{"gene":"PPL","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2026,"finding":"PPL (Periplakin) marks a morphologically distinct pro-regenerative subset of cholangiocytes. PPL overexpression reduced DDC-induced liver fibrosis, while PPL knockdown aggravated it. FACS-sorted PPL+ cholangiocytes, upon adoptive transfer, improved liver function, reduced collagen deposition, elevated MMP2/MMP12/MMP13/MMP14 and anti-inflammatory cytokines (IL-10, EGF, HGF), decreased TGF-β1 and TIMP1, and enhanced hepatocyte proliferation in vivo and in vitro. CellChat inference and co-culture assays demonstrated that PPL+ cholangiocytes activate hepatocytes via an NRG1-ERBB3-PI3K/AKT signalling axis.","method":"Single-nucleus RNA-seq, adenoviral/AAV overexpression and knockdown, FACS sorting, adoptive transfer, hepatocyte co-culture, Western blot, ELISA, IHC, CellChat intercellular signalling inference","journal":"Liver international : official journal of the International Association for the Study of the Liver","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO/OE with defined phenotype, adoptive transfer, co-culture, pathway validation) in a single lab; NRG1-ERBB3-PI3K/AKT axis validated in vitro but not independently replicated","pmids":["42141833"],"is_preprint":false}],"current_model":"Periplakin (PPL) functions as a cytoskeletal linker enriched in epithelial cells (particularly cholangiocytes), where it marks a pro-regenerative cell subset that attenuates liver fibrosis and promotes hepatocyte proliferation, at least in part through paracrine NRG1-ERBB3-PI3K/AKT signalling; broader mechanistic characterisation of its molecular functions remains sparse in the available literature."},"narrative":{"mechanistic_narrative":"Periplakin (PPL) marks a morphologically distinct, pro-regenerative subset of cholangiocytes that restrains liver fibrosis and promotes hepatic regeneration [PMID:42141833]. PPL overexpression reduces DDC-induced fibrosis whereas its knockdown aggravates it, and adoptive transfer of FACS-sorted PPL+ cholangiocytes improves liver function, lowers collagen deposition, raises matrix metalloproteinases (MMP2/12/13/14) and anti-inflammatory and growth factors (IL-10, EGF, HGF) while reducing TGF-β1 and TIMP1, and enhances hepatocyte proliferation [PMID:42141833]. PPL+ cholangiocytes drive hepatocyte activation through a paracrine NRG1-ERBB3-PI3K/AKT signalling axis [PMID:42141833]. Beyond this cholangiocyte regenerative role, no further molecular characterization of PPL has been established in the available corpus.","teleology":[{"year":2026,"claim":"It was unknown whether a specific cholangiocyte subpopulation could attenuate liver fibrosis; this work established PPL as a marker of a pro-regenerative cholangiocyte subset whose abundance bidirectionally controls fibrotic outcome and hepatocyte proliferation.","evidence":"Single-nucleus RNA-seq with adenoviral/AAV overexpression and knockdown, FACS sorting and adoptive transfer, hepatocyte co-culture, and CellChat signalling inference in a DDC liver fibrosis model","pmids":["42141833"],"confidence":"Medium","gaps":["NRG1-ERBB3-PI3K/AKT axis validated in vitro but not independently replicated","The intrinsic molecular/cytoskeletal function of PPL within cholangiocytes was not defined","Whether PPL is causally required for the regenerative phenotype versus a correlated marker is not fully resolved"]},{"year":null,"claim":"The biochemical activity of PPL, its direct molecular partners, and the mechanism by which it specifies the pro-regenerative cholangiocyte state remain undefined.","evidence":"No further discoveries in the available corpus","pmids":[],"confidence":"Medium","gaps":["No defined molecular activity or interaction partner for the PPL protein itself","No structural or subcellular mechanistic characterization in this context"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60437","full_name":"Periplakin","aliases":["190 kDa paraneoplastic pemphigus antigen","195 kDa cornified envelope precursor protein"],"length_aa":1756,"mass_kda":204.7,"function":"Component of the cornified envelope of keratinocytes. May link the cornified envelope to desmosomes and intermediate filaments. May act as a localization signal in PKB/AKT-mediated signaling","subcellular_location":"Cell junction, desmosome; Cytoplasm, cytoskeleton; Cell membrane; Lateral cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O60437/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPL","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPL","total_profiled":1310},"omim":[{"mim_id":"618301","title":"KAZRIN, PERIPLAKIN-INTERACTING PROTEIN; KAZN","url":"https://www.omim.org/entry/618301"},{"mim_id":"611579","title":"TRANSMEMBRANE PROTEIN 114; TMEM114","url":"https://www.omim.org/entry/611579"},{"mim_id":"610836","title":"AUTISM, SUSCEPTIBILITY TO, 11; AUTS11","url":"https://www.omim.org/entry/610836"},{"mim_id":"609771","title":"UBINUCLEIN 1; UBN1","url":"https://www.omim.org/entry/609771"},{"mim_id":"608833","title":"REGULATOR OF TELOMERE ELONGATION HELICASE 1; RTEL1","url":"https://www.omim.org/entry/608833"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Basal body","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":218.4},{"tissue":"esophagus","ntpm":697.4},{"tissue":"vagina","ntpm":274.1}],"url":"https://www.proteinatlas.org/search/PPL"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O60437","domains":[{"cath_id":"1.20.58.60","chopping":"23-131","consensus_level":"medium","plddt":82.8993,"start":23,"end":131},{"cath_id":"1.20.58.60","chopping":"138-185_195-294","consensus_level":"medium","plddt":88.3436,"start":138,"end":294},{"cath_id":"3.30.160.780","chopping":"1651-1754","consensus_level":"high","plddt":75.7811,"start":1651,"end":1754},{"cath_id":"1.10.287","chopping":"946-985_1006-1045_1086-1126","consensus_level":"medium","plddt":74.8488,"start":946,"end":1126},{"cath_id":"1.10.287","chopping":"1186-1223_1244-1282","consensus_level":"high","plddt":82.5814,"start":1186,"end":1282}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60437","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60437-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60437-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPL","jax_strain_url":"https://www.jax.org/strain/search?query=PPL"},"sequence":{"accession":"O60437","fasta_url":"https://rest.uniprot.org/uniprotkb/O60437.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60437/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60437"}},"corpus_meta":[{"pmid":"31986282","id":"PMC_31986282","title":"Immobilization of porcine pancreatic lipase onto a metal-organic framework, PPL@MOF: A new platform for efficient ligand discovery from natural herbs.","date":"2019","source":"Analytica chimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/31986282","citation_count":54,"is_preprint":false},{"pmid":"29279121","id":"PMC_29279121","title":"Fabrication of chitosan-mesoporous silica SBA-15 nanocomposites via functional ionic liquid as the bridging agent for PPL immobilization.","date":"2017","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/29279121","citation_count":28,"is_preprint":false},{"pmid":"1855972","id":"PMC_1855972","title":"Cloning, genetic analysis, and nucleotide sequence of a determinant coding for a 19-kilodalton peptidoglycan-associated protein (Ppl) of Legionella pneumophila.","date":"1991","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/1855972","citation_count":24,"is_preprint":false},{"pmid":"25945920","id":"PMC_25945920","title":"4-Hydroxy-2-nonenal (4-HNE) and Its Lipation Product 2-Pentylpyrrole Lysine (2-PPL) in Peanuts.","date":"2015","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25945920","citation_count":20,"is_preprint":false},{"pmid":"24631556","id":"PMC_24631556","title":"Heterologous expression of a lectin from Pleurocybella porrigens (PPL) in Phanerochaete sordida YK-624.","date":"2014","source":"Journal of microbiological methods","url":"https://pubmed.ncbi.nlm.nih.gov/24631556","citation_count":17,"is_preprint":false},{"pmid":"28446883","id":"PMC_28446883","title":"In Vitro and In Vivo Profile of PPL-101 and PPL-103: Mixed Opioid Partial Agonist Analgesics with Low Abuse Potential.","date":"2017","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28446883","citation_count":16,"is_preprint":false},{"pmid":"18694300","id":"PMC_18694300","title":"Alternate arrangement of PpL B3 domain and SpA D domain creates synergistic double-site binding to VH3 and Vkappa regions of fab.","date":"2008","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18694300","citation_count":16,"is_preprint":false},{"pmid":"8767928","id":"PMC_8767928","title":"Cloning, expression and purification of Ppl-1, a kappa-chain binding protein, based upon protein L from Peptostreptococcus