"finding":"L8 myoblast cells take up Sepp1 via apoER2-mediated endocytosis requiring heparin sulfate proteoglycan binding; siRNA knockdown of apoER2 (but not Lrp1) inhibited 75Se uptake; blockage of lysosome acidification prevented Sepp1 digestion and selenium utilization; the selenium-rich C-terminal domain (residues 240-361) is required for uptake.","method":"75Se-labeling uptake assays, siRNA knockdown of apoER2 and Lrp1, affinity chromatography (Sepp1 column) with mass spectrometry identification of receptors, protamine/chlorate inhibition, lysosome acidification blockage, truncation isoform comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (siRNA, pharmacological inhibitors, receptor pulldown with MS, truncation mutants) in single lab","pmids":["22761431"],"is_preprint":false},{"year":2014,"finding":"Urinary Sepp1 N-terminal fragments (Sepp1UF, residues 1-~183-208) possess peroxidase activity when coupled with thioredoxin reductase-1 (TrxR1), catalyzing NADPH oxidation with H2O2 or tert-butylhydroperoxide; activity requires the selenocysteine at position 40 (U40S mutant was inactive). Full-length Sepp1 and Sepp1Δ240-361 were also TrxR1 substrates. These fragments are filtered by the glomerulus and taken up by proximal convoluted tubule cells via megalin-mediated endocytosis.","method":"Purification of urinary Sepp1 forms from megalin-/- mice using monoclonal antibody, mass spectrometry identification of N-terminal fragments, in vitro TrxR1 peroxidase assay (NADPH oxidation), active-site mutant Sepp1(U40S) comparison","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with active-site mutagenesis, purified protein fractions identified by MS, single lab with multiple orthogonal approaches","pmids":["24434121"],"is_preprint":false},{"year":2023,"finding":"SELENOP interacts directly with the WNT co-receptors LRP5 and LRP6, and this protein-protein interaction contributes to SELENOP's ability to increase canonical WNT signaling activity; Selenop-KO tumor organoids showed decreased WNT target gene expression reversible by SELENOP restoration; Selenop KO in an intestinal APC-deletion mouse model decreased colon tumor incidence and size.","method":"Protein-protein interaction mapping (co-IP of SELENOP with LRP5/6), tumor organoid formation assay, WNT reporter assays in CRC and non-cancer cell lines, conditional KO mouse model (Selenop KO × Apc intestinal KO), scRNA-Seq of human colon tissue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal/functional Co-IP, organoid rescue, in vivo mouse model, multiple cell lines; single lab but orthogonal methods","pmids":["37166989"],"is_preprint":false},{"year":2022,"finding":"SELENOP is essential for preserving parvalbumin-expressing interneuron survival under limiting selenium supply; Selenop-/- mice on RDA diet developed epileptic seizures, ataxia, and tremor confirmed by video-EEG; selenium supplementation from birth or transgenic hepatocyte-specific human SELENOP expression prevented both neurological phenotypes; the effects were dose- and time-dependent.","method":"Constitutive Selenop knockout mice, video-electroencephalography, behavioral testing (ataxia/tremor scoring), selenium supplementation experiments (dose and timing variation), transgenic rescue (hepatocyte-specific SELENOP), brain GPx activity assay, histological analysis of interneurons","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined electrophysiological phenotype, transgenic rescue, dose-response supplementation, multiple neurological readouts; consistent with prior Sepp-/- mouse literature","pmids":["36182809"],"is_preprint":false},{"year":2025,"finding":"KAT8 catalyzes acetylation of SEPP1 at lysine residues K247 and K249, upregulating SEPP1 transcription and protein level; SEPP1 then signals through its receptor LRP8 on MDSCs to impair MDSC survival, thereby enabling CD8+ T cell-mediated anti-tumor immunity in pancreatic cancer.","method":"Co-immunoprecipitation (Co-IP) of KAT8, SEPP1, and LRP8; qRT-PCR and Western blot; flow cytometry for immune cell abundance and apoptosis; PC xenograft and liver metastasis mouse models; SEPP1 recombinant protein treatment combined with anti-PD-1","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies acetylation and receptor interaction, in vivo mouse models, single lab with multiple methods but acetylation mechanism not confirmed by mutagenesis of K247/249","pmids":["39972392"],"is_preprint":false},{"year":2014,"finding":"Exendin-4 (GLP-1 receptor agonist) reduces hepatic SEPP1 expression via AMPK activation; AMPK activator AICAR negatively regulated SEPP1 expression, and AMPK siRNA knockdown prevented the exendin-4-mediated reduction of SEPP1, placing AMPK upstream of SEPP1 expression in hepatocytes.","method":"HepG2 cell treatment with palmitic acid/tunicamycin ± exendin-4, AMPK siRNA knockdown, AICAR treatment, qRT-PCR and Western blotting for SEPP1 and ER stress markers","journal":"Endocrinology and metabolism (Seoul, Korea)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown epistasis plus pharmacological AMPK activation, two orthogonal approaches in single lab, cell-line only","pmids":["26194078"],"is_preprint":false},{"year":2022,"finding":"Lauric acid upregulates Selenop expression in hepatocytes via HNF4α; luciferase promoter assay identified an HNF4α binding site in the SELENOP promoter; ChIP showed lauric acid increased HNF4α binding to this promoter; Hnf4α siRNA knockdown canceled lauric acid-induced Selenop upregulation; Akt phosphorylation impairment by lauric acid was rescued by knockdown of either Hnf4α or Selenop.","method":"Luciferase promoter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown of Hnf4α and Selenop, Western blotting for Akt phosphorylation in Hepa1-6 cells and mouse liver","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase assay plus siRNA epistasis in single lab, multiple orthogonal methods, cell line + in vivo mouse liver","pmids":["35499234"],"is_preprint":false},{"year":2022,"finding":"FoxO1 knockdown accelerates EPA-mediated Selenop downregulation in hepatocytes independently of SREBP-1c; EPA upregulates Foxo1 mRNA via the ERK1/2 pathway without altering FoxO1 protein nuclear translocation, suggesting a redundant transcriptional network controlling Selenop expression.","method":"siRNA knockdown of Foxo1, ERK1/2 and PKA pharmacological inhibitors, RT-PCR, nuclear fractionation/translocation assay in H4IIEC3 hepatocytes","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA