{"gene":"ALDH1B1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1995,"finding":"ALDH1B1 (then called ALDH5) encodes an enzymatically active aldehyde dehydrogenase that is active with short-chain aldehydes (acetaldehyde, propionaldehyde) and NAD+ but not NADP+, and its activity is enriched in the mitochondrial fraction and is insensitive to disulfiram inhibition.","method":"Enzymatic activity assay in HuH7 hepatoma cell extracts; subcellular fractionation; cofactor specificity testing","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro enzymatic assay with subcellular fractionation and inhibitor testing, single lab, multiple orthogonal approaches","pmids":["7779080"],"is_preprint":false},{"year":2014,"finding":"Purified recombinant ALDH1B1 metabolizes nitroglycerin and all-trans retinaldehyde, and metabolizes 4-hydroxynonenal (4-HNE) with higher apparent affinity than previously described. The human polymorphic variant ALDH1B1*2 (A86V) is catalytically inactive due to poor NAD+ binding, while ALDH1B1*3 (L107R) and ALDH1B1*5 (M253V) retain activity.","method":"In vitro enzymatic assay with purified recombinant human ALDH1B1 and polymorphic variants expressed in bacterial system; computational molecular modeling for substrate and cofactor binding","journal":"Pharmaceutical research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant protein, active-site relevant mutagenesis, and computational modeling, single lab with multiple orthogonal methods","pmids":["25413692"],"is_preprint":false},{"year":2012,"finding":"Computational modeling predicts that ALDH1B1 and ALDH2 subunits can form heterotetramers, suggesting that inactive ALDH2*2 mutants may suppress ALDH1B1 activity via dominant-negative heterotetramerization, consistent with the observed lack of compensatory ALDH1B1 activity in ALDH2*2 individuals.","method":"Computational-based molecular modeling of protein-protein interactions; phylogenetic and sequence analysis","journal":"Chemico-biological interactions","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of heterotetramer formation reported in this abstract","pmids":["23247008"],"is_preprint":false},{"year":2015,"finding":"ALDH1B1 is a mitochondrial enzyme that metabolizes acetaldehyde in vivo; Aldh1b1 knockout mice show ~40% increased blood acetaldehyde levels after ethanol challenge, and also exhibit higher fasting blood glucose levels, implicating ALDH1B1 in glucose homeostasis.","method":"Global Aldh1b1 knockout mouse; ethanol pharmacokinetic analysis (blood acetaldehyde measurement); fasting blood glucose measurement","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo KO with two distinct functional readouts (acetaldehyde levels and glucose), single lab","pmids":["26086111"],"is_preprint":false},{"year":2015,"finding":"shRNA-mediated knockdown of ALDH1B1 in SW480 colon cancer cells reduces spheroid formation and xenograft tumor growth, and downregulates Wnt/β-catenin, Notch, and PI3K/Akt signaling pathways; six TCF/LEF binding elements in the ALDH1B1 promoter were identified but shown by dual luciferase reporter assay to not be required for ALDH1B1 mRNA expression.","method":"shRNA knockdown; 3D spheroid assay; nude mouse xenograft model; dual luciferase reporter assay; Western blot and mRNA expression analysis of signaling pathway components","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular and in vivo phenotype plus pathway analysis, single lab, multiple methods","pmids":["25950950"],"is_preprint":false},{"year":2019,"finding":"Aldh1b1-expressing centroacinar cells are adult pancreatic progenitors capable of self-renewal and contributing to all three pancreatic lineages. Genetic ablation of Aldh1b1 completely abrogates tumor development in a KrasG12D-driven pancreatic cancer mouse model, establishing Aldh1b1 as required for Kras-induced oncogenic transformation.","method":"Genetic lineage tracing; Aldh1b1 knockout combined with KrasG12D pancreatic cancer mouse model; single-cell RNA sequencing; organoid formation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo, lineage tracing, organoid assay, and scRNA-seq in single rigorous study","pmids":["31548432"],"is_preprint":false},{"year":2022,"finding":"EIF4E acts as an endogenous repressor of ALDH1B1 in mitochondria in a translation-independent manner. ALDH1B1 metabolizes the lipid peroxidation aldehyde 4-HNE; EIF4E-dependent inhibition of ALDH1B1 enhances ferroptotic sensitivity by allowing accumulation of lipid peroxidation products. Low concentrations of 4-HNE increase ferroptosis susceptibility by activating the NOX1 pathway.","method":"Mass spectrometry-based protein-protein interaction; co-immunoprecipitation; genetic KO and overexpression; in vitro and in vivo ferroptosis assays; 4-HNE treatment experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein-protein interaction by MS and Co-IP, genetic functional validation in vitro and in vivo, multiple orthogonal methods in single study","pmids":["36274088"],"is_preprint":false},{"year":2022,"finding":"Small-molecule inhibitors (bicyclic imidazoliums and guanidines) targeting the ALDH1B1 active site selectively abrogate ALDH1B1 enzymatic function in cells and block growth of colon cancer spheroids and organoids. Chemical and genetic perturbation of ALDH1B1 revealed a dependent transcriptome enriched for genes regulating mitochondrial metabolism and ribosomal function.","method":"Active-site-directed small molecule inhibitor development; proteome-wide target specificity profiling; colon cancer spheroid and organoid growth assays; transcriptomics after genetic KD and chemical inhibition","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site inhibitor with proteome-wide selectivity profiling, functional validation in multiple cancer models, and transcriptomic target deconvolution","pmids":["35788181"],"is_preprint":false},{"year":2021,"finding":"AMBRA1 negatively regulates ALDH1B1 by mediating its K27- and K33-linked noncanonical ubiquitination via cooperation with E3 ligase TRAF6. Ubiquitination sites K506, K511, and K515 are critical for K27-linked ubiquitination and K506 for K33-linked ubiquitination. Ubiquitination-defective ALDH1B1 mutants show increased