{"gene":"LIX1L","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"LIX1L is a putative RNA-binding protein (RBP) containing a double-stranded RNA binding motif. It interacts with proteins RIOK1, nucleolin (NCL), and PABPC4, as well as multiple miRNAs (has-miRNA-520a-5p, -300, -216b, -326, -190a, -548b-3p, -7-5p and -1296) in HEK-293 cells, as determined by MALDI-TOF/TOF mass spectrometry and RNA immunoprecipitation-sequencing.","method":"MALDI-TOF/TOF mass spectrometry, RNA immunoprecipitation-sequencing (RIP-seq)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome plus RIP-seq, single lab, two orthogonal methods","pmids":["26310847"],"is_preprint":false},{"year":2015,"finding":"LIX1L is phosphorylated at Tyr136, and this phosphorylation is required for LIX1L-induced cell proliferation. ROS1, HCK, ABL1, ABL2, JAK3, LCK, and TYRO3 were identified as candidate kinases responsible for pTyr136. A homeodomain peptide (PY136) that reduces pTyr136 inhibited LIX1L-induced cell proliferation in vitro and in vivo, and induced apoptosis.","method":"MALDI-TOF/TOF mass spectrometry (phosphosite identification), homeodomain peptide inhibition (PY136) in vitro and in vivo tumor models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphosite identified by MS and functionally validated by peptide inhibitor in vitro and in vivo, single lab","pmids":["26310847"],"is_preprint":false},{"year":2021,"finding":"LIX1L functions as a post-transcriptional regulator in cholestatic liver injury by suppressing miR-191-3p expression. miR-191-3p targets and downregulates LRH-1 (Lrh-1), thereby inhibiting Cyp7a1 and Cyp8b1 expression and bile acid synthesis. LIX1L deficiency restores miR-191-3p levels and attenuates cholestatic liver injury. Additionally, bile acid-induced LIX1L upregulation depends on Egr-1 binding to the LIX1L promoter, as shown by chromatin immunoprecipitation.","method":"Lix1l knockout mice, miRNA microarray profiling, AAV-mediated hepatic delivery of miR-191-3p, chromatin immunoprecipitation (ChIP) assay","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse models (multiple cholestasis models), ChIP assay, and AAV rescue experiment, multiple orthogonal methods in single study","pmids":["33746084"],"is_preprint":false},{"year":2021,"finding":"LIX1L promotes HCC progression by increasing miR-21-3p expression, which targets and suppresses fructose-1,6-bisphosphatase (FBP1), thereby enhancing glycolysis (glucose consumption and lactate production), cell proliferation, migration, and invasion. miR-21-3p inhibitor abrogated LIX1L-induced enhancement of cell migration, invasion, and glucose metabolism.","method":"LIX1L knockdown/overexpression in HCC cells (in vitro), orthotopic tumor mouse model (in vivo), miR-21-3p inhibitor rescue experiments","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays plus in vivo orthotopic model plus miR inhibitor rescue, single lab","pmids":["34221869"],"is_preprint":false},{"year":2022,"finding":"LIX1L physically interacts with DCHS1 (a cadherin involved in mitral valve development) and SEPT9 (a septin cytoskeletal protein). This DCHS1-LIX1L-SEPT9 axis promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape, linking DCHS1-based cell adhesions to the septin-actin cytoskeleton.","method":"Biochemical techniques (co-immunoprecipitation/pulldown implied), mouse and cell culture models","journal":"Journal of cardiovascular development and disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — biochemical interaction assays and mouse/cell culture models reported, but abstract does not specify reciprocal co-IP or mutagenesis; single lab","pmids":["35200715"],"is_preprint":false},{"year":2022,"finding":"LIX1L localizes to the nucleoli upon TGFβ1-induced EMT in NSCLC cells, where it physically interacts with the ribosome biogenesis regulator nucleolin (NCL), inducing ribosomal RNA (rRNA) synthesis. NCL knockdown or inhibition of rRNA synthesis reverses LIX1L-mediated enhancement of EMT, migration, invasion, anoikis resistance, EGFR-TKI resistance, and proliferation.","method":"Immunofluorescence/subcellular localization, co-immunoprecipitation (physical interaction with NCL), NCL knockdown, rRNA synthesis inhibition, functional cell assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization tied to functional