epistasis plus inhibitor studies but single lab, single cell type, no in vivo validation","pmids":["35321982"],"is_preprint":false},{"year":2021,"finding":"SELENOP deletion in dogs (homozygous 17,325 bp deletion removing entire protein-coding sequence) caused cerebellar ataxia, CNS atrophy, and reduced blood selenium to ~30% of wildtype, demonstrating that SELENOP is required for selenium transport into the CNS in a large-animal model.","method":"Whole genome sequencing, linkage/homozygosity mapping, genotyping of >600 dogs, selenium measurement by atomic absorption, histopathology","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — naturally occurring complete loss-of-function with multiple affected animals, selenium quantification, histopathology; not experimental manipulation but rigorous genetic evidence","pmids":["34339417"],"is_preprint":false},{"year":2021,"finding":"ZIKV infection knocked down SELENOP protein expression by ~99% in HEK293T cells without significant reduction in SELENOP mRNA, suggesting post-transcriptional/translational suppression; computationally predicted antisense hybridization between ZIKV RNA and SELENOP mRNA was confirmed at the DNA level by gel shift assay.","method":"ZIKV infection of HEK293T cells, Western blotting for SELENOP and TXNRD1, RT-qPCR for mRNA levels, gel shift assay with synthetic oligonucleotides","journal":"BBA advances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Western blot knockdown in single cell line, gel shift at DNA level only (not RNA), single lab, computational interaction not fully validated at RNA level","pmids":["34988542"],"is_preprint":false},{"year":2016,"finding":"Overexpression of SEPP1 in 786-O and 769-P renal carcinoma cells inhibited proliferation, reduced colony formation, and caused G2/M cell cycle arrest in 786-O cells.","method":"Lentiviral overexpression of SEPP1, MTS proliferation assay, colony formation assay, flow cytometry cell cycle analysis","journal":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain-of-function with phenotypic readout but no molecular pathway placement, single lab, single method set","pmids":["27371843"],"is_preprint":false},{"year":2025,"finding":"Hepatic Sepp1 depletion in HCC impairs selenium uptake in tumor-infiltrating neutrophils by disrupting Lrp8 receptor-mediated transport, suppressing intracellular selenium metabolism; this reduces hydrogen selenide (H2Se) production and increases S-adenosylmethionine (SAM) accumulation, leading to increased H3K4me3 modification in neutrophils and establishing a pro-senescence chromatin landscape that drives immunosuppression.","method":"scRNA-seq of HCC mouse tumors, macrophage/neutrophil-specific analyses, in vitro selenium uptake assays, chromatin modification (H3K4me3) measurement, selenium supplementation rescue experiments, anti-PD-1 combination therapy in mouse models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — mechanistic pathway proposed with scRNA-seq and in vitro data, preprint not peer-reviewed, single lab","pmids":["bio_10.1101_2025.06.24.661430"],"is_preprint":true},{"year":2024,"finding":"Macrophage-specific deletion of Sepp1 impaired the acquisition of the repair inflammatory profile, disrupted macrophage support of muscle stem cells in vitro and in vivo, and caused inefficient skeletal muscle regeneration; transplantation of young WT (but not Sepp1 KO) bone marrow restored muscle regeneration in aged mice.","method":"Macrophage-specific Sepp1 conditional KO, FACS isolation of niche cells, RNA-sequencing, in vitro co-culture of macrophages and muscle stem cells, bone marrow transplantation into aged mice, in vivo regeneration assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — cell-type-specific KO with defined phenotype and rescue, preprint not peer-reviewed, single lab","pmids":["bio_10.1101_2024.08.28.610036"],"is_preprint":true}],"current_model":"SELENOP (selenoprotein P) is a liver-secreted, selenium-rich extracellular protein that serves as the primary selenium transporter in plasma: hepatocytes synthesize and secrete SELENOP, which is taken up by peripheral tissues (including brain, testis, kidney, and muscle) via apoER2/LRP8-mediated endocytosis requiring heparin sulfate proteoglycans and lysosomal processing of its selenium-rich C-terminal domain; the N-terminal domain carries a redox-active selenocysteine (U40) in a thioredoxin fold that confers peroxidase activity when coupled with thioredoxin reductase-1; SELENOP additionally interacts with LRP5/6 WNT co-receptors to modulate canonical WNT signaling in the colon, is acetylated at K247/249 by KAT8 to regulate its expression and LRP8-mediated effects on immune cells, and its hepatic expression is regulated transcriptionally by HNF4α (induced by lauric acid) and negatively by AMPK (activated by GLP-1 signaling)."},"narrative":{"mechanistic_narrative":"SELENOP (selenoprotein P) is a liver-secreted, selenium-rich extracellular protein that functions as the principal transport vehicle distributing selenium from hepatocytes to peripheral tissues and as a redox-active enzyme [PMID:23038251, PMID:24434121]. Hepatocyte-specific deletion lowers plasma SELENOP to ~10% of normal, increases urinary selenium loss, and depletes selenium in extra-hepatic tissues, while hepatocyte-restricted transgenic expression of human SELENOP restores tissue selenium, selenoenzyme activity, fertility, and neurological function in Sepp-null mice — establishing liver-derived circulating SELENOP as the main selenium supply for brain, testis, kidney, and muscle [PMID:23038251, PMID:17961124]. Peripheral uptake proceeds through apoER2 (LRP8)-mediated endocytosis that depends on heparan sulfate proteoglycan binding and on the selenium-rich C-terminal domain (residues 240–361), followed by lysosomal processing that liberates selenium for utilization [PMID:22761431]. Beyond transport, the N-terminal domain carries a redox-active selenocysteine at position 40 within a thioredoxin-fold that confers thioredoxin reductase-1-coupled peroxidase activity, abolished by the U40S substitution [PMID:24434121]. SELENOP is essential for survival of parvalbumin-expressing interneurons under limiting selenium, and its loss produces epileptic seizures, ataxia, and tremor that are prevented by selenium supplementation or transgenic SELENOP, a CNS requirement confirmed by a naturally occurring complete-deletion phenotype in dogs [PMID:36182809, PMID:34339417]. SELENOP additionally engages signaling