self-association, suggesting ubiquitination negatively regulates ALDH1B1 oligomerization. AMBRA1 inversely regulates ALDH1B1-dependent expression of PTEN, β-catenin, and CSC-related β-catenin target genes.","method":"Co-immunoprecipitation; ubiquitination site mapping by mutagenesis; protein self-association assay; gene expression analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction validated by Co-IP, ubiquitination site mutagenesis, functional consequences assessed, single lab","pmids":["34769507"],"is_preprint":false},{"year":2024,"finding":"ALDH1B1 localizes to mitochondria and interacts with the transmembrane domain of MAVS to promote MAVS prion-like aggregation, enhancing RIG-I–MAVS interaction and IFN-β production. ALDH1B1 is an interferon-stimulated gene (ISG); its knockout increases RNA virus replication (VSV, ZIKV, DENV, IAV) and Aldh1b1-knockout mice develop more severe influenza symptoms.","method":"ALDH1B1 KO and overexpression in cells; mitochondrial localization by fractionation/imaging; co-immunoprecipitation of ALDH1B1 with MAVS transmembrane domain; MAVS aggregation assay; IFN-β reporter assay; in vivo influenza infection of Aldh1b1 KO mice","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP defining MAVS transmembrane domain interaction, functional KO and OE with viral replication readout, in vivo validation, multiple orthogonal methods","pmids":["38194477"],"is_preprint":false},{"year":2024,"finding":"NR5A2 transcriptionally regulates ALDH1B1 expression; loss of NR5A2 in hepatocytes reduces ALDH1B1, leading to elevated ROS, NF-κB pathway activation, and pyroptosis. Reintroduction of NR5A2 isoforms reverses pyroptosis in a manner dependent on ALDH1B1-mediated ROS modulation.","method":"Hepatocyte-specific Nr5a2 knockout mice; NR5A2 isoform reintroduction in haploinsufficient cell lines; ROS measurement; pyroptosis assays; NF-κB pathway analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo and rescue experiments, pathway analysis with multiple methods, single lab","pmids":["39438459"],"is_preprint":false},{"year":2017,"finding":"Aldh1b1 depletion in mice increases plasma acetaldehyde levels after ethanol consumption and significantly aggravates ethanol-induced intestinal hyperproliferation, leading to more advanced intestinal tumor features, establishing ALDH1B1 as a protective enzyme against acetaldehyde-induced intestinal damage.","method":"Aldh1b1-knockout mice with 1-year ethanol drinking water model; plasma acetaldehyde measurement; histopathological and immunohistochemical analysis; DNA damage quantification","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with defined biochemical (acetaldehyde levels) and histopathological phenotypic readouts, replicated across two genotype groups","pmids":["28026023"],"is_preprint":false},{"year":2019,"finding":"Protein methyltransferase inhibition (via AMI-5) induces Aldh1b1 expression in pancreatic progenitors, maintains Aldh1b1 expression in embryonic pancreas explants, selectively reduces endocrine specification via downregulation of Ngn3, and this effect is abolished in Aldh1b1-null pancreata, establishing that methyltransferase activity regulates endocrine differentiation through Aldh1b1.","method":"Small molecule screen with mES Aldh1b1-lacZ reporter; embryonic pancreas explant culture; Aldh1b1-null genetic rescue experiment; Ngn3 expression analysis","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in null pancreata, small molecule and reporter validation, single lab","pmids":["30681750"],"is_preprint":false},{"year":2012,"finding":"ALDH1B1 is expressed specifically in multipotent progenitor cells of the developing pancreas in a Pdx1-dependent manner during early development, and in a Ngn3-dependent manner in trunk epithelium at secondary transition. Blocking ALDH catalytic activity in pancreatic explants reduces explant size and accelerates differentiation, indicating ALDH activity is required for progenitor maintenance and expansion.","method":"In situ hybridization; immunofluorescence; explant culture with ALDH catalytic inhibitor; genetic analysis of Pdx1- and Ngn3-dependent expression","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by ISH/IF with functional consequence from pharmacological inhibition in explants, single lab","pmids":["23142317"],"is_preprint":false},{"year":2023,"finding":"ALDH1B1 loss combined with Msh2 inactivation (Lynch syndrome model) and ethanol exposure significantly increases colonic adenoma formation and dMMR crypt foci, with elevated plasma acetaldehyde levels, demonstrating that ALDH1B1-mediated acetaldehyde detoxification in intestinal epithelium protects against acetaldehyde-driven DNA damage that cooperates with mismatch repair deficiency to drive colonic tumorigenesis.","method":"Conditional and constitutive Aldh1b1 KO combined with Lgr5-CreER Msh2 conditional KO mice; ethanol treatment; plasma acetaldehyde measurement; histopathological quantification of adenomas and crypt foci","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in double-KO in vivo model, biochemical measurement of acetaldehyde, histopathological quantification, replicated across multiple genotypes","pmids":["37395714"],"is_preprint":false}],"current_model":"ALDH1B1 is a mitochondrial aldehyde dehydrogenase that oxidizes a broad range of aldehyde substrates (including acetaldehyde, 4-hydroxynonenal, all-trans retinaldehyde, and nitroglycerin) using NAD+ as cofactor; it is transcriptionally regulated by NR5A2 and post-translationally regulated by AMBRA1/TRAF6-mediated noncanonical ubiquitination and by EIF4E-dependent repression in mitochondria; it promotes MAVS aggregation to enhance antiviral IFN-β signaling; it maintains pancreatic progenitor cell identity and is required for KrasG12D-driven pancreatic oncogenesis; and it protects intestinal and hepatic epithelium from acetaldehyde-induced DNA damage and hyperproliferation, while its dysregulation in cancer promotes Wnt/β-catenin, Notch, and PI3K/Akt signaling to support tumor growth."