consequence, co-IP with NCL, NCL KD rescue, single lab with multiple orthogonal methods","pmids":["36478492"],"is_preprint":false},{"year":2024,"finding":"Metabolic stress promotes PARP1-mediated poly-ADP-ribosylation (PARylation) of LIX1L, which increases its stability and RNA-binding ability. PARylated LIX1L then binds to AU-rich elements in the 3'UTR and CDS of CD36 mRNA, stabilizing CD36 mRNA and upregulating CD36 protein, thereby promoting hepatic lipid accumulation, inflammation, fibrosis, and a tumor-prone liver microenvironment in MASH/HCC.","method":"PARP1 inhibition/modification assays, RNA binding assays (3'UTR/CDS binding), Lix1l knockout mouse models (MASH and HCC), mechanistic biochemical studies","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse models, PARylation mechanistic assay, RNA binding to CD36 mRNA, single lab with multiple orthogonal methods","pmids":["39725340"],"is_preprint":false},{"year":2019,"finding":"LIX1L is a target gene of miRNA-6089. The lncRNA TATDN1 sponges miRNA-6089, reducing its availability and thereby upregulating LIX1L expression. Overexpression of LIX1L partially reversed the inhibitory effect of miRNA-6089 on HCC cell proliferation and cell cycle progression.","method":"Dual-luciferase reporter assay (target validation), siRNA/overexpression in HCC cell lines","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase reporter and overexpression assays only, limited mechanistic depth for LIX1L itself","pmids":["31378885"],"is_preprint":false}],"current_model":"LIX1L is an RNA-binding protein (containing a double-stranded RNA binding motif) that operates at multiple levels: it is phosphorylated at Tyr136 by kinases including ROS1 to promote cell proliferation; it is poly-ADP-ribosylated by PARP1 under metabolic stress to stabilize CD36 mRNA via AU-rich element binding; it interacts with nucleolin in the nucleolus to drive rRNA synthesis and EMT; it suppresses miR-191-3p to activate bile acid synthesis genes (LRH-1/CYP7A1/CYP8B1) in cholestasis; it upregulates miR-21-3p to suppress FBP1 and promote glycolysis in HCC; and it physically links DCHS1 cell adhesions to the SEPT9 septin-actin cytoskeleton during cardiac valve development."},"narrative":{"mechanistic_narrative":"LIX1L is a putative double-stranded RNA-binding protein that functions as a post-transcriptional regulator coupling RNA metabolism to cell proliferation, metabolic stress responses, and tissue morphogenesis [PMID:26310847, PMID:33746084]. It associates with ribosome biogenesis and RNA-handling factors, including nucleolin (NCL), RIOK1, and PABPC4, and binds multiple miRNAs [PMID:26310847]. Phosphorylation at Tyr136 by candidate tyrosine kinases including ROS1 is required for LIX1L-driven cell proliferation, and a peptide that reduces pTyr136 inhibits proliferation and induces apoptosis [PMID:26310847]. LIX1L acts on miRNA circuits in liver disease: it suppresses miR-191-3p to relieve repression of LRH-1 and activate the bile acid synthesis genes CYP7A1 and CYP8B1 in cholestasis, with its own expression induced by Egr-1 binding the LIX1L promoter [PMID:33746084], and it raises miR-21-3p to suppress FBP1 and enhance glycolysis, proliferation, and invasion in hepatocellular carcinoma [PMID:34221869]. Under metabolic stress it is PARylated by PARP1, which stabilizes the protein and enhances its RNA binding, allowing it to bind AU-rich elements in CD36 mRNA and promote hepatic lipid accumulation, inflammation, and fibrosis [PMID:39725340]. During TGFβ1-induced EMT it localizes to the nucleolus and interacts with NCL to drive rRNA synthesis, supporting migration, invasion, and therapy resistance in NSCLC [PMID:36478492]. Distinct from its RNA roles, LIX1L bridges DCHS1-based cell adhesions to the SEPT9 septin-actin cytoskeleton to organize filamentous actin during cardiac valve development [PMID:35200715].","teleology":[{"year":2015,"claim":"Established LIX1L as an RNA-binding protein with a defined interactome, answering what molecular class it belongs to and which RNA/protein partners it engages.","evidence":"MALDI-TOF/TOF mass spectrometry and RIP-seq in HEK-293 cells","pmids":["26310847"],"confidence":"Medium","gaps":["Functional consequence of binding individual miRNAs not tested","Direct RNA targets versus indirect associations not resolved","No