{"gene":"ALDH3A2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2005,"finding":"ALDH3A2 (FALDH) encodes a fatty aldehyde dehydrogenase that catalyzes the oxidation of long-chain aliphatic aldehydes derived from lipid metabolism; missense mutations cause profound reduction in enzyme activity as demonstrated by expression studies in patient cells.","method":"Expression studies in cultured fibroblasts, mutation analysis, enzymatic activity assays","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple independent labs, extensive mutation-function correlations replicated across >72 mutations","pmids":["15931689"],"is_preprint":false},{"year":1997,"finding":"ALDH3A2 (FALDH/ALDH10) is widely expressed as three transcripts and encodes an alternatively spliced isoform containing an extra exon that likely alters membrane-binding properties of the enzyme.","method":"Northern blot, genomic organization analysis, transcription initiation mapping (S1 nuclease protection, primer extension), in vitro transcription assay with nuclear extracts","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Northern blot, S1 protection, primer extension, in vitro transcription) in single study","pmids":["9027499"],"is_preprint":false},{"year":1997,"finding":"The ALDH3A2 gene has a TATA-less promoter with GC-rich sequences that interact with proteins in HeLa nuclear extracts and promote transcription in vitro; the gene produces transcripts via differential use of two polyadenylation sites.","method":"In vitro transcription assay, nuclear extract binding, Northern blot, S1 nuclease protection, primer extension","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro transcription reconstitution and multiple orthogonal methods","pmids":["9027499"],"is_preprint":false},{"year":2016,"finding":"ALDH3A2 is the major fatty aldehyde dehydrogenase active in undifferentiated keratinocytes; its loss impairs long-chain base metabolism, causes keratinocyte hyperproliferation with widened intercellular spaces, upregulates oxidative stress-induced genes, and retards skin barrier recovery after stratum corneum perturbation.","method":"Aldh3a2 knockout mice, enzymatic activity assays, gene expression profiling, transepidermal water loss measurement, histology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and metabolic phenotypes, multiple orthogonal readouts","pmids":["27053112"],"is_preprint":false},{"year":2008,"finding":"FALDH (ALDH3A2) detoxifies 4-hydroxynonenal (HNE) by oxidizing it, thereby reducing HNE adduct formation on IRS-1/IRS-2; adenoviral overexpression of FALDH partially restores HNE-impaired insulin-induced IRS-1 tyrosine phosphorylation and downstream PI3K/PKB signaling in 3T3-L1 adipocytes.","method":"Adenoviral overexpression, co-immunoprecipitation/adduct detection, insulin signaling assays (tyrosine phosphorylation, PI3K activity, PKB activity), glucose uptake measurement","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function rescue with multiple downstream pathway readouts","pmids":["18174527"],"is_preprint":false},{"year":2006,"finding":"ALDH3A2 expression is under the control of PPAR signaling; treatment with the pan-PPAR agonist bezafibrate induces FALDH activity and mRNA ~1.4–1.8-fold in human fibroblasts, and can partially restore enzymatic activity in SLS patients with residual enzyme.","method":"FALDH enzymatic activity assays, mRNA analysis in fibroblasts treated with bezafibrate","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzymatic and mRNA measurements, single lab, orthologous animal data cited","pmids":["16837225"],"is_preprint":false},{"year":2004,"finding":"A missense mutation (c.1139G>A, Ser380Asn) in the evolutionarily conserved catalytic domain of ALDH3A2 results in a protein with profoundly reduced enzymatic activity when expressed in a mammalian system.","method":"Site-directed mutagenesis, mammalian expression, enzymatic activity assay, RT-PCR of splice-site mutants","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1-2 — direct expression and activity assay with defined mutation in conserved catalytic domain","pmids":["15241804"],"is_preprint":false},{"year":2021,"finding":"ALDH3A2 mutations in structural and functional domains (including the C-terminal α-helix, substrate-gating region, and catalytic domain) reduce fatty aldehyde-oxidizing activity; mammalian expression studies confirmed profound reduction in enzymatic activity for exon-9 mutants, and patient fibroblasts showed diminished aldehyde-oxidizing activity.","method":"Mammalian expression of mutant constructs, enzymatic activity assay, patient fibroblast assay, skin biopsy histology","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro expression assays with activity measurements, single lab","pmids":["34082469"],"is_preprint":false},{"year":2018,"finding":"During mesendoderm differentiation of human embryonic stem cells, Activin/Smad2 promotes EZH2 degradation reducing H3K27me3, and the forkhead protein FOXH1 integrates Activin/Smad2 and Wnt/β-catenin signals to activate ALDH3A2 expression; knockdown of ALDH3A2 greatly attenuates mesendoderm differentiation.","method":"ChIP-seq, knockdown experiments, differentiation assays, Western blot for histone modifications and EZH2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via KD phenotype with pathway placement and chromatin evidence, single lab","pmids":["30282636"],"is_preprint":false},{"year":2023,"finding":"ALDH3A2 knockout in ovarian cancer cells elevates ferroptosis sensitivity, and its overexpression attenuates ferroptosis; ALDH3A2 