},"narrative":{"mechanistic_narrative":"ALDH1B1 is a mitochondrial NAD+-dependent aldehyde dehydrogenase that detoxifies reactive aldehydes and serves as a determinant of progenitor cell identity, antiviral immunity, and tumorigenesis [PMID:7779080, PMID:31548432, PMID:38194477]. The enzyme oxidizes short-chain aldehydes including acetaldehyde and propionaldehyde, and purified recombinant protein also metabolizes nitroglycerin, all-trans retinaldehyde, and the lipid-peroxidation product 4-hydroxynonenal; naturally occurring human variants differ in catalytic competence, with the A86V (ALDH1B1*2) substitution abolishing activity by impairing NAD+ binding [PMID:7779080, PMID:25413692]. In vivo, ALDH1B1-mediated acetaldehyde clearance protects epithelial tissue: Aldh1b1-knockout mice accumulate blood and plasma acetaldehyde after ethanol exposure and develop aggravated intestinal hyperproliferation and tumor features, and combined loss with mismatch-repair deficiency drives colonic adenoma formation, establishing the enzyme as a barrier against acetaldehyde-induced DNA damage [PMID:26086111, PMID:28026023, PMID:37395714]. ALDH1B1 marks self-renewing centroacinar pancreatic progenitors and is genetically required for both progenitor maintenance and KrasG12D-driven pancreatic oncogenesis, and its support of colon cancer spheroid and xenograft growth is accompanied by activation of Wnt/β-catenin, Notch, and PI3K/Akt signaling [PMID:25950950, PMID:31548432, PMID:23142317]. In innate immunity, ALDH1B1 is an interferon-stimulated gene that interacts with the MAVS transmembrane domain to promote MAVS prion-like aggregation and IFN-β production, restricting RNA virus replication [PMID:38194477]. Its abundance and activity are controlled at multiple levels: transcriptionally by NR5A2 (loss of which elevates ROS and triggers pyroptosis), post-translationally by AMBRA1/TRAF6-mediated K27/K33-linked noncanonical ubiquitination that constrains its oligomerization, and translation-independently by EIF4E, whose repression of ALDH1B1 in mitochondria sensitizes cells to ferroptosis by permitting 4-HNE accumulation [PMID:36274088, PMID:34769507, PMID:39438459].","teleology":[{"year":1995,"claim":"Established that ALDH1B1 (ALDH5) is a catalytically active, mitochondrially enriched enzyme distinct in cofactor and inhibitor profile, answering whether the gene encodes a functional aldehyde dehydrogenase.","evidence":"Enzymatic assays, subcellular fractionation, and cofactor/inhibitor testing in HuH7 hepatoma extracts","pmids":["7779080"],"confidence":"Medium","gaps":["Substrate range tested only for short-chain aldehydes","No recombinant protein or structural data"]},{"year":2012,"claim":"Defined the developmental context of ALDH1B1 by showing its expression in multipotent pancreatic progenitors under Pdx1 and Ngn3 control and that ALDH activity is needed for progenitor maintenance.","evidence":"ISH, immunofluorescence, and explant culture with ALDH inhibitor in developing pancreas","pmids":["23142317"],"confidence":"Medium","gaps":["Pharmacological inhibitor not ALDH1B1-selective","Mechanism linking enzyme activity to progenitor state unknown"]},{"year":2012,"claim":"Raised the possibility that ALDH1B1 activity is modulated by heterotetramerization with ALDH2, offering an explanation for absent compensatory activity in ALDH2*2 individuals.","evidence":"Computational protein-protein interaction modeling and sequence analysis","pmids":["23247008"],"confidence":"Low","gaps":["Computational prediction only; heterotetramer formation not experimentally validated","No functional dominant-negative data"]},{"year":2014,"claim":"Defined the substrate and variant landscape by showing recombinant ALDH1B1 metabolizes nitroglycerin, retinaldehyde, and 4-HNE, and that polymorphic variants differ in catalytic competence.","evidence":"In vitro assays with purified recombinant protein and polymorphic variants plus molecular modeling","pmids":["25413692"],"confidence":"High","gaps":["Physiological relevance of each substrate not established in vivo","No crystal structure to confirm modeled binding modes"]},{"year":2015,"claim":"Demonstrated in vivo that ALDH1B1 metabolizes acetaldehyde and links it to glucose homeostasis, moving beyond in vitro activity to organismal function.","evidence":"Global Aldh1b1 knockout mice with ethanol pharmacokinetics and fasting glucose measurement","pmids":["26086111"],"confidence":"High","gaps":["Mechanism connecting ALDH1B1 to glucose regulation unresolved","Tissue responsible for acetaldehyde clearance not pinpointed"]},{"year":2015,"claim":"Established a pro-tumorigenic role in colon cancer, showing ALDH1B1 knockdown reduces tumor growth and downregulates Wnt/β-catenin, Notch, and PI3K/Akt signaling.","evidence":"shRNA knockdown, spheroid and xenograft assays, signaling pathway and promoter reporter analysis in SW480 cells","pmids":["25950950"],"confidence":"Medium","gaps":["Whether catalytic activity drives signaling not addressed","Direct molecular link between enzyme and Wnt/Notch/PI3K unknown"]},{"year":2017,"claim":"Showed that ALDH1B1-mediated acetaldehyde detoxification protects the intestinal epithelium, as its loss aggravates ethanol-induced hyperproliferation and tumor features.","evidence":"Long-term ethanol drinking model in Aldh1b1-knockout mice with histopathology and DNA damage quantification","pmids":["28026023"],"confidence":"High","gaps":["Cooperating genetic events not yet defined in this study","Cell-of-origin within the epithelium not resolved"]},{"year":2019,"claim":"Provided genetic proof that Aldh1b1-expressing centroacinar cells are pancreatic progenitors and that ALDH1B1 is required for KrasG12D-driven pancreatic oncogenesis.","evidence":"Lineage tracing, Aldh1b1 KO crossed to KrasG12D model, scRNA-seq, and organoid assays","pmids":["31548432"],"confidence":"High","gaps":["Mechanism by which ALDH1B1 enables Kras transformation not defined","Role of catalytic activity versus protein presence unclear"]},{"year":2019,"claim":"Connected methyltransferase signaling to ALDH1B1 in endocrine differentiation, showing Aldh1b1 is required for methyltransferase-inhibitor effects on Ngn3 and endocrine specification.","evidence":"Reporter-based small-molecule screen, pancreas explant culture, and Aldh1b1-null genetic epistasis","pmids":["30681750"],"confidence":"Medium","gaps":["Methyltransferase target acting