magnus.","date":"1995","source":"Bioseparation","url":"https://pubmed.ncbi.nlm.nih.gov/8767928","citation_count":14,"is_preprint":false},{"pmid":"11249642","id":"PMC_11249642","title":"Technology evaluation: transgenic alpha-1-antitrypsin (AAT), PPL therapeutics.","date":"2000","source":"Current opinion in molecular therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/11249642","citation_count":13,"is_preprint":false},{"pmid":"1709146","id":"PMC_1709146","title":"[Effect of a new 10% hydroxyethyl starch solution HES/270/0.5 on blood coagulation, blood loss and hemodynamics in comparison with 3.5% PPL].","date":"1990","source":"Infusionstherapie (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/1709146","citation_count":9,"is_preprint":false},{"pmid":"8429685","id":"PMC_8429685","title":"Isolation and characterisation of a CDw50 negative Jurkat T-cell line variant (PPL.1).","date":"1993","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/8429685","citation_count":8,"is_preprint":false},{"pmid":"22875783","id":"PMC_22875783","title":"Effects of microvascular density on primary pulmonary non-Hodgkin's lymphoma (PPL).","date":"2012","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22875783","citation_count":7,"is_preprint":false},{"pmid":"31096642","id":"PMC_31096642","title":"Writing Behavior of Phospholipids in Polymer Pen Lithography (PPL) for Bioactive Micropatterns.","date":"2019","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/31096642","citation_count":6,"is_preprint":false},{"pmid":"23626600","id":"PMC_23626600","title":"Employing MCMC under the PPL framework to analyze sequence data in large pedigrees.","date":"2013","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23626600","citation_count":6,"is_preprint":false},{"pmid":"35225872","id":"PMC_35225872","title":"More Than Meets the Kappa for Antibody Superantigen Protein L (PpL).","date":"2022","source":"Antibodies (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35225872","citation_count":4,"is_preprint":false},{"pmid":"34769273","id":"PMC_34769273","title":"Downregulation of lncRNA PpL-T31511 and Pp-miRn182 Promotes Hydrogen Cyanamide-Induced Endodormancy Release through the PP2C-H2O2 Pathway in Pear (Pyrus pyrifolia).","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34769273","citation_count":4,"is_preprint":false},{"pmid":"38143023","id":"PMC_38143023","title":"The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema.","date":"2023","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38143023","citation_count":3,"is_preprint":false},{"pmid":"40782008","id":"PMC_40782008","title":"The opioid partial agonist PPL-138 reduces alcohol self-administration in rats susceptible to post-traumatic stress disorder.","date":"2025","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40782008","citation_count":3,"is_preprint":false},{"pmid":"35798174","id":"PMC_35798174","title":"PPL-103: A mixed opioid partial agonist with desirable anti-cocaine properties.","date":"2022","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35798174","citation_count":2,"is_preprint":false},{"pmid":"41344330","id":"PMC_41344330","title":"The Ppl protein senses 3'-hydroxyl DNA overhangs and NTP depletion to halt phage infection.","date":"2025","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/41344330","citation_count":0,"is_preprint":false},{"pmid":"41342409","id":"PMC_41342409","title":"Crystal and Cryo-EM structure of PPL, a novel hexameric R-type lectin from the poisonous mushroom Pleurocybella porrigens.","date":"2025","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/41342409","citation_count":0,"is_preprint":false},{"pmid":"42141833","id":"PMC_42141833","title":"PPL+ Cholangiocytes Define a Pro-Regenerative Subset Associated With NRG1-ERBB3-PI3K/AKT Signalling During Liver Fibrosis.","date":"2026","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/42141833","citation_count":0,"is_preprint":false},{"pmid":"41695373","id":"PMC_41695373","title":"Assessment of tissue homogenate levels of TGM1, PPL and KRT8 in a group of patients with HNSCC tumors and matched surgical margin samples.