knockout activates lipid metabolic, GSH metabolic, phospholipid metabolic, and aldehyde metabolic pathways as revealed by transcriptomic sequencing.","method":"ALDH3A2 knockout/overexpression, ferroptosis sensitivity assays, RNA sequencing","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss/gain of function with defined ferroptosis phenotype and transcriptomic pathway analysis, single lab","pmids":["37247796"],"is_preprint":false},{"year":2023,"finding":"ALDH3A2 silencing in ccRCC cells promotes lipid accumulation by activating the PI3K-AKT pathway; ALDH3A2 expression is negatively regulated by miR-1182 which binds its transcript.","method":"siRNA knockdown, PI3K-AKT pathway western blot, lipid droplet staining, miRNA target validation","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic validation of PI3K-AKT pathway placement","pmids":["38039946"],"is_preprint":false},{"year":2025,"finding":"ALDH3A2 overexpression in rat pulmonary artery smooth muscle cells suppresses proliferation, inhibits cell cycle progression, inhibits hypoxia-induced migration, and inhibits glycolytic enzymes (HK2, PGK1) and lactate dehydrogenase activity.","method":"ALDH3A2 overexpression in RPASMCs, proliferation assay, cell cycle analysis, migration assay, glycolytic enzyme activity measurement, MCT-induced PAH rat model","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, overexpression with phenotypic readouts but limited mechanistic depth","pmids":["40618980"],"is_preprint":false},{"year":2025,"finding":"ALDH3A2 impairs mitochondrial unfolded protein response (UPRmt) by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and ferroptosis in gastric cancer cells; ALDH3A2-induced ferroptosis promotes IL-6 release which drives M1 macrophage polarization.","method":"ALDH3A2 overexpression/knockdown, GPX4 rescue experiments, UPRmt rescue, NRF2 nuclear localization assay, co-culture with macrophages, in vivo tumor model","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — single lab, multiple pathway claims with rescue experiments but limited orthogonal validation","pmids":["41444219"],"is_preprint":false},{"year":2025,"finding":"ALDH3A2 overexpression in TNBC cells drives arachidonic acid enrichment, increases lipid droplet formation and triglycerides, suppresses AMPK phosphorylation, and activates mTOR/SREBP1 signaling; mTOR inhibition attenuates ALDH3A2-induced lipid metabolic alterations.","method":"ALDH3A2 overexpression, lipidomic profiling, Western blot for AMPK/mTOR/SREBP1, lipid droplet quantification, murine metastasis model, mTOR inhibitor rescue","journal":"Breast cancer research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pathway rescue with mTOR inhibitor supports mechanistic claim but limited orthogonal validation","pmids":["41413590"],"is_preprint":false}],"current_model":"ALDH3A2 encodes fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that oxidizes long-chain aliphatic aldehydes (including those from sphingolipid/fatty alcohol metabolism and lipid peroxidation products such as 4-HNE) to fatty acids; its loss causes toxic aldehyde accumulation leading to oxidative stress, keratinocyte hyperproliferation, impaired lipid/sphingolipid metabolism in skin, defective myelination, and insulin resistance, while its expression is regulated by PPAR signaling and, during development, by Activin/Smad2-Wnt/β-catenin-FOXH1-mediated epigenetic activation."},"narrative":{"teleology":[{"year":1997,"claim":"Defining the gene structure and transcriptional regulation of ALDH3A2 established it as a widely expressed, alternatively spliced gene with a TATA-less, GC-rich promoter, explaining how multiple FALDH isoforms with potentially distinct membrane-binding properties arise.","evidence":"Northern blot, S1 nuclease protection, primer extension, and in vitro transcription assays using HeLa nuclear extracts","pmids":["9027499"],"confidence":"High","gaps":["Functional consequence of the alternatively spliced exon on membrane anchoring was not directly tested","Transcription factor identity at the GC-rich promoter elements was not resolved"]},{"year":2005,"claim":"Systematic mutation–activity correlation across >72 ALDH3A2 mutations demonstrated that missense changes throughout the catalytic domain profoundly reduce FALDH enzymatic activity, establishing the genotype–phenotype basis of Sjögren–Larsson syndrome.","evidence":"Expression studies in cultured patient fibroblasts with enzymatic activity assays and mutation analysis","pmids":["15931689","15241804"],"confidence":"High","gaps":["No crystal structure to explain how individual mutations alter catalysis","Residual activity thresholds predicting disease severity were not defined"]},{"year":2006,"claim":"Identification of PPAR-dependent transcriptional induction of ALDH3A2 by bezafibrate revealed a druggable regulatory axis and suggested a pharmacological strategy to boost residual FALDH activity in patients.","evidence":"FALDH enzymatic activity and mRNA measurements in fibroblasts treated with bezafibrate","pmids":["16837225"],"confidence":"Medium","gaps":["Direct PPAR binding to the ALDH3A2 promoter was not shown","In vivo efficacy and clinical relevance of bezafibrate-mediated induction were not established"]},{"year":2008,"claim":"Demonstrating that FALDH detoxifies 4-HNE and thereby preserves IRS-1/IRS-2 from adduct formation expanded ALDH3A2 function beyond lipid metabolism to insulin signaling protection.","evidence":"Adenoviral FALDH overexpression in 3T3-L1 adipocytes with co-immunoprecipitation of HNE adducts, insulin-stimulated