receptors: it binds the WNT co-receptors LRP5/6 to amplify canonical WNT signaling and promote intestinal tumorigenesis [PMID:37166989], and it signals through LRP8 on myeloid cells to shape anti-tumor immunity [PMID:39972392]. Hepatic SELENOP expression is transcriptionally controlled, induced by lauric acid via HNF4α and repressed by AMPK downstream of GLP-1 receptor signaling [PMID:26194078, PMID:35499234].","teleology":[{"year":2008,"claim":"Established that liver-derived circulating SELENOP, not local synthesis, is the form that supplies selenium to distant tissues, answering whether SELENOP acts systemically as a transport protein.","evidence":"Hepatocyte-specific transgenic human SEPP1 rescue in Sepp-/- mice with selenium, selenoenzyme, fertility, and neurological readouts","pmids":["17961124"],"confidence":"High","gaps":["Did not define the receptor or uptake route in recipient tissues","Did not resolve which domain mediates delivery versus enzymatic function"]},{"year":2012,"claim":"Defined the hepatocyte as the obligatory source of plasma SELENOP and showed its role in organism-wide selenium retention and distribution.","evidence":"Hepatocyte-specific conditional Sepp1 knockout mice with plasma/urine/tissue selenium tracking","pmids":["23038251"],"confidence":"High","gaps":["Did not address tissue uptake mechanism","Did not separate transport from enzymatic roles"]},{"year":2012,"claim":"Identified the cellular uptake mechanism, showing SELENOP is internalized via apoER2/LRP8 with heparan sulfate dependence and lysosomal processing of its C-terminal selenium-rich domain.","evidence":"75Se uptake assays, apoER2/Lrp1 siRNA, receptor pulldown with MS, truncation mutants, lysosome acidification block in L8 myoblasts","pmids":["22761431"],"confidence":"High","gaps":["Tested in one myoblast cell line","Did not establish tissue-specific receptor usage in vivo"]},{"year":2014,"claim":"Demonstrated that SELENOP is itself a redox enzyme, with an N-terminal selenocysteine (U40) conferring TrxR1-coupled peroxidase activity, separating its catalytic from its transport function.","evidence":"Purification of urinary N-terminal fragments, in vitro TrxR1 peroxidase assay, U40S active-site mutant","pmids":["24434121"],"confidence":"High","gaps":["Physiological substrate and in vivo antioxidant role not defined","Significance of renal megalin-mediated fragment uptake unclear"]},{"year":2022,"claim":"Established a non-transport CNS requirement, showing SELENOP preserves parvalbumin interneuron survival and prevents seizures under limiting selenium.","evidence":"Constitutive Selenop KO with video-EEG, dose/timing selenium supplementation, hepatocyte-specific transgenic rescue, interneuron histology","pmids":["36182809"],"confidence":"High","gaps":["Molecular basis of interneuron selectivity not resolved","Does not separate enzymatic from selenium-delivery contribution to neuroprotection"]},{"year":2021,"claim":"Confirmed in a large-animal model that SELENOP is required for selenium delivery to the CNS, generalizing the murine findings.","evidence":"Naturally occurring homozygous SELENOP deletion in dogs, WGS, selenium measurement, histopathology","pmids":["34339417"],"confidence":"Medium","gaps":["Natural variant, not engineered control","Tissue uptake mechanism not directly examined"]},{"year":2023,"claim":"Revealed a signaling function distinct from selenium transport, showing SELENOP binds LRP5/6 to amplify canonical WNT signaling and drive colon tumorigenesis.","evidence":"Co-IP with LRP5/6, WNT reporter assays, tumor organoid rescue, Selenop×Apc intestinal KO mouse model, scRNA-seq","pmids":["37166989"],"confidence":"High","gaps":["Whether selenocysteine/redox activity is needed for WNT effect unresolved","Binding interface on LRP5/6 not mapped"]},{"year":2025,"claim":"Linked post-translational acetylation of SELENOP to its expression and to LRP8-dependent modulation of myeloid cells in anti-tumor immunity.","evidence":"Co-IP of KAT8/SEPP1/LRP8, qRT-PCR/Western, flow cytometry, pancreatic cancer xenograft and metastasis models with anti-PD-1","pmids":["39972392"],"confidence":"Medium","gaps":["K247/K249 acetylation not confirmed by site mutagenesis","Mechanism linking acetylation to transcription unclear"]},{"year":2022,"claim":"Defined transcriptional control of hepatic SELENOP, identifying HNF4α as a lauric-acid-induced activator and AMPK as a GLP-1-driven repressor.","evidence":"Luciferase promoter assay, ChIP, Hnf4α/Selenop siRNA in hepatocytes and mouse liver; AMPK siRNA epistasis and AICAR in HepG2 cells","pmids":["35499234","26194078"],"confidence":"Medium","gaps":["FoxO1 contribution appears redundant and incompletely defined","Largely cell-line based; integration of opposing signals in vivo unclear"]},{"year":null,"claim":"How SELENOP's distinct activities — selenium transport, TrxR1-coupled peroxidase catalysis, and LRP5/6 and LRP8 receptor signaling — are coordinated and which require the selenocysteine remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model integrating transport and signaling functions","Whether redox activity is required for WNT/immune signaling untested","Physiological enzymatic substrates undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":[],"partners":["LRP8","LRP5","LRP6","TXNRD1","KAT8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49908","full_name":"Selenoprotein P","aliases":[],"length_aa":381,"mass_kda":43.2,"function":"Might be responsible for some of the extracellular antioxidant defense properties of selenium or might be involved in the transport of selenium. May supply selenium to tissues such as brain and testis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P49908/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SELENOP","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SELENOP","total_profiled":1310},"omim":[{"mim_id":"621274","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 152; CCDC152","url":"https://www.omim.org/entry/621274"},{"mim_id":"601484","title":"SELENOPROTEIN P; SELENOP","url":"https://www.omim.org/entry/601484"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Golgi apparatus","reliability":"Uncertain"},{"location":"Connecting piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":1966.1},{"tissue":"liver","ntpm":5860.1}],"url":"https://www.proteinatlas.org/search/SELENOP"},"hgnc":{"alias_symbol":["SeP","SELP","SEPP"],"prev_symbol":["SEPP1"]},"alphafold":{"accession":"P49908","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49908","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SELENOP","jax_strain_url":"https://www.jax.org/strain/search?query=SELENOP"},"sequence":{"accession":"P49908","fasta_url":"https://rest.uniprot.org/uniprotkb/P49908.