upstream unidentified","Molecular link between ALDH1B1 and Ngn3 regulation unknown"]},{"year":2021,"claim":"Identified post-translational control of ALDH1B1 via AMBRA1/TRAF6-mediated noncanonical ubiquitination that limits its oligomerization and downstream PTEN/β-catenin signaling.","evidence":"Co-IP, ubiquitination site mutagenesis, self-association assays, and gene expression analysis","pmids":["34769507"],"confidence":"Medium","gaps":["Functional consequence of altered oligomerization on enzymatic activity not measured","Single-lab Co-IP; in vivo relevance untested"]},{"year":2022,"claim":"Revealed EIF4E as a translation-independent mitochondrial repressor of ALDH1B1 that, by limiting 4-HNE clearance, controls ferroptotic sensitivity.","evidence":"MS-based interactomics, reciprocal Co-IP, genetic KO/overexpression, and ferroptosis assays in vitro and in vivo","pmids":["36274088"],"confidence":"High","gaps":["Mechanism of EIF4E mitochondrial localization to ALDH1B1 unresolved","Quantitative contribution of ALDH1B1 to lipid-peroxide pool not defined"]},{"year":2022,"claim":"Delivered active-site-directed selective inhibitors confirming ALDH1B1 is a druggable cancer dependency and linked its activity to mitochondrial metabolism and ribosomal gene programs.","evidence":"Active-site inhibitor development, proteome-wide selectivity profiling, spheroid/organoid assays, and transcriptomics","pmids":["35788181"],"confidence":"High","gaps":["Direct substrates underlying the dependent transcriptome not identified","How enzyme activity shapes ribosomal/metabolic genes unknown"]},{"year":2023,"claim":"Showed ALDH1B1 acetaldehyde detoxification cooperates with mismatch-repair status, as its loss with Msh2 inactivation and ethanol drives colonic tumorigenesis.","evidence":"Aldh1b1/Msh2 double-knockout mice with ethanol exposure, plasma acetaldehyde measurement, and adenoma quantification","pmids":["37395714"],"confidence":"High","gaps":["Molecular nature of acetaldehyde-induced lesions cooperating with dMMR not detailed","Human relevance of the genetic interaction untested"]},{"year":2024,"claim":"Defined a non-detoxification antiviral function, with ALDH1B1 binding the MAVS transmembrane domain to promote MAVS aggregation and IFN-β signaling that restricts RNA viruses.","evidence":"KO/overexpression, mitochondrial fractionation/imaging, reciprocal Co-IP, MAVS aggregation and IFN-β reporter assays, and in vivo influenza infection","pmids":["38194477"],"confidence":"High","gaps":["Whether catalytic activity is required for MAVS aggregation unresolved","Structural basis of the ALDH1B1–MAVS interaction unknown"]},{"year":2024,"claim":"Established transcriptional control of ALDH1B1 by NR5A2 governing ROS levels and pyroptosis in hepatocytes.","evidence":"Hepatocyte-specific Nr5a2 KO mice, isoform reintroduction rescue, ROS and pyroptosis assays, and NF-κB analysis","pmids":["39438459"],"confidence":"Medium","gaps":["Direct NR5A2 binding at the ALDH1B1 locus not confirmed in this study","Substrate basis of ALDH1B1-dependent ROS modulation undefined"]},{"year":null,"claim":"Whether the diverse roles of ALDH1B1 (acetaldehyde detoxification, ferroptosis control, oncogenic signaling, MAVS-dependent antiviral immunity) all depend on its catalytic activity, and what its physiological substrates are in each context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of ALDH1B1 alone or in complex","Catalysis-versus-scaffold contributions to antiviral and oncogenic roles not dissected","Endogenous substrate spectrum in each tissue context undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3,6,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,14]}],"complexes":[],"partners":["MAVS","EIF4E","AMBRA1","TRAF6","NR5A2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30837","full_name":"Aldehyde dehydrogenase X, mitochondrial","aliases":["Aldehyde dehydrogenase 5","Aldehyde dehydrogenase family 1 member B1"],"length_aa":517,"mass_kda":57.2,"function":"ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde. They are involved in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P30837/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALDH1B1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ASS1","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HEATR3","stoichiometry":0.2},{"gene":"MYH9","stoichiometry":0.2},{"gene":"PHGDH","stoichiometry":0.2},{"gene":"RER1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ALDH1B1","total_profiled":1310},"omim":[{"mim_id":"100670","title":"ALDEHYDE DEHYDROGENASE 1 FAMILY, MEMBER B1; ALDH1B1","url":"https://www.omim.org/entry/100670"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":138.0},{"tissue":"liver","ntpm":161.4}],"url":"https://www.proteinatlas.org/search/ALDH1B1"},"hgnc":{"alias_symbol":["ALDHX"],"prev_symbol":["ALDH5"]},"alphafold":{"accession":"P30837","domains":[{"cath_id":"3.40.605.10","chopping":"40-287_492-505","consensus_level":"high","plddt":98.7333,"start":40,"end":505},{"cath_id":"3.40.309.10","chopping":"292-479","consensus_level":"high","plddt":98.4659,"start":292,"end":479}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30837","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30837-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30837-F1-predicted_aligned_error_v6.png","plddt_mean":95.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALDH1B1","jax_strain_url":"https://www.jax.org/strain/search?query=ALDH1B1"},"sequence":{"accession":"P30837","fasta_url":"https://rest.uniprot.org/uniprotkb/P30837.