IRS-1 phosphorylation, PI3K activity, PKB activity, and glucose uptake assays","pmids":["18174527"],"confidence":"High","gaps":["Endogenous FALDH loss-of-function effect on insulin signaling in vivo was not tested","Relative contribution of FALDH vs. other 4-HNE-metabolizing enzymes in adipocytes was not quantified"]},{"year":2016,"claim":"Aldh3a2 knockout mice revealed that FALDH is the dominant aldehyde-oxidizing enzyme in undifferentiated keratinocytes and that its loss causes hyperproliferation, impaired sphingolipid metabolism, and defective skin barrier—recapitulating key features of Sjögren–Larsson syndrome.","evidence":"Aldh3a2 knockout mice with enzymatic activity assays, gene expression profiling, histology, and transepidermal water loss measurement","pmids":["27053112"],"confidence":"High","gaps":["CNS myelination defect was not characterized in this model","Identity of accumulating toxic aldehyde species in skin was not fully resolved"]},{"year":2018,"claim":"Placing ALDH3A2 downstream of Activin/Smad2–Wnt/β-catenin–FOXH1 signaling during mesendoderm differentiation revealed an unexpected developmental role, where ALDH3A2 knockdown severely attenuated differentiation of human embryonic stem cells.","evidence":"ChIP-seq, knockdown experiments, differentiation assays, and Western blot for H3K27me3/EZH2 in hESCs","pmids":["30282636"],"confidence":"Medium","gaps":["Mechanism by which FALDH enzymatic activity promotes mesendoderm differentiation is unknown","Whether aldehyde detoxification or a non-canonical function drives the differentiation phenotype was not resolved"]},{"year":2021,"claim":"Extending structure–function mapping to the C-terminal α-helix and substrate-gating region refined understanding of FALDH domain architecture and confirmed that mutations outside the catalytic center also abolish activity.","evidence":"Mammalian expression of mutant constructs with enzymatic activity assays and patient fibroblast analysis","pmids":["34082469"],"confidence":"Medium","gaps":["No high-resolution structural data to model substrate access or gating mechanism","Protein stability vs. catalytic defect was not distinguished for all mutants"]},{"year":2023,"claim":"ALDH3A2 knockout in ovarian cancer cells elevated ferroptosis sensitivity while overexpression attenuated it, linking FALDH's aldehyde-detoxifying function to protection against lipid peroxidation-dependent cell death.","evidence":"CRISPR knockout and overexpression with ferroptosis sensitivity assays and RNA-seq pathway analysis in ovarian cancer cells","pmids":["37247796"],"confidence":"Medium","gaps":["Specific lipid aldehyde substrates driving ferroptosis sensitization were not identified","Whether ferroptosis protection is a general or cancer cell-type-specific function is unknown"]},{"year":null,"claim":"The three-dimensional structure of FALDH, the identity of its full aldehyde substrate repertoire in vivo, and the mechanism by which its enzymatic activity supports mesendoderm differentiation and CNS myelination remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of FALDH","Substrate specificity in different tissues has not been systematically profiled","Mechanism linking FALDH loss to myelination failure in the CNS is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,3,4,6,7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,4,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8]}],"complexes":[],"partners":["FOXH1","IRS1","IRS2","NRF2","GPX4"],"other_free_text":[]},"mechanistic_narrative":"ALDH3A2 encodes fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that catalyzes the NAD⁺-dependent oxidation of long-chain aliphatic aldehydes—including lipid peroxidation-derived 4-hydroxynonenal (4-HNE) and intermediates of sphingolipid/fatty alcohol metabolism—to their corresponding fatty acids. Loss-of-function mutations in the catalytic domain, substrate-gating region, or C-terminal α-helix profoundly reduce enzymatic activity in patient fibroblasts and expression systems, causing Sjögren–Larsson syndrome characterized by ichthyosis and defective myelination [PMID:15931689, PMID:34082469]. In skin, ALDH3A2 is the predominant fatty aldehyde dehydrogenase in undifferentiated keratinocytes; its knockout leads to impaired long-chain base metabolism, keratinocyte hyperproliferation, oxidative stress gene upregulation, and delayed barrier recovery [PMID:27053112]. ALDH3A2 also protects against lipid peroxidation–driven damage: it detoxifies 4-HNE to preserve insulin receptor substrate signaling in adipocytes [PMID:18174527], and its loss sensitizes cells to ferroptosis by disrupting lipid and glutathione homeostasis [PMID:37247796]."},"prefetch_data":{"uniprot":{"accession":"P51648","full_name":"Aldehyde dehydrogenase family 3 member A2","aliases":["Aldehyde dehydrogenase 10","Fatty aldehyde dehydrogenase","Microsomal aldehyde dehydrogenase"],"length_aa":485,"mass_kda":54.8,"function":"Catalyzes the oxidation of medium and long chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length (PubMed:18035827, PubMed:18182499, PubMed:22633490, PubMed:25047030, PubMed:9133646, PubMed:9662422). Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid (PubMed:22633490)","subcellular_location":"Microsome membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P51648/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALDH3A2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CDS1","stoichiometry":0.2},{"gene":"CDS2","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"RELA","stoichiometry":0.2},{"gene":"RER1","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2},{"gene":"SPTLC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ALDH3A2","total_profiled":1310},"omim":[{"mim_id":"613738","title":"ALKYLGLYCEROL MONOOXYGENASE; AGMO","url":"https://www.omim.org/entry/613738"},{"mim_id":"609523","title":"ALDEHYDE DEHYDROGENASE, FAMILY 3, SUBFAMILY A, MEMBER 2; ALDH3A2","url":"https://www.omim.org/entry/609523"},{"mim_id":"270200","title":"SJOGREN-LARSSON SYNDROME; SLS","url":"https://www.omim.org/entry/270200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":269.4}],"url":"https://www.proteinatlas.org/search/ALDH3A2"},"hgnc":{"alias_symbol":["FALDH"],"prev_symbol":["SLS","ALDH10"]},"alphafold":{"accession":"P51648","domains":[{"cath_id":"3.40.605.10","chopping":"2-209_411-425","consensus_level":"high","plddt":98.5997,"start":2,"end":425},{"cath_id":"3.40.309.10","chopping":"214-401","consensus_level":"high","plddt":98.6289,"start":214,"end":401},{"cath_id":"-","chopping":"433-484","consensus_level":"medium","plddt":81.9483,"start":433,"end":484}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51648","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51648-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51648-F1-predicted_aligned_error_v6.png","plddt_mean":96.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALDH3A2","jax_strain_url":"https://www.jax.org/strain/search?query=ALDH3A2"},"sequence":{"accession":"P51648","fasta_url":"https://rest.uniprot.org/uniprotkb/P51648.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51648/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51648"}},"corpus_meta":[{"pmid":"15931689","id":"PMC_15931689","title":"Sjögren-Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2).","date":"2005","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15931689","citation_count":98,"is_preprint":false},{"pmid":"17316686","id":"PMC_17316686","title":"Modular proteins from the Drosophila sallimus (sls) gene and their expression in muscles with different extensibility.","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17316686","citation_count":84,"is_preprint":false},{"pmid":"18174527","id":"PMC_18174527","title":"FALDH reverses the deleterious action of oxidative stress induced by lipid peroxidation product 4-hydroxynonenal on insulin signaling in 3T3-L1 adipocytes.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18174527","citation_count":83,"is_preprint":false},{"pmid":"20107599","id":"PMC_20107599","title":"Persistent ER stress induces the spliced leader RNA silencing pathway (SLS), leading to programmed cell death in Trypanosoma brucei.","date":"2010","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/20107599","citation_count":73,"is_preprint":false},{"pmid":"7798140","id":"PMC_7798140","title":"Isolation, sequencing, and mutagenesis of the gene encoding NAD- and glutathione-dependent formaldehyde dehydrogenase (GD-FALDH) from Paracoccus denitrificans, in which GD-FALDH is essential for methylotrophic growth.","date":"1995","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/7798140","citation_count":68,"is_preprint":false},{"pmid":"9027499","id":"PMC_9027499","title":"Genomic organization and expression of the human fatty aldehyde dehydrogenase gene (FALDH).","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9027499","citation_count":57,"is_preprint":false},{"pmid":"10227616","id":"PMC_10227616","title":"Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients.","date":"1999","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10227616","citation_count":49,"is_preprint":false},{"pmid":"8828661","id":"PMC_8828661","title":"Effect of SLS-2 spaceflight on immunologic parameters of rats.","date":"1996","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/8828661","citation_count":48,"is_preprint":false},{"pmid":"31002395","id":"PMC_31002395","title":"Multi-subtype classification model for non-small cell lung cancer based on radiomics: SLS model.","date":"2019","source":"Medical physics","url":"https://pubmed.ncbi.nlm.nih.gov/31002395","citation_count":46,"is_preprint":false},{"pmid":"22345508","id":"PMC_22345508","title":"Amino acid residues critical for the specificity for betaine aldehyde of the plant ALDH10 isoenzyme involved in the synthesis of glycine betaine.","date":"2012","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22345508","citation_count":42,"is_preprint":false},{"pmid":"9829906","id":"PMC_9829906","title":"Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome.","date":"1998","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/9829906","citation_count":40,"is_preprint":false},{"pmid":"9070922","id":"PMC_9070922","title":"Human fatty aldehyde dehydrogenase gene (ALDH10): organization and tissue-dependent expression.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9070922","citation_count":38,"is_preprint":false},{"pmid":"23408433","id":"PMC_23408433","title":"Plant ALDH10 family: identifying critical residues for substrate specificity and trapping a thiohemiacetal intermediate.