structural basis for dsRNA binding"]},{"year":2015,"claim":"Identified Tyr136 phosphorylation as a proliferation-driving modification and candidate kinases, linking LIX1L to a druggable proliferative signal.","evidence":"MS phosphosite mapping and PY136 peptide inhibition in vitro and in vivo tumor models","pmids":["26310847"],"confidence":"Medium","gaps":["Which of the candidate kinases (ROS1, HCK, ABL1/2, JAK3, LCK, TYRO3) acts physiologically not determined","Downstream effectors of pTyr136 unknown","How phosphorylation alters RNA binding not addressed"]},{"year":2019,"claim":"Placed LIX1L downstream of a lncRNA-miRNA axis (TATDN1/miR-6089), addressing how LIX1L expression is regulated in HCC.","evidence":"Dual-luciferase reporter and siRNA/overexpression in HCC cell lines","pmids":["31378885"],"confidence":"Low","gaps":["Luciferase/overexpression only, no endogenous validation","Limited mechanistic depth for LIX1L itself","In vivo relevance untested"]},{"year":2021,"claim":"Defined LIX1L as a post-transcriptional controller of bile acid synthesis via miR-191-3p/LRH-1, and identified Egr-1 as its upstream transcriptional inducer in cholestasis.","evidence":"Lix1l knockout mice across cholestasis models, miRNA microarray, AAV-mediated miR-191-3p delivery, and ChIP","pmids":["33746084"],"confidence":"High","gaps":["Mechanism by which LIX1L suppresses miR-191-3p not defined","Whether direct RNA binding mediates miR-191-3p suppression unknown"]},{"year":2021,"claim":"Showed LIX1L promotes HCC glycolysis and aggression through miR-21-3p-mediated FBP1 suppression, connecting it to metabolic reprogramming.","evidence":"Knockdown/overexpression in HCC cells, orthotopic mouse model, and miR-21-3p inhibitor rescue","pmids":["34221869"],"confidence":"Medium","gaps":["How LIX1L upregulates miR-21-3p not established","Direct versus indirect regulation unresolved"]},{"year":2022,"claim":"Revealed a non-RNA structural role: LIX1L bridges DCHS1 adhesions to the SEPT9 septin-actin cytoskeleton to organize actin during valve morphogenesis.","evidence":"Biochemical interaction assays with DCHS1 and SEPT9 in mouse and cell culture models","pmids":["35200715"],"confidence":"Medium","gaps":["Reciprocal co-IP and interaction domain mapping not specified","Whether RNA binding is involved in this role unknown","Direct versus complex-mediated interaction unresolved"]},{"year":2022,"claim":"Linked LIX1L to ribosome biogenesis by showing nucleolar relocalization and NCL interaction drive rRNA synthesis and EMT/therapy resistance.","evidence":"Immunofluorescence, co-IP with NCL, NCL knockdown, and rRNA synthesis inhibition with functional cell assays in NSCLC","pmids":["36478492"],"confidence":"Medium","gaps":["Signal triggering nucleolar relocalization beyond TGFβ1 unclear","How LIX1L promotes rRNA transcription mechanistically not defined"]},{"year":2024,"claim":"Established PARP1-mediated PARylation as a metabolic-stress switch that stabilizes LIX1L and enhances RNA binding to stabilize CD36 mRNA, tying it to MASH/HCC.","evidence":"PARP1 inhibition/modification assays, CD36 3'UTR/CDS RNA binding assays, and Lix1l knockout MASH/HCC mouse models","pmids":["39725340"],"confidence":"Medium","gaps":["PARylation site(s) on LIX1L not mapped","Whether PARylation governs other RNA targets unknown"]},{"year":null,"claim":"How LIX1L's multiple modes (Tyr136 phosphorylation, PARylation, miRNA regulation, nucleolar rRNA synthesis, cytoskeletal bridging) are integrated within one protein and which is primary remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the dsRNA-binding motif or its target specificity","Unified mechanism connecting RNA-binding and cytoskeletal functions absent","Tissue-specific selection among its diverse roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,3,6]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3,6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,6]}],"complexes":[],"partners":["NCL","RIOK1","PABPC4","DCHS1","SEPT9","PARP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IVB5","full_name":"LIX1-like protein","aliases":[],"length_aa":337,"mass_kda":36.6,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8IVB5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIX1L","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LIX1L","total_profiled":1310},"omim":[{"mim_id":"621464","title":"LIMB- AND