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49908/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49908"}},"corpus_meta":[{"pmid":"22174280","id":"PMC_22174280","title":"SEPP: SATé-enabled phylogenetic placement.","date":"2012","source":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","url":"https://pubmed.ncbi.nlm.nih.gov/22174280","citation_count":198,"is_preprint":false},{"pmid":"23038251","id":"PMC_23038251","title":"Production of selenoprotein P (Sepp1) by hepatocytes is central to selenium homeostasis.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23038251","citation_count":117,"is_preprint":false},{"pmid":"17961124","id":"PMC_17961124","title":"Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17961124","citation_count":113,"is_preprint":false},{"pmid":"15203372","id":"PMC_15203372","title":"Expression profiling and genetic alterations of the selenoproteins GI-GPx and SePP in colorectal carcinogenesis.","date":"2004","source":"Nutrition and 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Hispanics.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24161883","citation_count":43,"is_preprint":false},{"pmid":"19058871","id":"PMC_19058871","title":"Expression of selenoprotein-coding genes SEPP1, SEP15 and hGPX1 in non-small cell lung cancer.","date":"2008","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/19058871","citation_count":39,"is_preprint":false},{"pmid":"24434121","id":"PMC_24434121","title":"Sepp1(UF) forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1.","date":"2014","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24434121","citation_count":35,"is_preprint":false},{"pmid":"30612060","id":"PMC_30612060","title":"Arsenic metabolites; selenium; and AS3MT, MTHFR, AQP4, AQP9, SELENOP, INMT, and MT2A polymorphisms in Croatian-Slovenian population from PHIME-CROME study.","date":"2018","source":"Environmental 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polymorphisms.","date":"2018","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29648467","citation_count":12,"is_preprint":false},{"pmid":"33840662","id":"PMC_33840662","title":"Coix lacryma-jobi Seed Oil Reduces Fat Accumulation in Nonalcoholic Fatty Liver Disease by Inhibiting the Activation of the p-AMPK/SePP1/apoER2 Pathway.","date":"2021","source":"Journal of oleo science","url":"https://pubmed.ncbi.nlm.nih.gov/33840662","citation_count":12,"is_preprint":false},{"pmid":"35499234","id":"PMC_35499234","title":"Lauric acid impairs insulin-induced Akt phosphorylation by upregulating SELENOP expression via HNF4α induction.","date":"2022","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35499234","citation_count":11,"is_preprint":false},{"pmid":"31158358","id":"PMC_31158358","title":"HMGB1 and SEPP1 as predictors of hepatocellular carcinoma in patients with viral C hepatitis: Effect of DAAs.","date":"2019","source":"Clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31158358","citation_count":11,"is_preprint":false},{"pmid":"35205233","id":"PMC_35205233","title":"An Assessment of GPX1 (rs1050450), DIO2 (rs225014) and SEPP1 (rs7579) Gene Polymorphisms in Women with Endometrial Cancer.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35205233","citation_count":9,"is_preprint":false},{"pmid":"38543751","id":"PMC_38543751","title":"Bacteriophage vB_SepP_134 and Endolysin LysSte_134_1 as Potential Staphylococcus-Biofilm-Removing Biological Agents.","date":"2024","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/38543751","citation_count":8,"is_preprint":false},{"pmid":"27164173","id":"PMC_27164173","title":"Plasma Selenium Protein P Isoform 1 (SEPP1): A Predictor of Selenium Status in Nepalese Children Detected by Plasma Proteomics.","date":"2016","source":"International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/27164173","citation_count":8,"is_preprint":false},{"pmid":"39972392","id":"PMC_39972392","title":"KAT8 catalyzes the acetylation of SEPP1 at lysine 247/249 and modulates the activity of CD8+ T cells via LRP8 to promote anti-tumor immunity in pancreatic cancer.","date":"2025","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/39972392","citation_count":7,"is_preprint":false},{"pmid":"31542866","id":"PMC_31542866","title":"Effect of single nucleotide polymorphisms in SEPS1 and SEPP1 on expression in the protein level in metabolic syndrome in subjects with cardiovascular disease.","date":"2019","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31542866","citation_count":6,"is_preprint":false},{"pmid":"39708777","id":"PMC_39708777","title":"Selenium promotes neural development through the regulation of GPX4 and SEPP1 in an iPSC-derived neuronal model.","date":"2024","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/39708777","citation_count":6,"is_preprint":false},{"pmid":"30582190","id":"PMC_30582190","title":"Interaction of NKX3.1 and SELENOP genotype with prostate cancer recurrence.","date":"2018","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/30582190","citation_count":5,"is_preprint":false},{"pmid":"31523666","id":"PMC_31523666","title":"Evaluation of SEPP1 and Selenoprotein S Gene Polymorphisms (rs7579 and rs34713741) in Relation to Colorectal Cancer Susceptibility in Subset of Iranian Population: A Case-control Study.","date":"2019","source":"Advanced biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/31523666","citation_count":5,"is_preprint":false},{"pmid":"34988542","id":"PMC_34988542","title":"Inhibition of selenoprotein synthesis by Zika virus may contribute to congenital Zika syndrome and microcephaly by mimicking SELENOP knockout and the genetic disease PCCA.","date":"2021","source":"BBA advances","url":"https://pubmed.ncbi.nlm.nih.gov/34988542","citation_count":5,"is_preprint":false},{"pmid":"24482687","id":"PMC_24482687","title":"Hypoxia induced changes of SePP1 expression in rat preadipocytes and its impact on vascular fibroblasts.","date":"2014","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24482687","citation_count":4,"is_preprint":false},{"pmid":"27371843","id":"PMC_27371843","title":"[Overexpression of SEPP1 inhibits the proliferation and induces cell cycle G2/M arrest of 786-O and 769-P human renal carcinoma cells].","date":"2016","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27371843","citation_count":4,"is_preprint":false},{"pmid":"35651983","id":"PMC_35651983","title":"The Association Between Selenium, Selenoprotein P (SEPP1), Fluid Intelligence, and Exercise in the UK Biobank Cohort.