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23408433","citation_count":36,"is_preprint":false},{"pmid":"27053112","id":"PMC_27053112","title":"Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27053112","citation_count":33,"is_preprint":false},{"pmid":"16699917","id":"PMC_16699917","title":"Drosophila rolling pebbles colocalises and putatively interacts with alpha-Actinin and the Sls isoform Zormin in the Z-discs of the sarcomere and with Dumbfounded/Kirre, alpha-Actinin and Zormin in the terminal Z-discs.","date":"2006","source":"Journal of muscle research and cell motility","url":"https://pubmed.ncbi.nlm.nih.gov/16699917","citation_count":33,"is_preprint":false},{"pmid":"12102660","id":"PMC_12102660","title":"Effect of skin barrier competence on SLS and water-induced IL-1alpha expression.","date":"2002","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/12102660","citation_count":32,"is_preprint":false},{"pmid":"26512860","id":"PMC_26512860","title":"Hydrolysis-acidogenesis of food waste in solid-liquid-separating continuous stirred tank reactor (SLS-CSTR) for volatile organic acid production.","date":"2015","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/26512860","citation_count":32,"is_preprint":false},{"pmid":"25604991","id":"PMC_25604991","title":"Alteration of osa-miR156e expression affects rice plant architecture and strigolactones (SLs) pathway.","date":"2015","source":"Plant cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25604991","citation_count":32,"is_preprint":false},{"pmid":"9254849","id":"PMC_9254849","title":"A missense mutation in the FALDH gene identified in Sjögren-Larsson syndrome patients originating from the northern part of Sweden.","date":"1997","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9254849","citation_count":28,"is_preprint":false},{"pmid":"23180673","id":"PMC_23180673","title":"Strigolactone analogs as molecular probes in chasing the (SLs) receptor/s: design and synthesis of fluorescent labeled molecules.","date":"2012","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/23180673","citation_count":27,"is_preprint":false},{"pmid":"15241804","id":"PMC_15241804","title":"Sjögren-Larsson syndrome: seven novel mutations in the fatty aldehyde dehydrogenase gene ALDH3A2.","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15241804","citation_count":23,"is_preprint":false},{"pmid":"16837225","id":"PMC_16837225","title":"Bezafibrate induces FALDH in human fibroblasts; implications for Sjögren-Larsson syndrome.","date":"2006","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/16837225","citation_count":23,"is_preprint":false},{"pmid":"32085885","id":"PMC_32085885","title":"Comprehensive in silico screening and molecular dynamics studies of missense mutations in Sjogren-Larsson syndrome associated with the ALDH3A2 gene.","date":"2020","source":"Advances in protein chemistry and structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/32085885","citation_count":21,"is_preprint":false},{"pmid":"22650251","id":"PMC_22650251","title":"Spliced leader RNA silencing (SLS) - a programmed cell death pathway in Trypanosoma brucei that is induced upon ER stress.","date":"2012","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/22650251","citation_count":21,"is_preprint":false},{"pmid":"22281431","id":"PMC_22281431","title":"Patterns of autophagy in urothelial cell carcinomas--the significance of \"stone-like\" structures (SLS) in transurethral resection biopsies.","date":"2012","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22281431","citation_count":18,"is_preprint":false},{"pmid":"25855245","id":"PMC_25855245","title":"Case of Sjögren-Larsson syndrome with a large deletion in the ALDH3A2 gene confirmed by single nucleotide polymorphism array analysis.","date":"2015","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25855245","citation_count":16,"is_preprint":false},{"pmid":"37247796","id":"PMC_37247796","title":"Inhibit ALDH3A2 reduce ovarian cancer cells survival via elevating ferroptosis sensitivity.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/37247796","citation_count":16,"is_preprint":false},{"pmid":"8161323","id":"PMC_8161323","title":"ANP binding sites are increased in choroid plexus of SLS-1 rats after 9 days of spaceflight.","date":"1994","source":"Aviation, space, and environmental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8161323","citation_count":15,"is_preprint":false},{"pmid":"24884441","id":"PMC_24884441","title":"Exploring the evolutionary route of the acquisition of betaine aldehyde dehydrogenase activity by plant ALDH10 enzymes: implications for the synthesis of the osmoprotectant glycine betaine.","date":"2014","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/24884441","citation_count":14,"is_preprint":false},{"pmid":"17902024","id":"PMC_17902024","title":"Novel and recurrent ALDH3A2 mutations in Italian patients with Sjögren-Larsson syndrome.","date":"2007","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17902024","citation_count":14,"is_preprint":false},{"pmid":"38039946","id":"PMC_38039946","title":"miR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.","date":"2023","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38039946","citation_count":12,"is_preprint":false},{"pmid":"8338496","id":"PMC_8338496","title":"Norepinephrine content in discrete brain areas and neurohypophysial vasopressin in rats after a 9-d spaceflight (SLS-1).","date":"1993","source":"Aviation, space, and environmental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8338496","citation_count":12,"is_preprint":false},{"pmid":"30282636","id":"PMC_30282636","title":"Activin/Smad2 and Wnt/β-catenin up-regulate HAS2 and ALDH3A2 to facilitate mesendoderm differentiation of human embryonic stem cells.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30282636","citation_count":11,"is_preprint":false},{"pmid":"11540975","id":"PMC_11540975","title":"Choroidal responses in microgravity. (SLS-1, SLS-2 and hindlimb-suspension experiments).","date":"1995","source":"Acta astronautica","url":"https://pubmed.ncbi.nlm.nih.gov/11540975","citation_count":11,"is_preprint":false},{"pmid":"36822526","id":"PMC_36822526","title":"SLs signal transduction gene CsMAX2 of cucumber positively regulated to salt, drought and ABA stress in Arabidopsis thaliana L.