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30837/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30837"}},"corpus_meta":[{"pmid":"21216231","id":"PMC_21216231","title":"Aldehyde 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osteosarcoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29416787","citation_count":14,"is_preprint":false},{"pmid":"38194477","id":"PMC_38194477","title":"The aldehyde dehydrogenase ALDH1B1 exerts antiviral effects through the aggregation of the adaptor MAVS.","date":"2024","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/38194477","citation_count":12,"is_preprint":false},{"pmid":"34769507","id":"PMC_34769507","title":"AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34769507","citation_count":12,"is_preprint":false},{"pmid":"36676146","id":"PMC_36676146","title":"The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression.","date":"2023","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36676146","citation_count":11,"is_preprint":false},{"pmid":"28026023","id":"PMC_28026023","title":"Effects of long-term ethanol consumption and Aldh1b1 depletion on intestinal tumourigenesis in mice.","date":"2017","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28026023","citation_count":11,"is_preprint":false},{"pmid":"8244338","id":"PMC_8244338","title":"Diverse polymorphism within a short coding region of the human aldehyde dehydrogenase-5 (ALDH5) gene.","date":"1993","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8244338","citation_count":11,"is_preprint":false},{"pmid":"29859945","id":"PMC_29859945","title":"The murine hepatic sequelae of long-term ethanol consumption are sex-specific and exacerbated by Aldh1b1 loss.","date":"2018","source":"Experimental and molecular 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Learning","date":"2025-06-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.04.657800","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16548,"output_tokens":4189,"usd":0.056239,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12199,"output_tokens":4877,"usd":0.09146,"stage2_stop_reason":"end_turn"},"total_usd":0.147699,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"ALDH1B1 (then called ALDH5) encodes an enzymatically active aldehyde dehydrogenase that is active with short-chain aldehydes (acetaldehyde, propionaldehyde) and NAD+ but not NADP+, and its activity is enriched in the mitochondrial fraction and is insensitive to disulfiram inhibition.\",\n      \"method\": \"Enzymatic activity assay in HuH7 hepatoma cell extracts; subcellular fractionation; cofactor specificity testing\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro enzymatic assay with subcellular fractionation and inhibitor testing, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"7779080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Purified recombinant ALDH1B1 metabolizes nitroglycerin and all-trans retinaldehyde, and metabolizes 4-hydroxynonenal (4-HNE) with higher apparent affinity than previously described. The human polymorphic variant ALDH1B1*2 (A86V) is catalytically inactive due to poor NAD+ binding, while ALDH1B1*3 (L107R) and ALDH1B1*5 (M253V) retain activity.\",\n      \"method\": \"In vitro enzymatic assay with purified recombinant human ALDH1B1 and polymorphic variants expressed in bacterial system; computational molecular modeling for substrate and cofactor binding\",\n      \"journal\": \"Pharmaceutical research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant protein, active-site relevant mutagenesis, and computational modeling, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25413692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Computational modeling predicts that ALDH1B1 and ALDH2 subunits can form heterotetramers, suggesting that inactive ALDH2*2 mutants may suppress ALDH1B1 activity via dominant-negative heterotetramerization, consistent with the observed lack of compensatory ALDH1B1 activity in ALDH2*2 individuals.\",\n      \"method\": \"Computational-based molecular modeling of protein-protein interactions; phylogenetic and sequence analysis\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of heterotetramer formation reported in this abstract\",\n      \"pmids\": [\"23247008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ALDH1B1 is a mitochondrial enzyme that metabolizes acetaldehyde in vivo; Aldh1b1 knockout mice show ~40% increased blood acetaldehyde levels after ethanol challenge, and also exhibit higher fasting blood glucose levels, implicating ALDH1B1 in glucose homeostasis.\",\n      \"method\": \"Global Aldh1b1 knockout mouse; ethanol pharmacokinetic analysis (blood acetaldehyde measurement); fasting blood glucose measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KO with two distinct functional readouts (acetaldehyde levels and glucose), single lab\",\n      \"pmids\": [\"26086111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"shRNA-mediated knockdown of ALDH1B1 in SW480 colon cancer cells reduces spheroid formation and xenograft tumor growth, and downregulates Wnt/β-catenin, Notch, and PI3K/Akt signaling pathways; six TCF/LEF binding elements in the ALDH1B1 promoter were identified but shown by dual luciferase reporter assay to not be required for ALDH1B1 mRNA expression.\",\n      \"method\": \"shRNA knockdown; 3D spheroid assay; nude mouse xenograft model; dual luciferase reporter assay; Western blot and mRNA expression analysis of signaling pathway components\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular and in vivo phenotype plus pathway analysis, single lab, multiple methods\",\n      \"pmids\": [\"25950950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Aldh1b1-expressing centroacinar cells are adult pancreatic progenitors capable of self-renewal and contributing to all three pancreatic lineages. Genetic ablation of Aldh1b1 completely abrogates tumor development in a KrasG12D-driven pancreatic cancer mouse model, establishing Aldh1b1 as required for Kras-induced oncogenic transformation.\",\n      \"method\": \"Genetic lineage tracing; Aldh1b1 knockout combined with KrasG12D pancreatic cancer mouse model; single-cell RNA sequencing; organoid formation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo, lineage tracing, organoid assay, and scRNA-seq in single rigorous study\",\n      \"pmids\": [\"31548432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF4E acts as an endogenous repressor of ALDH1B1 in mitochondria in a translation-independent manner. ALDH1B1 metabolizes the lipid peroxidation aldehyde 4-HNE; EIF4E-dependent inhibition of ALDH1B1 enhances ferroptotic sensitivity by allowing accumulation of lipid peroxidation products. Low concentrations of 4-HNE increase ferroptosis susceptibility by activating the NOX1 pathway.