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/35651983","citation_count":4,"is_preprint":false},{"pmid":"34950691","id":"PMC_34950691","title":"A Functional Variant in SEPP1 Interacts With Plasma Selenium Concentrations on 3-Year Lipid Changes: A Prospective Cohort Study.","date":"2021","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/34950691","citation_count":4,"is_preprint":false},{"pmid":"39077596","id":"PMC_39077596","title":"Selenoprotein P-1 (SEPP1) as an Early Biomarker of Acute Kidney Injury in Patients Undergoing Cardiopulmonary Bypass.","date":"2022","source":"Reviews in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39077596","citation_count":3,"is_preprint":false},{"pmid":"35321982","id":"PMC_35321982","title":"Forkhead box protein O1 (FoxO1) knockdown accelerates the eicosapentaenoic acid (EPA)-mediated Selenop downregulation independently of sterol regulatory element-binding protein-1c (SREBP-1c) in H4IIEC3 hepatocytes.","date":"2022","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/35321982","citation_count":2,"is_preprint":false},{"pmid":"40821907","id":"PMC_40821907","title":"Integrated multi-omics analysis identifies SELENOP and PKMYT1 as immune-metabolic hub genes in breast cancer.","date":"2025","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/40821907","citation_count":1,"is_preprint":false},{"pmid":"38929492","id":"PMC_38929492","title":"Selenoprotein-P1 (SEPP1) Expression in Human Proximal Tubule Cells after Ischemia-Reperfusion Injury: An In Vitro Model.","date":"2024","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/38929492","citation_count":1,"is_preprint":false},{"pmid":"41001101","id":"PMC_41001101","title":"The SELENOP Polymorphism rs7579 Predicts Hepatic Steatosis in Females With Insulin Resistance in the General Population.","date":"2025","source":"Journal of the Endocrine Society","url":"https://pubmed.ncbi.nlm.nih.gov/41001101","citation_count":1,"is_preprint":false},{"pmid":"41526347","id":"PMC_41526347","title":"Hypoxia-driven remodeling of SELENOP+ macrophages shapes T cell dynamics and promotes ovarian cancer metastasis.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41526347","citation_count":0,"is_preprint":false},{"pmid":"41862151","id":"PMC_41862151","title":"Bone marrow SELENOP+ macrophages support hematopoiesis after transplantation via GAS6-AXL signaling pathway.","date":"2026","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/41862151","citation_count":0,"is_preprint":false},{"pmid":"27301226","id":"PMC_27301226","title":"[Production effect comparison of SEPP and GPx between HepG2 and Hela cells with different selenocompounds].","date":"2016","source":"Wei sheng yan jiu = Journal of hygiene research","url":"https://pubmed.ncbi.nlm.nih.gov/27301226","citation_count":0,"is_preprint":false},{"pmid":"38792487","id":"PMC_38792487","title":"Selenoprotein P-1 (SEPP1) as an Early Biomarker of Myocardial Injury in Patients Undergoing Cardiopulmonary Bypass.","date":"2024","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38792487","citation_count":0,"is_preprint":false},{"pmid":"41371460","id":"PMC_41371460","title":"Neurobehavioral effects of mercury, lead, and selenium co-exposure in the Brazilian amazon: Insights from bayesian mixture modeling and SELENOP genetic variation.","date":"2025","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41371460","citation_count":0,"is_preprint":false},{"pmid":"41666325","id":"PMC_41666325","title":"Bioisostere-Driven Discovery of SePP: A Selenium-Containing Polypharmacological Agent Relevant to Fragile X Syndrome.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41666325","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.24.661430","title":"Selenoprotein P Deficiency Drives Hepatocellular Carcinoma Progression via Induction of Neutrophil Senescence and Immunosuppressive Microenvironment","date":"2025-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.24.661430","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.25.25332222","title":"Neuro-immune, metabolic, and oxidative pathways in depression due to hypothyroidism and Hashimoto’s thyroiditis","date":"2025-07-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.25.25332222","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.28.610036","title":"Immune aging impairs muscle regeneration via macrophage-derived anti-oxidant selenoprotein P","date":"2024-08-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.28.610036","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.29.656587","title":"Tracing the vertebrate selenoproteome evolution reveals expansions in ray-finned fishes and convergent depletions in tetrapods","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.29.656587","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33311,"output_tokens":4339,"usd":0.082509,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12458,"output_tokens":3327,"usd":0.072733,"stage2_stop_reason":"end_turn"},"total_usd":0.155242,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Hepatocyte-specific deletion of Sepp1 lowered plasma Sepp1 to ~10% of controls, increased urinary selenium excretion, and reduced selenium in extra-hepatic tissues, establishing that hepatocyte-produced Sepp1 is central to retaining selenium in the organism and distributing it from liver to peripheral tissues.\",\n      \"method\": \"Conditional knockout mouse (hepatocyte-specific Sepp1 deletion via alb-cre), selenium measurements in plasma/urine/tissues, mRNA quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined tissue-level phenotype, quantitative selenium tracking, replicated concept across multiple tissues and dietary conditions\",\n      \"pmids\": [\"23038251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transgenic hepatocyte-specific expression of human SELENOP in Sepp-/- mice restored selenium content and selenoenzyme activities in serum, kidney, testis, and brain, rescued male fertility and neurological defects under selenium-adequate diet, demonstrating that liver-derived circulating SePP is the main transport form supplying selenium to peripheral tissues including testis and brain.