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/36822526","citation_count":10,"is_preprint":false},{"pmid":"29594067","id":"PMC_29594067","title":"Route of Glucose Uptake in the Group a Streptococcus Impacts SLS-Mediated Hemolysis and Survival in Human Blood.","date":"2018","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29594067","citation_count":10,"is_preprint":false},{"pmid":"31273323","id":"PMC_31273323","title":"Phenotypic and mutational spectrum of thirty-five patients with Sjögren-Larsson syndrome: identification of eleven novel ALDH3A2 mutations and founder effects.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31273323","citation_count":9,"is_preprint":false},{"pmid":"15016027","id":"PMC_15016027","title":"Influence of a SLS-containing dentifrice on the anti-plaque efficacy of a chlorhexidine mouthrinse.","date":"2004","source":"Journal of clinical periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/15016027","citation_count":9,"is_preprint":false},{"pmid":"25985970","id":"PMC_25985970","title":"The response of trypanosomes and other eukaryotes to ER stress and the spliced leader RNA silencing (SLS) pathway in Trypanosoma brucei.","date":"2015","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25985970","citation_count":9,"is_preprint":false},{"pmid":"36232996","id":"PMC_36232996","title":"ALDH3A2, ODF2, QSOX2, and MicroRNA-503-5p Expression to Forecast Recurrence in TMPRSS2-ERG-Positive Prostate Cancer.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36232996","citation_count":8,"is_preprint":false},{"pmid":"31132807","id":"PMC_31132807","title":"Potential role of ALDH3A2 on the lipid and glucose metabolism regulated by (-)-hydroxycitric acid in chicken embryos.","date":"2019","source":"Animal science journal = Nihon chikusan Gakkaiho","url":"https://pubmed.ncbi.nlm.nih.gov/31132807","citation_count":8,"is_preprint":false},{"pmid":"37939039","id":"PMC_37939039","title":"SLS 3D Printing To Fabricate Poly(vinyl alcohol)/Hydroxyapatite Bioactive Composite Porous Scaffolds and Their Bone Defect Repair Property.","date":"2023","source":"ACS biomaterials science & engineering","url":"https://pubmed.ncbi.nlm.nih.gov/37939039","citation_count":8,"is_preprint":false},{"pmid":"8725473","id":"PMC_8725473","title":"Central and peripheral noradrenergic responses to 14 days of spaceflight (SLS-2) or hindlimb suspension in rats.","date":"1996","source":"Aviation, space, and environmental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8725473","citation_count":8,"is_preprint":false},{"pmid":"34498760","id":"PMC_34498760","title":"Strigolactones (SLs) modulate the plastochron by regulating KLUH (KLU) transcript abundance in Arabidopsis.","date":"2021","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/34498760","citation_count":8,"is_preprint":false},{"pmid":"31388754","id":"PMC_31388754","title":"Genetic assessment of ten Egyptian patients with Sjögren-Larsson syndrome: expanding the clinical spectrum and reporting a novel ALDH3A2 mutation.","date":"2019","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/31388754","citation_count":7,"is_preprint":false},{"pmid":"21872273","id":"PMC_21872273","title":"Sjögren-Larsson syndrome: novel mutations in the ALDH3A2 gene in a French cohort.","date":"2011","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21872273","citation_count":7,"is_preprint":false},{"pmid":"24101836","id":"PMC_24101836","title":"A Turkish family with Sjögren-Larsson syndrome caused by a novel ALDH3A2 mutation.","date":"2013","source":"Annals of Indian Academy of Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24101836","citation_count":7,"is_preprint":false},{"pmid":"10667097","id":"PMC_10667097","title":"Comparative effects of UW and SLS solutions on concentrative proline uptake in cold preserved rat hepatocytes.","date":"1999","source":"Therapie","url":"https://pubmed.ncbi.nlm.nih.gov/10667097","citation_count":7,"is_preprint":false},{"pmid":"34082469","id":"PMC_34082469","title":"Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson syndrome patients.","date":"2021","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/34082469","citation_count":5,"is_preprint":false},{"pmid":"35364534","id":"PMC_35364534","title":"The plant streptolysin S (SLS)-associated gene B confers nitroaromatic tolerance and detoxification.","date":"2022","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/35364534","citation_count":5,"is_preprint":false},{"pmid":"20883264","id":"PMC_20883264","title":"An Indian family with Sjögren-Larsson syndrome caused by a novel ALDH3A2 mutation.","date":"2010","source":"International journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20883264","citation_count":5,"is_preprint":false},{"pmid":"35905477","id":"PMC_35905477","title":"Ultra-/Small Angle X-ray Scattering (USAXS/SAXS) and Static Light Scattering (SLS) Modeling as a Tool to Determine Structural Changes and Effect on Growth in S. epidermidis.","date":"2022","source":"ACS applied bio materials","url":"https://pubmed.ncbi.nlm.nih.gov/35905477","citation_count":4,"is_preprint":false},{"pmid":"37007019","id":"PMC_37007019","title":"Protective effects of extracts from Acer truncatum leaves on SLS-induced HaCaT cells.