CNS-EXPRESSED GENE 1-LIKE; LIX1L","url":"https://www.omim.org/entry/621464"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LIX1L"},"hgnc":{"alias_symbol":["MGC46719"],"prev_symbol":[]},"alphafold":{"accession":"Q8IVB5","domains":[{"cath_id":"3.30.160.20","chopping":"73-176","consensus_level":"high","plddt":88.5117,"start":73,"end":176}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVB5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVB5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVB5-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIX1L","jax_strain_url":"https://www.jax.org/strain/search?query=LIX1L"},"sequence":{"accession":"Q8IVB5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IVB5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IVB5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVB5"}},"corpus_meta":[{"pmid":"30553813","id":"PMC_30553813","title":"CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines.","date":"2018","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/30553813","citation_count":118,"is_preprint":false},{"pmid":"33746084","id":"PMC_33746084","title":"Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism.","date":"2021","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/33746084","citation_count":53,"is_preprint":false},{"pmid":"25785048","id":"PMC_25785048","title":"Upregulated MiR-1269 in hepatocellular carcinoma and its clinical significance.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25785048","citation_count":33,"is_preprint":false},{"pmid":"34221869","id":"PMC_34221869","title":"LIX1-like protein promotes liver cancer progression via miR-21-3p-mediated inhibition of fructose-1,6-bisphosphatase.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/34221869","citation_count":23,"is_preprint":false},{"pmid":"31378885","id":"PMC_31378885","title":"LncRNA TATDN1 induces the progression of hepatocellular carcinoma via targeting miRNA-6089.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31378885","citation_count":13,"is_preprint":false},{"pmid":"35200715","id":"PMC_35200715","title":"DCHS1, Lix1L, and the Septin Cytoskeleton: Molecular and Developmental Etiology of Mitral Valve Prolapse.","date":"2022","source":"Journal of cardiovascular development and disease","url":"https://pubmed.ncbi.nlm.nih.gov/35200715","citation_count":11,"is_preprint":false},{"pmid":"26310847","id":"PMC_26310847","title":"Novel roles for LIX1L in promoting cancer cell proliferation through ROS1-mediated LIX1L phosphorylation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26310847","citation_count":10,"is_preprint":false},{"pmid":"36478492","id":"PMC_36478492","title":"Limb expression 1-like protein promotes epithelial-mesenchymal transition and epidermal growth factor receptor-tyrosine kinase inhibitor resistance via nucleolin-mediated ribosomal RNA synthesis in non-small cell lung cancer.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36478492","citation_count":8,"is_preprint":false},{"pmid":"39725340","id":"PMC_39725340","title":"LIX1L aggravates MASH-HCC progression by reprogramming of hepatic metabolism and microenvironment via CD36.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/39725340","citation_count":5,"is_preprint":false},{"pmid":"38911375","id":"PMC_38911375","title":"A-to-I edited miR-154-p13-5p inhibited cell proliferation and migration and induced apoptosis by targeting LIX1L in the bladder cancer.","date":"2024","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38911375","citation_count":4,"is_preprint":false},{"pmid":"35692142","id":"PMC_35692142","title":"Construction of a Competitive Endogenous RNA Network Related to Exosomes in Diabetic Retinopathy.","date":"2023","source":"Combinatorial chemistry & high throughput screening","url":"https://pubmed.ncbi.nlm.nih.gov/35692142","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8060,"output_tokens":2377,"usd":0.029917,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9465,"output_tokens":3119,"usd":0.06265,"stage2_stop_reason":"end_turn"},"total_usd":0.092567,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"LIX1L is a putative RNA-binding protein (RBP) containing a double-stranded RNA binding motif. It interacts with proteins RIOK1, nucleolin (NCL), and PABPC4, as well as multiple miRNAs (has-miRNA-520a-5p, -300, -216b, -326, -190a, -548b-3p, -7-5p and -1296) in HEK-293 cells, as determined by MALDI-TOF/TOF mass spectrometry and RNA immunoprecipitation-sequencing.