\",\n      \"method\": \"Transgenic rescue in Sepp-/- mice (hepatocyte-specific transthyretin promoter driving human SEPP1), selenium measurements, selenoenzyme activity assays, behavioral assessment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic rescue experiment with multiple orthogonal readouts (selenium levels, enzyme activity, fertility, neurological behavior), consistent with conditional KO data\",\n      \"pmids\": [\"17961124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"L8 myoblast cells take up Sepp1 via apoER2-mediated endocytosis requiring heparin sulfate proteoglycan binding; siRNA knockdown of apoER2 (but not Lrp1) inhibited 75Se uptake; blockage of lysosome acidification prevented Sepp1 digestion and selenium utilization; the selenium-rich C-terminal domain (residues 240-361) is required for uptake.\",\n      \"method\": \"75Se-labeling uptake assays, siRNA knockdown of apoER2 and Lrp1, affinity chromatography (Sepp1 column) with mass spectrometry identification of receptors, protamine/chlorate inhibition, lysosome acidification blockage, truncation isoform comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (siRNA, pharmacological inhibitors, receptor pulldown with MS, truncation mutants) in single lab\",\n      \"pmids\": [\"22761431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Urinary Sepp1 N-terminal fragments (Sepp1UF, residues 1-~183-208) possess peroxidase activity when coupled with thioredoxin reductase-1 (TrxR1), catalyzing NADPH oxidation with H2O2 or tert-butylhydroperoxide; activity requires the selenocysteine at position 40 (U40S mutant was inactive). Full-length Sepp1 and Sepp1Δ240-361 were also TrxR1 substrates. These fragments are filtered by the glomerulus and taken up by proximal convoluted tubule cells via megalin-mediated endocytosis.\",\n      \"method\": \"Purification of urinary Sepp1 forms from megalin-/- mice using monoclonal antibody, mass spectrometry identification of N-terminal fragments, in vitro TrxR1 peroxidase assay (NADPH oxidation), active-site mutant Sepp1(U40S) comparison\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with active-site mutagenesis, purified protein fractions identified by MS, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"24434121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SELENOP interacts directly with the WNT co-receptors LRP5 and LRP6, and this protein-protein interaction contributes to SELENOP's ability to increase canonical WNT signaling activity; Selenop-KO tumor organoids showed decreased WNT target gene expression reversible by SELENOP restoration; Selenop KO in an intestinal APC-deletion mouse model decreased colon tumor incidence and size.\",\n      \"method\": \"Protein-protein interaction mapping (co-IP of SELENOP with LRP5/6), tumor organoid formation assay, WNT reporter assays in CRC and non-cancer cell lines, conditional KO mouse model (Selenop KO × Apc intestinal KO), scRNA-Seq of human colon tissue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal/functional Co-IP, organoid rescue, in vivo mouse model, multiple cell lines; single lab but orthogonal methods\",\n      \"pmids\": [\"37166989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SELENOP is essential for preserving parvalbumin-expressing interneuron survival under limiting selenium supply; Selenop-/- mice on RDA diet developed epileptic seizures, ataxia, and tremor confirmed by video-EEG; selenium supplementation from birth or transgenic hepatocyte-specific human SELENOP expression prevented both neurological phenotypes; the effects were dose- and time-dependent.\",\n      \"method\": \"Constitutive Selenop knockout mice, video-electroencephalography, behavioral testing (ataxia/tremor scoring), selenium supplementation experiments (dose and timing variation), transgenic rescue (hepatocyte-specific SELENOP), brain GPx activity assay, histological analysis of interneurons\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined electrophysiological phenotype, transgenic rescue, dose-response supplementation, multiple neurological readouts; consistent with prior Sepp-/- mouse literature\",\n      \"pmids\": [\"36182809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT8 catalyzes acetylation of SEPP1 at lysine residues K247 and K249, upregulating SEPP1 transcription and protein level; SEPP1 then signals through its receptor LRP8 on MDSCs to impair MDSC survival, thereby enabling CD8+ T cell-mediated anti-tumor immunity in pancreatic cancer.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) of KAT8, SEPP1, and LRP8; qRT-PCR and Western blot; flow cytometry for immune cell abundance and apoptosis; PC xenograft and liver metastasis mouse models; SEPP1 recombinant protein treatment combined with anti-PD-1\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies acetylation and receptor interaction, in vivo mouse models, single lab with multiple methods but acetylation mechanism not confirmed by mutagenesis of K247/249\",\n      \"pmids\": [\"39972392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Exendin-4 (GLP-1 receptor agonist) reduces hepatic SEPP1 expression via AMPK activation; AMPK activator AICAR negatively regulated SEPP1 expression, and AMPK siRNA knockdown prevented the exendin-4-mediated reduction of SEPP1, placing AMPK upstream of SEPP1 expression in hepatocytes.\",\n      \"method\": \"HepG2 cell treatment with palmitic acid/tunicamycin ± exendin-4, AMPK siRNA knockdown, AICAR treatment, qRT-PCR and Western blotting for SEPP1 and ER stress markers\",\n      \"journal\": \"Endocrinology and metabolism (Seoul, Korea)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown epistasis plus pharmacological AMPK activation, two orthogonal approaches in single lab, cell-line only\",\n      \"pmids\": [\"26194078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lauric acid upregulates Selenop expression in hepatocytes via HNF4α; luciferase promoter assay identified an HNF4α binding site in the SELENOP promoter; ChIP showed lauric acid increased HNF4α binding to this promoter; Hnf4α siRNA knockdown canceled lauric acid-induced Selenop upregulation; Akt phosphorylation impairment by lauric acid was rescued by knockdown of either Hnf4α or Selenop.