\",\n      \"method\": \"Mass spectrometry-based protein-protein interaction; co-immunoprecipitation; genetic KO and overexpression; in vitro and in vivo ferroptosis assays; 4-HNE treatment experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein-protein interaction by MS and Co-IP, genetic functional validation in vitro and in vivo, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36274088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Small-molecule inhibitors (bicyclic imidazoliums and guanidines) targeting the ALDH1B1 active site selectively abrogate ALDH1B1 enzymatic function in cells and block growth of colon cancer spheroids and organoids. Chemical and genetic perturbation of ALDH1B1 revealed a dependent transcriptome enriched for genes regulating mitochondrial metabolism and ribosomal function.\",\n      \"method\": \"Active-site-directed small molecule inhibitor development; proteome-wide target specificity profiling; colon cancer spheroid and organoid growth assays; transcriptomics after genetic KD and chemical inhibition\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site inhibitor with proteome-wide selectivity profiling, functional validation in multiple cancer models, and transcriptomic target deconvolution\",\n      \"pmids\": [\"35788181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMBRA1 negatively regulates ALDH1B1 by mediating its K27- and K33-linked noncanonical ubiquitination via cooperation with E3 ligase TRAF6. Ubiquitination sites K506, K511, and K515 are critical for K27-linked ubiquitination and K506 for K33-linked ubiquitination. Ubiquitination-defective ALDH1B1 mutants show increased self-association, suggesting ubiquitination negatively regulates ALDH1B1 oligomerization. AMBRA1 inversely regulates ALDH1B1-dependent expression of PTEN, β-catenin, and CSC-related β-catenin target genes.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination site mapping by mutagenesis; protein self-association assay; gene expression analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction validated by Co-IP, ubiquitination site mutagenesis, functional consequences assessed, single lab\",\n      \"pmids\": [\"34769507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALDH1B1 localizes to mitochondria and interacts with the transmembrane domain of MAVS to promote MAVS prion-like aggregation, enhancing RIG-I–MAVS interaction and IFN-β production. ALDH1B1 is an interferon-stimulated gene (ISG); its knockout increases RNA virus replication (VSV, ZIKV, DENV, IAV) and Aldh1b1-knockout mice develop more severe influenza symptoms.\",\n      \"method\": \"ALDH1B1 KO and overexpression in cells; mitochondrial localization by fractionation/imaging; co-immunoprecipitation of ALDH1B1 with MAVS transmembrane domain; MAVS aggregation assay; IFN-β reporter assay; in vivo influenza infection of Aldh1b1 KO mice\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP defining MAVS transmembrane domain interaction, functional KO and OE with viral replication readout, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"38194477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR5A2 transcriptionally regulates ALDH1B1 expression; loss of NR5A2 in hepatocytes reduces ALDH1B1, leading to elevated ROS, NF-κB pathway activation, and pyroptosis. Reintroduction of NR5A2 isoforms reverses pyroptosis in a manner dependent on ALDH1B1-mediated ROS modulation.\",\n      \"method\": \"Hepatocyte-specific Nr5a2 knockout mice; NR5A2 isoform reintroduction in haploinsufficient cell lines; ROS measurement; pyroptosis assays; NF-κB pathway analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo and rescue experiments, pathway analysis with multiple methods, single lab\",\n      \"pmids\": [\"39438459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Aldh1b1 depletion in mice increases plasma acetaldehyde levels after ethanol consumption and significantly aggravates ethanol-induced intestinal hyperproliferation, leading to more advanced intestinal tumor features, establishing ALDH1B1 as a protective enzyme against acetaldehyde-induced intestinal damage.\",\n      \"method\": \"Aldh1b1-knockout mice with 1-year ethanol drinking water model; plasma acetaldehyde measurement; histopathological and immunohistochemical analysis; DNA damage quantification\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with defined biochemical (acetaldehyde levels) and histopathological phenotypic readouts, replicated across two genotype groups\",\n      \"pmids\": [\"28026023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Protein methyltransferase inhibition (via AMI-5) induces Aldh1b1 expression in pancreatic progenitors, maintains Aldh1b1 expression in embryonic pancreas explants, selectively reduces endocrine specification via downregulation of Ngn3, and this effect is abolished in Aldh1b1-null pancreata, establishing that methyltransferase activity regulates endocrine differentiation through Aldh1b1.\",\n      \"method\": \"Small molecule screen with mES Aldh1b1-lacZ reporter; embryonic pancreas explant culture; Aldh1b1-null genetic rescue experiment; Ngn3 expression analysis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in null pancreata, small molecule and reporter validation, single lab\",\n      \"pmids\": [\"30681750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ALDH1B1 is expressed specifically in multipotent progenitor cells of the developing pancreas in a Pdx1-dependent manner during early development, and in a Ngn3-dependent manner in trunk epithelium at secondary transition. Blocking ALDH catalytic activity in pancreatic explants reduces explant size and accelerates differentiation, indicating ALDH activity is required for progenitor maintenance and expansion.\",\n      \"method\": \"In situ hybridization; immunofluorescence; explant culture with ALDH catalytic inhibitor; genetic analysis of Pdx1- and Ngn3-dependent expression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by ISH/IF with functional consequence from pharmacological inhibition in explants, single lab\",\n      \"pmids\": [\"23142317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDH1B1 loss combined with Msh2 inactivation (Lynch syndrome model) and ethanol exposure significantly increases colonic adenoma formation and dMMR crypt foci, with elevated plasma acetaldehyde levels, demonstrating that ALDH1B1-mediated acetaldehyde detoxification in intestinal epithelium protects against acetaldehyde-driven DNA damage that cooperates with mismatch repair deficiency to drive colonic tumorigenesis.