\",\n      \"method\": \"MALDI-TOF/TOF mass spectrometry, RNA immunoprecipitation-sequencing (RIP-seq)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome plus RIP-seq, single lab, two orthogonal methods\",\n      \"pmids\": [\"26310847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LIX1L is phosphorylated at Tyr136, and this phosphorylation is required for LIX1L-induced cell proliferation. ROS1, HCK, ABL1, ABL2, JAK3, LCK, and TYRO3 were identified as candidate kinases responsible for pTyr136. A homeodomain peptide (PY136) that reduces pTyr136 inhibited LIX1L-induced cell proliferation in vitro and in vivo, and induced apoptosis.\",\n      \"method\": \"MALDI-TOF/TOF mass spectrometry (phosphosite identification), homeodomain peptide inhibition (PY136) in vitro and in vivo tumor models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphosite identified by MS and functionally validated by peptide inhibitor in vitro and in vivo, single lab\",\n      \"pmids\": [\"26310847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIX1L functions as a post-transcriptional regulator in cholestatic liver injury by suppressing miR-191-3p expression. miR-191-3p targets and downregulates LRH-1 (Lrh-1), thereby inhibiting Cyp7a1 and Cyp8b1 expression and bile acid synthesis. LIX1L deficiency restores miR-191-3p levels and attenuates cholestatic liver injury. Additionally, bile acid-induced LIX1L upregulation depends on Egr-1 binding to the LIX1L promoter, as shown by chromatin immunoprecipitation.\",\n      \"method\": \"Lix1l knockout mice, miRNA microarray profiling, AAV-mediated hepatic delivery of miR-191-3p, chromatin immunoprecipitation (ChIP) assay\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse models (multiple cholestasis models), ChIP assay, and AAV rescue experiment, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33746084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIX1L promotes HCC progression by increasing miR-21-3p expression, which targets and suppresses fructose-1,6-bisphosphatase (FBP1), thereby enhancing glycolysis (glucose consumption and lactate production), cell proliferation, migration, and invasion. miR-21-3p inhibitor abrogated LIX1L-induced enhancement of cell migration, invasion, and glucose metabolism.\",\n      \"method\": \"LIX1L knockdown/overexpression in HCC cells (in vitro), orthotopic tumor mouse model (in vivo), miR-21-3p inhibitor rescue experiments\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays plus in vivo orthotopic model plus miR inhibitor rescue, single lab\",\n      \"pmids\": [\"34221869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LIX1L physically interacts with DCHS1 (a cadherin involved in mitral valve development) and SEPT9 (a septin cytoskeletal protein). This DCHS1-LIX1L-SEPT9 axis promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape, linking DCHS1-based cell adhesions to the septin-actin cytoskeleton.\",\n      \"method\": \"Biochemical techniques (co-immunoprecipitation/pulldown implied), mouse and cell culture models\",\n      \"journal\": \"Journal of cardiovascular development and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — biochemical interaction assays and mouse/cell culture models reported, but abstract does not specify reciprocal co-IP or mutagenesis; single lab\",\n      \"pmids\": [\"35200715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LIX1L localizes to the nucleoli upon TGFβ1-induced EMT in NSCLC cells, where it physically interacts with the ribosome biogenesis regulator nucleolin (NCL), inducing ribosomal RNA (rRNA) synthesis. NCL knockdown or inhibition of rRNA synthesis reverses LIX1L-mediated enhancement of EMT, migration, invasion, anoikis resistance, EGFR-TKI resistance, and proliferation.