\",\n      \"method\": \"Luciferase promoter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown of Hnf4α and Selenop, Western blotting for Akt phosphorylation in Hepa1-6 cells and mouse liver\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase assay plus siRNA epistasis in single lab, multiple orthogonal methods, cell line + in vivo mouse liver\",\n      \"pmids\": [\"35499234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FoxO1 knockdown accelerates EPA-mediated Selenop downregulation in hepatocytes independently of SREBP-1c; EPA upregulates Foxo1 mRNA via the ERK1/2 pathway without altering FoxO1 protein nuclear translocation, suggesting a redundant transcriptional network controlling Selenop expression.\",\n      \"method\": \"siRNA knockdown of Foxo1, ERK1/2 and PKA pharmacological inhibitors, RT-PCR, nuclear fractionation/translocation assay in H4IIEC3 hepatocytes\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA epistasis plus inhibitor studies but single lab, single cell type, no in vivo validation\",\n      \"pmids\": [\"35321982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SELENOP deletion in dogs (homozygous 17,325 bp deletion removing entire protein-coding sequence) caused cerebellar ataxia, CNS atrophy, and reduced blood selenium to ~30% of wildtype, demonstrating that SELENOP is required for selenium transport into the CNS in a large-animal model.\",\n      \"method\": \"Whole genome sequencing, linkage/homozygosity mapping, genotyping of >600 dogs, selenium measurement by atomic absorption, histopathology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — naturally occurring complete loss-of-function with multiple affected animals, selenium quantification, histopathology; not experimental manipulation but rigorous genetic evidence\",\n      \"pmids\": [\"34339417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZIKV infection knocked down SELENOP protein expression by ~99% in HEK293T cells without significant reduction in SELENOP mRNA, suggesting post-transcriptional/translational suppression; computationally predicted antisense hybridization between ZIKV RNA and SELENOP mRNA was confirmed at the DNA level by gel shift assay.\",\n      \"method\": \"ZIKV infection of HEK293T cells, Western blotting for SELENOP and TXNRD1, RT-qPCR for mRNA levels, gel shift assay with synthetic oligonucleotides\",\n      \"journal\": \"BBA advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Western blot knockdown in single cell line, gel shift at DNA level only (not RNA), single lab, computational interaction not fully validated at RNA level\",\n      \"pmids\": [\"34988542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Overexpression of SEPP1 in 786-O and 769-P renal carcinoma cells inhibited proliferation, reduced colony formation, and caused G2/M cell cycle arrest in 786-O cells.\",\n      \"method\": \"Lentiviral overexpression of SEPP1, MTS proliferation assay, colony formation assay, flow cytometry cell cycle analysis\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain-of-function with phenotypic readout but no molecular pathway placement, single lab, single method set\",\n      \"pmids\": [\"27371843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hepatic Sepp1 depletion in HCC impairs selenium uptake in tumor-infiltrating neutrophils by disrupting Lrp8 receptor-mediated transport, suppressing intracellular selenium metabolism; this reduces hydrogen selenide (H2Se) production and increases S-adenosylmethionine (SAM) accumulation, leading to increased H3K4me3 modification in neutrophils and establishing a pro-senescence chromatin landscape that drives immunosuppression.\",\n      \"method\": \"scRNA-seq of HCC mouse tumors, macrophage/neutrophil-specific analyses, in vitro selenium uptake assays, chromatin modification (H3K4me3) measurement, selenium supplementation rescue experiments, anti-PD-1 combination therapy in mouse models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic pathway proposed with scRNA-seq and in vitro data, preprint not peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.24.661430\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Macrophage-specific deletion of Sepp1 impaired the acquisition of the repair inflammatory profile, disrupted macrophage support of muscle stem cells in vitro and in vivo, and caused inefficient skeletal muscle regeneration; transplantation of young WT (but not Sepp1 KO) bone marrow restored muscle regeneration in aged mice.\",\n      \"method\": \"Macrophage-specific Sepp1 conditional KO, FACS isolation of niche cells, RNA-sequencing, in vitro co-culture of macrophages and muscle stem cells, bone marrow transplantation into aged mice, in vivo regeneration assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-type-specific KO with defined phenotype and rescue, preprint not peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.08.28.610036\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SELENOP (selenoprotein P) is a liver-secreted, selenium-rich extracellular protein that serves as the primary selenium transporter in plasma: hepatocytes synthesize and secrete SELENOP, which is taken up by peripheral tissues (including brain, testis, kidney, and muscle) via apoER2/LRP8-mediated endocytosis requiring heparin sulfate proteoglycans and lysosomal processing of its selenium-rich C-terminal domain; the N-terminal domain carries a redox-active selenocysteine (U40) in a thioredoxin fold that confers peroxidase activity when coupled with thioredoxin reductase-1; SELENOP additionally interacts with LRP5/6 WNT co-receptors to modulate canonical WNT signaling in the colon, is acetylated at K247/249 by KAT8 to regulate its expression and LRP8-mediated effects on immune cells, and its hepatic expression is regulated transcriptionally by HNF4α (induced by lauric acid) and negatively by AMPK (activated by GLP-1 signaling).