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37007019","citation_count":4,"is_preprint":false},{"pmid":"39170800","id":"PMC_39170800","title":"Evaluation of a rapid multi-attribute combinatorial high-throughput UV-Vis/DLS/SLS analytical platform for rAAV quantification and characterization.","date":"2024","source":"Molecular therapy. Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/39170800","citation_count":4,"is_preprint":false},{"pmid":"38348580","id":"PMC_38348580","title":"3D printing modality effect: Distinct printing outcomes dependent on selective laser sintering (SLS) and melt extrusion.","date":"2024","source":"Journal of biomedical materials research. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38348580","citation_count":3,"is_preprint":false},{"pmid":"29375833","id":"PMC_29375833","title":"Identification of a novel deletion within ALDH3A2 gene in an Iranian Family with Sjögren-Larsson Syndrome.","date":"2017","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/29375833","citation_count":3,"is_preprint":false},{"pmid":"36430536","id":"PMC_36430536","title":"Whole Genome Analysis of SLs Pathway Genes and Functional Characterization of DlSMXL6 in Longan Early Somatic Embryo Development.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36430536","citation_count":3,"is_preprint":false},{"pmid":"23180547","id":"PMC_23180547","title":"Oxidation of fatty aldehydes to fatty acids by Escherichia coli cells expressing the Vibrio harveyi fatty aldehyde dehydrogenase (FALDH).","date":"2012","source":"World journal of microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23180547","citation_count":3,"is_preprint":false},{"pmid":"34844425","id":"PMC_34844425","title":"The Spliced Leader RNA Silencing (SLS) Pathway in Trypanosoma brucei Is Induced by Perturbations of Endoplasmic Reticulum, Golgi Complex, or Mitochondrial Protein Factors: Functional Analysis of SLS-Inducing Kinase PK3.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/34844425","citation_count":3,"is_preprint":false},{"pmid":"9686973","id":"PMC_9686973","title":"Keratin 17 is expressed during the course of SLS-induced irritant contact dermatitis, but unlike keratin 16, the degree of expression is unrelated to the density of dividing keratinocytes.","date":"1998","source":"Contact dermatitis","url":"https://pubmed.ncbi.nlm.nih.gov/9686973","citation_count":3,"is_preprint":false},{"pmid":"36151387","id":"PMC_36151387","title":"Segment-Long-Spacing (SLS) and the Polymorphic Structures of Fibrillar Collagen.","date":"2022","source":"Sub-cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36151387","citation_count":2,"is_preprint":false},{"pmid":"39902209","id":"PMC_39902209","title":"Effects of exogenous SLs on growth and physiological characteristics of flue-cured tobacco seedlings under different degrees of drought stress.","date":"2025","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/39902209","citation_count":2,"is_preprint":false},{"pmid":"31944864","id":"PMC_31944864","title":"Compound heterozygous mutations in the ALDH3A2 gene cause Sjögren-Larsson syndrome: a case report.","date":"2020","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31944864","citation_count":2,"is_preprint":false},{"pmid":"18548750","id":"PMC_18548750","title":"Resonance light-scattering enhancement effect of the protein-Y3+-TTA-SLS system and its analytical application.","date":"2008","source":"Luminescence : the journal of biological and chemical luminescence","url":"https://pubmed.ncbi.nlm.nih.gov/18548750","citation_count":2,"is_preprint":false},{"pmid":"41012261","id":"PMC_41012261","title":"Bone Regeneration in SLS-Manufactured Resorbable 3D-Scaffolds-An Experimental Pilot Study in Minipigs.","date":"2025","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/41012261","citation_count":1,"is_preprint":false},{"pmid":"38449472","id":"PMC_38449472","title":"A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide.","date":"2024","source":"Psychopharmacology bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/38449472","citation_count":1,"is_preprint":false},{"pmid":"40618980","id":"PMC_40618980","title":"Significance of ALDH3A2, a mitochondrial metabolism and glycolysis related gene, in pulmonary arterial hypertension.","date":"2025","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40618980","citation_count":0,"is_preprint":false},{"pmid":"41413590","id":"PMC_41413590","title":"ALDH3A2 targets arachidonic acid to promote cell metastasis in TNBC via AMPK/m-TOR signaling pathway.","date":"2025","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/41413590","citation_count":0,"is_preprint":false},{"pmid":"41444219","id":"PMC_41444219","title":"ALDH3A2 negatively orchestrates gastric cancer progression through a synergistic induction of ferroptosis and ferroptosis-driven macrophage reprogramming.