\",\n      \"method\": \"Immunofluorescence/subcellular localization, co-immunoprecipitation (physical interaction with NCL), NCL knockdown, rRNA synthesis inhibition, functional cell assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization tied to functional consequence, co-IP with NCL, NCL KD rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36478492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Metabolic stress promotes PARP1-mediated poly-ADP-ribosylation (PARylation) of LIX1L, which increases its stability and RNA-binding ability. PARylated LIX1L then binds to AU-rich elements in the 3'UTR and CDS of CD36 mRNA, stabilizing CD36 mRNA and upregulating CD36 protein, thereby promoting hepatic lipid accumulation, inflammation, fibrosis, and a tumor-prone liver microenvironment in MASH/HCC.\",\n      \"method\": \"PARP1 inhibition/modification assays, RNA binding assays (3'UTR/CDS binding), Lix1l knockout mouse models (MASH and HCC), mechanistic biochemical studies\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse models, PARylation mechanistic assay, RNA binding to CD36 mRNA, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39725340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LIX1L is a target gene of miRNA-6089. The lncRNA TATDN1 sponges miRNA-6089, reducing its availability and thereby upregulating LIX1L expression. Overexpression of LIX1L partially reversed the inhibitory effect of miRNA-6089 on HCC cell proliferation and cell cycle progression.\",\n      \"method\": \"Dual-luciferase reporter assay (target validation), siRNA/overexpression in HCC cell lines\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase reporter and overexpression assays only, limited mechanistic depth for LIX1L itself\",\n      \"pmids\": [\"31378885\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIX1L is an RNA-binding protein (containing a double-stranded RNA binding motif) that operates at multiple levels: it is phosphorylated at Tyr136 by kinases including ROS1 to promote cell proliferation; it is poly-ADP-ribosylated by PARP1 under metabolic stress to stabilize CD36 mRNA via AU-rich element binding; it interacts with nucleolin in the nucleolus to drive rRNA synthesis and EMT; it suppresses miR-191-3p to activate bile acid synthesis genes (LRH-1/CYP7A1/CYP8B1) in cholestasis; it upregulates miR-21-3p to suppress FBP1 and promote glycolysis in HCC; and it physically links DCHS1 cell adhesions to the SEPT9 septin-actin cytoskeleton during cardiac valve development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIX1L is a putative double-stranded RNA-binding protein that functions as a post-transcriptional regulator coupling RNA metabolism to cell proliferation, metabolic stress responses, and tissue morphogenesis [#0, #2]. It associates with ribosome biogenesis and RNA-handling factors, including nucleolin (NCL), RIOK1, and PABPC4, and binds multiple miRNAs [#0]. Phosphorylation at Tyr136 by candidate tyrosine kinases including ROS1 is required for LIX1L-driven cell proliferation, and a peptide that reduces pTyr136 inhibits proliferation and induces apoptosis [#1]. LIX1L acts on miRNA circuits in liver disease: it suppresses miR-191-3p to relieve repression of LRH-1 and activate the bile acid synthesis genes CYP7A1 and CYP8B1 in cholestasis, with its own expression induced by Egr-1 binding the LIX1L promoter [#2], and it raises miR-21-3p to suppress FBP1 and enhance glycolysis, proliferation, and invasion in hepatocellular carcinoma [#3]. Under metabolic stress it is PARylated by PARP1, which stabilizes the protein and enhances its RNA binding, allowing it to bind AU-rich elements in CD36 mRNA and promote hepatic lipid accumulation, inflammation, and fibrosis [#6]. During TGFβ1-induced EMT it localizes to the nucleolus and interacts with NCL to drive rRNA synthesis, supporting migration, invasion, and therapy resistance in NSCLC [#5]. Distinct from its RNA roles, LIX1L bridges DCHS1-based cell adhesions to the SEPT9 septin-actin cytoskeleton to organize filamentous actin during cardiac valve development [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established LIX1L as an RNA-binding protein with a defined interactome, answering what molecular class it belongs to and which RNA/protein partners it engages.\",\n      \"evidence\": \"MALDI-TOF/TOF mass spectrometry and RIP-seq in HEK-293 cells\",\n      \"pmids\": [\"26310847\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of binding individual miRNAs not tested\", \"Direct RNA targets versus indirect associations not resolved\", \"No structural basis for dsRNA binding\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified Tyr136 phosphorylation as a proliferation-driving modification and candidate kinases, linking LIX1L to a druggable proliferative signal.