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41695373","citation_count":0,"is_preprint":false},{"pmid":"7305314","id":"PMC_7305314","title":"[Changes in Bacillus pumilus antibiotic activity and sensitivity with integration and disintegration of plasmid pPL 7065].","date":"1981","source":"Antibiotiki","url":"https://pubmed.ncbi.nlm.nih.gov/7305314","citation_count":0,"is_preprint":false},{"pmid":"7213833","id":"PMC_7213833","title":"[Integration of plasmid pPL 7065 into chromosome of Bac. pumilis].","date":"1980","source":"Biokhimiia (Moscow, Russia)","url":"https://pubmed.ncbi.nlm.nih.gov/7213833","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.09.25337647","title":"Machine-learning-based analysis of transcriptomics data for the identification of molecular signatures in cancer","date":"2025-10-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.09.25337647","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.19.25329969","title":"Robotic versus Electromagnetic Bronchoscopy for Pulmonary LesIon AssessmeNT using integrated intraprocedural imaging: study protocol for the RELIANT 2 trial","date":"2025-06-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.19.25329969","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.27.655536","title":"Engineered yeast biofilms deliver plastic degrading enzymes to PET substrates","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.27.655536","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.19.24313958","title":"Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans","date":"2024-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.19.24313958","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.18.677201","title":"Multiscale Analysis of  <i>Candida albicans</i>  Biofilms","date":"2025-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.18.677201","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.28.685203","title":"Neuromodulation of a peripheral nerve using fully polymeric cuff electrodes: Understanding predictability of selective stimulation","date":"2025-10-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.28.685203","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.15.676291","title":"Selective genetic targeting of the mouse efferent vestibular nucleus identifies monosynaptic inputs and indicates function as multimodal integrator","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.15.676291","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.28.691111","title":"Identifying phenotype-genotype-function coupling in 3D organoid imaging using Shape, Appearance and Motion Phenotype Observation Tool (SPOT)","date":"2025-11-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.28.691111","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.07.25325355","title":"Hierarchical representation learning of preeclampsia interactome connecting endometrial maturation, placentation, chorioamnionitis, and HELLP syndrome","date":"2025-04-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.07.25325355","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17460,"output_tokens":1150,"usd":0.034815,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6858,"output_tokens":977,"usd":0.029358,"stage2_stop_reason":"end_turn"},"total_usd":0.064173,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical human gene PPL (Periplakin), which is a cornified envelope precursor protein / cytoskeletal linker protein expressed in epithelial cells.\n\nLet me classify each paper:\n- Papers 1-2: Porcine pancreatic lipase (PPL) - symbol collision, unrelated enzyme\n- Paper 3: Legionella pneumophila Ppl - bacterial protein, symbol collision\n- Paper 4: 2-PPL (2-pentylpyrrole lysine) - chemical compound, not the gene\n- Paper 5: PPL lectin from mushroom - symbol collision\n- Paper 6: PPL-101/103 opioid compounds - pharmaceutical compounds, not the gene\n- Paper 7: PpL = Protein L from Peptostreptococcus - bacterial protein, symbol collision\n- Paper 8: Ppl-1 = domain of Protein L - bacterial protein, symbol collision\n- Paper 9: PPL Therapeutics company - not the gene\n- Paper 10: PPL = plasma protein solution - not the gene\n- Paper 11: PPL.1 = Jurkat cell line variant - not the gene\n- Paper 12: PPL = primary pulmonary lymphoma - not the gene\n- Paper 13: PPL = polymer pen lithography - not the gene\n- Paper 14: PPL = posterior probability of linkage - statistical framework\n- Paper 15: PpL = Protein L - bacterial protein\n- Paper 16: PpL = pear lncRNA - plant, not the gene\n- Paper 17: PPL WG = working group on lymphedema - not the gene\n- Paper 18: PPL-138 = opioid compound - not the gene\n- Paper 19: PPL-103 = opioid compound - not the gene\n- Paper 20: Ppl defense system in E. coli - bacterial antiphage system, symbol collision\n- Paper 21: PPL lectin from mushroom - symbol collision\n- Paper 22: PPL = Periplakin in cholangiocytes - THIS IS THE CANONICAL GENE\n- Paper 23: PPL in HNSCC - mentions Periplakin (PPL) - expression/correlation study\n- Papers 24-25: Bacillus plasmid pPL - not the gene\n- Papers 26-34: Various unrelated uses of PPL acronym or computational studies\n\nOnly Paper 22 describes the canonical human PPL (Periplakin) with mechanistic experiments. Paper 23 mentions PPL but is purely correlational (ELISA levels, no mechanism).