\",\n      \"method\": \"Conditional and constitutive Aldh1b1 KO combined with Lgr5-CreER Msh2 conditional KO mice; ethanol treatment; plasma acetaldehyde measurement; histopathological quantification of adenomas and crypt foci\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in double-KO in vivo model, biochemical measurement of acetaldehyde, histopathological quantification, replicated across multiple genotypes\",\n      \"pmids\": [\"37395714\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALDH1B1 is a mitochondrial aldehyde dehydrogenase that oxidizes a broad range of aldehyde substrates (including acetaldehyde, 4-hydroxynonenal, all-trans retinaldehyde, and nitroglycerin) using NAD+ as cofactor; it is transcriptionally regulated by NR5A2 and post-translationally regulated by AMBRA1/TRAF6-mediated noncanonical ubiquitination and by EIF4E-dependent repression in mitochondria; it promotes MAVS aggregation to enhance antiviral IFN-β signaling; it maintains pancreatic progenitor cell identity and is required for KrasG12D-driven pancreatic oncogenesis; and it protects intestinal and hepatic epithelium from acetaldehyde-induced DNA damage and hyperproliferation, while its dysregulation in cancer promotes Wnt/β-catenin, Notch, and PI3K/Akt signaling to support tumor growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ALDH1B1 is a mitochondrial NAD+-dependent aldehyde dehydrogenase that detoxifies reactive aldehydes and serves as a determinant of progenitor cell identity, antiviral immunity, and tumorigenesis [#0, #5, #9]. The enzyme oxidizes short-chain aldehydes including acetaldehyde and propionaldehyde, and purified recombinant protein also metabolizes nitroglycerin, all-trans retinaldehyde, and the lipid-peroxidation product 4-hydroxynonenal; naturally occurring human variants differ in catalytic competence, with the A86V (ALDH1B1*2) substitution abolishing activity by impairing NAD+ binding [#0, #1]. In vivo, ALDH1B1-mediated acetaldehyde clearance protects epithelial tissue: Aldh1b1-knockout mice accumulate blood and plasma acetaldehyde after ethanol exposure and develop aggravated intestinal hyperproliferation and tumor features, and combined loss with mismatch-repair deficiency drives colonic adenoma formation, establishing the enzyme as a barrier against acetaldehyde-induced DNA damage [#3, #11, #14]. ALDH1B1 marks self-renewing centroacinar pancreatic progenitors and is genetically required for both progenitor maintenance and KrasG12D-driven pancreatic oncogenesis, and its support of colon cancer spheroid and xenograft growth is accompanied by activation of Wnt/\\u03b2-catenin, Notch, and PI3K/Akt signaling [#4, #5, #13]. In innate immunity, ALDH1B1 is an interferon-stimulated gene that interacts with the MAVS transmembrane domain to promote MAVS prion-like aggregation and IFN-\\u03b2 production, restricting RNA virus replication [#9]. Its abundance and activity are controlled at multiple levels: transcriptionally by NR5A2 (loss of which elevates ROS and triggers pyroptosis), post-translationally by AMBRA1/TRAF6-mediated K27/K33-linked noncanonical ubiquitination that constrains its oligomerization, and translation-independently by EIF4E, whose repression of ALDH1B1 in mitochondria sensitizes cells to ferroptosis by permitting 4-HNE accumulation [#6, #8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that ALDH1B1 (ALDH5) is a catalytically active, mitochondrially enriched enzyme distinct in cofactor and inhibitor profile, answering whether the gene encodes a functional aldehyde dehydrogenase.\",\n      \"evidence\": \"Enzymatic assays, subcellular fractionation, and cofactor/inhibitor testing in HuH7 hepatoma extracts\",\n      \"pmids\": [\"7779080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate range tested only for short-chain aldehydes\", \"No recombinant protein or structural data\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the developmental context of ALDH1B1 by showing its expression in multipotent pancreatic progenitors under Pdx1 and Ngn3 control and that ALDH activity is needed for progenitor maintenance.\",\n      \"evidence\": \"ISH, immunofluorescence, and explant culture with ALDH inhibitor in developing pancreas\",\n      \"pmids\": [\"23142317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibitor not ALDH1B1-selective\", \"Mechanism linking enzyme activity to progenitor state unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Raised the possibility that ALDH1B1 activity is modulated by heterotetramerization with ALDH2, offering an explanation for absent compensatory activity in ALDH2*2 individuals.\",\n      \"evidence\": \"Computational protein-protein interaction modeling and sequence analysis\",\n      \"pmids\": [\"23247008\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only; heterotetramer formation not experimentally validated\", \"No functional dominant-negative data\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the substrate and variant landscape by showing recombinant ALDH1B1 metabolizes nitroglycerin, retinaldehyde, and 4-HNE, and that polymorphic variants differ in catalytic competence.\",\n      \"evidence\": \"In vitro assays with purified recombinant protein and polymorphic variants plus molecular modeling\",\n      \"pmids\": [\"25413692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of each substrate not established in vivo\", \"No crystal structure to confirm modeled binding modes\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that ALDH1B1 metabolizes acetaldehyde and links it to glucose homeostasis, moving beyond in vitro activity to organismal function.\",\n      \"evidence\": \"Global Aldh1b1 knockout mice with ethanol pharmacokinetics and fasting glucose measurement\",\n      \"pmids\": [\"26086111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting ALDH1B1 to glucose regulation unresolved\", \"Tissue responsible for acetaldehyde clearance not pinpointed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a pro-tumorigenic role in colon cancer, showing ALDH1B1 knockdown reduces tumor growth and downregulates Wnt/\\u03b2-catenin, Notch, and PI3K/Akt signaling.