\",\n      \"evidence\": \"MS phosphosite mapping and PY136 peptide inhibition in vitro and in vivo tumor models\",\n      \"pmids\": [\"26310847\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Which of the candidate kinases (ROS1, HCK, ABL1/2, JAK3, LCK, TYRO3) acts physiologically not determined\", \"Downstream effectors of pTyr136 unknown\", \"How phosphorylation alters RNA binding not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed LIX1L downstream of a lncRNA-miRNA axis (TATDN1/miR-6089), addressing how LIX1L expression is regulated in HCC.\",\n      \"evidence\": \"Dual-luciferase reporter and siRNA/overexpression in HCC cell lines\",\n      \"pmids\": [\"31378885\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Luciferase/overexpression only, no endogenous validation\", \"Limited mechanistic depth for LIX1L itself\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined LIX1L as a post-transcriptional controller of bile acid synthesis via miR-191-3p/LRH-1, and identified Egr-1 as its upstream transcriptional inducer in cholestasis.\",\n      \"evidence\": \"Lix1l knockout mice across cholestasis models, miRNA microarray, AAV-mediated miR-191-3p delivery, and ChIP\",\n      \"pmids\": [\"33746084\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which LIX1L suppresses miR-191-3p not defined\", \"Whether direct RNA binding mediates miR-191-3p suppression unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed LIX1L promotes HCC glycolysis and aggression through miR-21-3p-mediated FBP1 suppression, connecting it to metabolic reprogramming.\",\n      \"evidence\": \"Knockdown/overexpression in HCC cells, orthotopic mouse model, and miR-21-3p inhibitor rescue\",\n      \"pmids\": [\"34221869\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How LIX1L upregulates miR-21-3p not established\", \"Direct versus indirect regulation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-RNA structural role: LIX1L bridges DCHS1 adhesions to the SEPT9 septin-actin cytoskeleton to organize actin during valve morphogenesis.\",\n      \"evidence\": \"Biochemical interaction assays with DCHS1 and SEPT9 in mouse and cell culture models\",\n      \"pmids\": [\"35200715\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Reciprocal co-IP and interaction domain mapping not specified\", \"Whether RNA binding is involved in this role unknown\", \"Direct versus complex-mediated interaction unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked LIX1L to ribosome biogenesis by showing nucleolar relocalization and NCL interaction drive rRNA synthesis and EMT/therapy resistance.\",\n      \"evidence\": \"Immunofluorescence, co-IP with NCL, NCL knockdown, and rRNA synthesis inhibition with functional cell assays in NSCLC\",\n      \"pmids\": [\"36478492\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signal triggering nucleolar relocalization beyond TGFβ1 unclear\", \"How LIX1L promotes rRNA transcription mechanistically not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established PARP1-mediated PARylation as a metabolic-stress switch that stabilizes LIX1L and enhances RNA binding to stabilize CD36 mRNA, tying it to MASH/HCC.\",\n      \"evidence\": \"PARP1 inhibition/modification assays, CD36 3'UTR/CDS RNA binding assays, and Lix1l knockout MASH/HCC mouse models\",\n      \"pmids\": [\"39725340\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"PARylation site(s) on LIX1L not mapped\", \"Whether PARylation governs other RNA targets unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LIX1L's multiple modes (Tyr136 phosphorylation, PARylation, miRNA regulation, nucleolar rRNA synthesis, cytoskeletal bridging) are integrated within one protein and which is primary remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the dsRNA-binding motif or its target specificity\", \"Unified mechanism connecting RNA-binding and cytoskeletal functions absent\", \"Tissue-specific selection among its diverse roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NCL\", \"RIOK1\", \"PABPC4\", \"DCHS1\", \"SEPT9\", \"PARP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}