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"PPL (Periplakin) marks a morphologically distinct pro-regenerative subset of cholangiocytes. PPL overexpression reduced DDC-induced liver fibrosis, while PPL knockdown aggravated it. FACS-sorted PPL+ cholangiocytes, upon adoptive transfer, improved liver function, reduced collagen deposition, elevated MMP2/MMP12/MMP13/MMP14 and anti-inflammatory cytokines (IL-10, EGF, HGF), decreased TGF-β1 and TIMP1, and enhanced hepatocyte proliferation in vivo and in vitro. CellChat inference and co-culture assays demonstrated that PPL+ cholangiocytes activate hepatocytes via an NRG1-ERBB3-PI3K/AKT signalling axis.\",\n      \"method\": \"Single-nucleus RNA-seq, adenoviral/AAV overexpression and knockdown, FACS sorting, adoptive transfer, hepatocyte co-culture, Western blot, ELISA, IHC, CellChat intercellular signalling inference\",\n      \"journal\": \"Liver international : official journal of the International Association for the Study of the Liver\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO/OE with defined phenotype, adoptive transfer, co-culture, pathway validation) in a single lab; NRG1-ERBB3-PI3K/AKT axis validated in vitro but not independently replicated\",\n      \"pmids\": [\"42141833\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Periplakin (PPL) functions as a cytoskeletal linker enriched in epithelial cells (particularly cholangiocytes), where it marks a pro-regenerative cell subset that attenuates liver fibrosis and promotes hepatocyte proliferation, at least in part through paracrine NRG1-ERBB3-PI3K/AKT signalling; broader mechanistic characterisation of its molecular functions remains sparse in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Periplakin (PPL) marks a morphologically distinct, pro-regenerative subset of cholangiocytes that restrains liver fibrosis and promotes hepatic regeneration [#0]. PPL overexpression reduces DDC-induced fibrosis whereas its knockdown aggravates it, and adoptive transfer of FACS-sorted PPL+ cholangiocytes improves liver function, lowers collagen deposition, raises matrix metalloproteinases (MMP2/12/13/14) and anti-inflammatory and growth factors (IL-10, EGF, HGF) while reducing TGF-β1 and TIMP1, and enhances hepatocyte proliferation [#0]. PPL+ cholangiocytes drive hepatocyte activation through a paracrine NRG1-ERBB3-PI3K/AKT signalling axis [#0]. Beyond this cholangiocyte regenerative role, no further molecular characterization of PPL has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2026,\n      \"claim\": \"It was unknown whether a specific cholangiocyte subpopulation could attenuate liver fibrosis; this work established PPL as a marker of a pro-regenerative cholangiocyte subset whose abundance bidirectionally controls fibrotic outcome and hepatocyte proliferation.\",\n      \"evidence\": \"Single-nucleus RNA-seq with adenoviral/AAV overexpression and knockdown, FACS sorting and adoptive transfer, hepatocyte co-culture, and CellChat signalling inference in a DDC liver fibrosis model\",\n      \"pmids\": [\"42141833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NRG1-ERBB3-PI3K/AKT axis validated in vitro but not independently replicated\",\n        \"The intrinsic molecular/cytoskeletal function of PPL within cholangiocytes was not defined\",\n        \"Whether PPL is causally required for the regenerative phenotype versus a correlated marker is not fully resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of PPL, its direct molecular partners, and the mechanism by which it specifies the pro-regenerative cholangiocyte state remain undefined.\",\n      \"evidence\": \"No further discoveries in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No defined molecular activity or interaction partner for the PPL protein itself\",\n        \"No structural or subcellular mechanistic characterization in this context\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}