\",\n      \"evidence\": \"shRNA knockdown, spheroid and xenograft assays, signaling pathway and promoter reporter analysis in SW480 cells\",\n      \"pmids\": [\"25950950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity drives signaling not addressed\", \"Direct molecular link between enzyme and Wnt/Notch/PI3K unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that ALDH1B1-mediated acetaldehyde detoxification protects the intestinal epithelium, as its loss aggravates ethanol-induced hyperproliferation and tumor features.\",\n      \"evidence\": \"Long-term ethanol drinking model in Aldh1b1-knockout mice with histopathology and DNA damage quantification\",\n      \"pmids\": [\"28026023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cooperating genetic events not yet defined in this study\", \"Cell-of-origin within the epithelium not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided genetic proof that Aldh1b1-expressing centroacinar cells are pancreatic progenitors and that ALDH1B1 is required for KrasG12D-driven pancreatic oncogenesis.\",\n      \"evidence\": \"Lineage tracing, Aldh1b1 KO crossed to KrasG12D model, scRNA-seq, and organoid assays\",\n      \"pmids\": [\"31548432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ALDH1B1 enables Kras transformation not defined\", \"Role of catalytic activity versus protein presence unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected methyltransferase signaling to ALDH1B1 in endocrine differentiation, showing Aldh1b1 is required for methyltransferase-inhibitor effects on Ngn3 and endocrine specification.\",\n      \"evidence\": \"Reporter-based small-molecule screen, pancreas explant culture, and Aldh1b1-null genetic epistasis\",\n      \"pmids\": [\"30681750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methyltransferase target acting upstream unidentified\", \"Molecular link between ALDH1B1 and Ngn3 regulation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified post-translational control of ALDH1B1 via AMBRA1/TRAF6-mediated noncanonical ubiquitination that limits its oligomerization and downstream PTEN/\\u03b2-catenin signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination site mutagenesis, self-association assays, and gene expression analysis\",\n      \"pmids\": [\"34769507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of altered oligomerization on enzymatic activity not measured\", \"Single-lab Co-IP; in vivo relevance untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed EIF4E as a translation-independent mitochondrial repressor of ALDH1B1 that, by limiting 4-HNE clearance, controls ferroptotic sensitivity.\",\n      \"evidence\": \"MS-based interactomics, reciprocal Co-IP, genetic KO/overexpression, and ferroptosis assays in vitro and in vivo\",\n      \"pmids\": [\"36274088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of EIF4E mitochondrial localization to ALDH1B1 unresolved\", \"Quantitative contribution of ALDH1B1 to lipid-peroxide pool not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Delivered active-site-directed selective inhibitors confirming ALDH1B1 is a druggable cancer dependency and linked its activity to mitochondrial metabolism and ribosomal gene programs.\",\n      \"evidence\": \"Active-site inhibitor development, proteome-wide selectivity profiling, spheroid/organoid assays, and transcriptomics\",\n      \"pmids\": [\"35788181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates underlying the dependent transcriptome not identified\", \"How enzyme activity shapes ribosomal/metabolic genes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ALDH1B1 acetaldehyde detoxification cooperates with mismatch-repair status, as its loss with Msh2 inactivation and ethanol drives colonic tumorigenesis.\",\n      \"evidence\": \"Aldh1b1/Msh2 double-knockout mice with ethanol exposure, plasma acetaldehyde measurement, and adenoma quantification\",\n      \"pmids\": [\"37395714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of acetaldehyde-induced lesions cooperating with dMMR not detailed\", \"Human relevance of the genetic interaction untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a non-detoxification antiviral function, with ALDH1B1 binding the MAVS transmembrane domain to promote MAVS aggregation and IFN-\\u03b2 signaling that restricts RNA viruses.\",\n      \"evidence\": \"KO/overexpression, mitochondrial fractionation/imaging, reciprocal Co-IP, MAVS aggregation and IFN-\\u03b2 reporter assays, and in vivo influenza infection\",\n      \"pmids\": [\"38194477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity is required for MAVS aggregation unresolved\", \"Structural basis of the ALDH1B1\\u2013MAVS interaction unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established transcriptional control of ALDH1B1 by NR5A2 governing ROS levels and pyroptosis in hepatocytes.\",\n      \"evidence\": \"Hepatocyte-specific Nr5a2 KO mice, isoform reintroduction rescue, ROS and pyroptosis assays, and NF-\\u03baB analysis\",\n      \"pmids\": [\"39438459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR5A2 binding at the ALDH1B1 locus not confirmed in this study\", \"Substrate basis of ALDH1B1-dependent ROS modulation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the diverse roles of ALDH1B1 (acetaldehyde detoxification, ferroptosis control, oncogenic signaling, MAVS-dependent antiviral immunity) all depend on its catalytic activity, and what its physiological substrates are in each context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of ALDH1B1 alone or in complex\", \"Catalysis-versus-scaffold contributions to antiviral and oncogenic roles not dissected\", \"Endogenous substrate spectrum in each tissue context undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3, 6, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAVS\", \"EIF4E\", \"AMBRA1\", \"TRAF6\", \"NR5A2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}