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SELENOP (selenoprotein P) is a liver-secreted, selenium-rich extracellular protein that functions as the principal transport vehicle distributing selenium from hepatocytes to peripheral tissues and as a redox-active enzyme [#0, #3]. Hepatocyte-specific deletion lowers plasma SELENOP to ~10% of normal, increases urinary selenium loss, and depletes selenium in extra-hepatic tissues, while hepatocyte-restricted transgenic expression of human SELENOP restores tissue selenium, selenoenzyme activity, fertility, and neurological function in Sepp-null mice — establishing liver-derived circulating SELENOP as the main selenium supply for brain, testis, kidney, and muscle [#0, #1]. Peripheral uptake proceeds through apoER2 (LRP8)-mediated endocytosis that depends on heparan sulfate proteoglycan binding and on the selenium-rich C-terminal domain (residues 240–361), followed by lysosomal processing that liberates selenium for utilization [#2]. Beyond transport, the N-terminal domain carries a redox-active selenocysteine at position 40 within a thioredoxin-fold that confers thioredoxin reductase-1-coupled peroxidase activity, abolished by the U40S substitution [#3]. SELENOP is essential for survival of parvalbumin-expressing interneurons under limiting selenium, and its loss produces epileptic seizures, ataxia, and tremor that are prevented by selenium supplementation or transgenic SELENOP, a CNS requirement confirmed by a naturally occurring complete-deletion phenotype in dogs [#5, #10]. SELENOP additionally engages signaling receptors: it binds the WNT co-receptors LRP5/6 to amplify canonical WNT signaling and promote intestinal tumorigenesis [#4], and it signals through LRP8 on myeloid cells to shape anti-tumor immunity [#6]. Hepatic SELENOP expression is transcriptionally controlled, induced by lauric acid via HNF4α and repressed by AMPK downstream of GLP-1 receptor signaling [#7, #8].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that liver-derived circulating SELENOP, not local synthesis, is the form that supplies selenium to distant tissues, answering whether SELENOP acts systemically as a transport protein.\",\n      \"evidence\": \"Hepatocyte-specific transgenic human SEPP1 rescue in Sepp-/- mice with selenium, selenoenzyme, fertility, and neurological readouts\",\n      \"pmids\": [\"17961124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor or uptake route in recipient tissues\", \"Did not resolve which domain mediates delivery versus enzymatic function\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the hepatocyte as the obligatory source of plasma SELENOP and showed its role in organism-wide selenium retention and distribution.\",\n      \"evidence\": \"Hepatocyte-specific conditional Sepp1 knockout mice with plasma/urine/tissue selenium tracking\",\n      \"pmids\": [\"23038251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address tissue uptake mechanism\", \"Did not separate transport from enzymatic roles\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the cellular uptake mechanism, showing SELENOP is internalized via apoER2/LRP8 with heparan sulfate dependence and lysosomal processing of its C-terminal selenium-rich domain.\",\n      \"evidence\": \"75Se uptake assays, apoER2/Lrp1 siRNA, receptor pulldown with MS, truncation mutants, lysosome acidification block in L8 myoblasts\",\n      \"pmids\": [\"22761431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested in one myoblast cell line\", \"Did not establish tissue-specific receptor usage in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that SELENOP is itself a redox enzyme, with an N-terminal selenocysteine (U40) conferring TrxR1-coupled peroxidase activity, separating its catalytic from its transport function.\",\n      \"evidence\": \"Purification of urinary N-terminal fragments, in vitro TrxR1 peroxidase assay, U40S active-site mutant\",\n      \"pmids\": [\"24434121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate and in vivo antioxidant role not defined\", \"Significance of renal megalin-mediated fragment uptake unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a non-transport CNS requirement, showing SELENOP preserves parvalbumin interneuron survival and prevents seizures under limiting selenium.\",\n      \"evidence\": \"Constitutive Selenop KO with video-EEG, dose/timing selenium supplementation, hepatocyte-specific transgenic rescue, interneuron histology\",\n      \"pmids\": [\"36182809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of interneuron selectivity not resolved\", \"Does not separate enzymatic from selenium-delivery contribution to neuroprotection\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed in a large-animal model that SELENOP is required for selenium delivery to the CNS, generalizing the murine findings.\",\n      \"evidence\": \"Naturally occurring homozygous SELENOP deletion in dogs, WGS, selenium measurement, histopathology\",\n      \"pmids\": [\"34339417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Natural variant, not engineered control\", \"Tissue uptake mechanism not directly examined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a signaling function distinct from selenium transport, showing SELENOP binds LRP5/6 to amplify canonical WNT signaling and drive colon tumorigenesis.\",\n      \"evidence\": \"Co-IP with LRP5/6, WNT reporter assays, tumor organoid rescue, Selenop×Apc intestinal KO mouse model, scRNA-seq\",\n      \"pmids\": [\"37166989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether selenocysteine/redox activity is needed for WNT effect unresolved\", \"Binding interface on LRP5/6 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked post-translational acetylation of SELENOP to its expression and to LRP8-dependent modulation of myeloid cells in anti-tumor immunity.\",\n      \"evidence\": \"Co-IP of KAT8/SEPP1/LRP8, qRT-PCR/Western, flow cytometry, pancreatic cancer xenograft and metastasis models with anti-PD-1\",\n      \"pmids\": [\"39972392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"K247/K249 acetylation not confirmed by site mutagenesis\", \"Mechanism linking acetylation to transcription unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined transcriptional control of hepatic SELENOP, identifying HNF4α as a lauric-acid-induced activator and AMPK as a GLP-1-driven repressor.\",\n      \"evidence\": \"Luciferase promoter assay, ChIP, Hnf4α/Selenop siRNA in hepatocytes and mouse liver; AMPK siRNA epistasis and AICAR in HepG2 cells\",\n      \"pmids\": [\"35499234\", \"26194078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FoxO1 contribution appears redundant and incompletely defined\", \"Largely cell-line based; integration of opposing signals in vivo unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SELENOP's distinct activities — selenium transport, TrxR1-coupled peroxidase catalysis, and LRP5/6 and LRP8 receptor signaling — are coordinated and which require the selenocysteine remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model integrating transport and signaling functions\", \"Whether redox activity is required for WNT/immune signaling untested\", \"Physiological enzymatic substrates undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LRP8\", \"LRP5\", \"LRP6\", \"TXNRD1\", \"KAT8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}