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41444219","citation_count":0,"is_preprint":false},{"pmid":"41879511","id":"PMC_41879511","title":"Sharper, smaller, brighter: enhanced optical performance at the X06DA-PXIII beamline after the SLS 2.0 upgrade.","date":"2026","source":"Journal of synchrotron radiation","url":"https://pubmed.ncbi.nlm.nih.gov/41879511","citation_count":0,"is_preprint":false},{"pmid":"1491672","id":"PMC_1491672","title":"[SLS--a new type of polynucleotide chain folding].","date":"1992","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/1491672","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.17.25340398","title":"Stroboscopic Light Stimulation Safety Within and Beyond Laboratory Settings: Observational Evidence and Practical Guidance","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.17.25340398","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.15.688585","title":"Phase-targeting rapid cryofixation of the beating heart and histological analysis unveil contractile state-dependent sarcomere dynamics","date":"2025-11-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.15.688585","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.18.688998","title":"<i>In Vitro</i>  Dynamic and Quantitative Monitoring of Strigolactone-signaling Complex Formation by Time-resolved FRET","date":"2025-11-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.18.688998","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.03.673831","title":"Adaptation of motor control strategies and physiological arousal during repeated blocks of split-belt walking","date":"2025-09-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.03.673831","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.28.679090","title":"A Novel Method for the Mechanical Testing of Human Cerebrovascular Tissue: A Validation Study","date":"2025-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.28.679090","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.25.689980","title":"Cumulative cgMLST provides increased discrimination of nested phylogenetic groups","date":"2025-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.25.689980","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40122,"output_tokens":3159,"usd":0.083876},"stage2":{"model":"claude-opus-4-6","input_tokens":6554,"output_tokens":2351,"usd":0.137318},"total_usd":0.221194,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"ALDH3A2 (FALDH) encodes a fatty aldehyde dehydrogenase that catalyzes the oxidation of long-chain aliphatic aldehydes derived from lipid metabolism; missense mutations cause profound reduction in enzyme activity as demonstrated by expression studies in patient cells.\",\n      \"method\": \"Expression studies in cultured fibroblasts, mutation analysis, enzymatic activity assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple independent labs, extensive mutation-function correlations replicated across >72 mutations\",\n      \"pmids\": [\"15931689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ALDH3A2 (FALDH/ALDH10) is widely expressed as three transcripts and encodes an alternatively spliced isoform containing an extra exon that likely alters membrane-binding properties of the enzyme.\",\n      \"method\": \"Northern blot, genomic organization analysis, transcription initiation mapping (S1 nuclease protection, primer extension), in vitro transcription assay with nuclear extracts\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Northern blot, S1 protection, primer extension, in vitro transcription) in single study\",\n      \"pmids\": [\"9027499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The ALDH3A2 gene has a TATA-less promoter with GC-rich sequences that interact with proteins in HeLa nuclear extracts and promote transcription in vitro; the gene produces transcripts via differential use of two polyadenylation sites.\",\n      \"method\": \"In vitro transcription assay, nuclear extract binding, Northern blot, S1 nuclease protection, primer extension\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro transcription reconstitution and multiple orthogonal methods\",\n      \"pmids\": [\"9027499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ALDH3A2 is the major fatty aldehyde dehydrogenase active in undifferentiated keratinocytes; its loss impairs long-chain base metabolism, causes keratinocyte hyperproliferation with widened intercellular spaces, upregulates oxidative stress-induced genes, and retards skin barrier recovery after stratum corneum perturbation.\",\n      \"method\": \"Aldh3a2 knockout mice, enzymatic activity assays, gene expression profiling, transepidermal water loss measurement, histology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and metabolic phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"27053112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FALDH (ALDH3A2) detoxifies 4-hydroxynonenal (HNE) by oxidizing it, thereby reducing HNE adduct formation on IRS-1/IRS-2; adenoviral overexpression of FALDH partially restores HNE-impaired insulin-induced IRS-1 tyrosine phosphorylation and downstream PI3K/PKB signaling in 3T3-L1 adipocytes.\",\n      \"method\": \"Adenoviral overexpression, co-immunoprecipitation/adduct detection, insulin signaling assays (tyrosine phosphorylation, PI3K activity, PKB activity), glucose uptake measurement\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function rescue with multiple downstream pathway readouts\",\n      \"pmids\": [\"18174527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ALDH3A2 expression is under the control of PPAR signaling; treatment with the pan-PPAR agonist bezafibrate induces FALDH activity and mRNA ~1.4–1.8-fold in human fibroblasts, and can partially restore enzymatic activity in SLS patients with residual enzyme.\",\n      \"method\": \"FALDH enzymatic activity assays, mRNA analysis in fibroblasts treated with bezafibrate\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzymatic and mRNA measurements, single lab, orthologous animal data cited\",\n      \"pmids\": [\"16837225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A missense mutation (c.1139G>A, Ser380Asn) in the evolutionarily conserved catalytic domain of ALDH3A2 results in a protein with profoundly reduced enzymatic activity when expressed in a mammalian system.\",\n      \"method\": \"Site-directed mutagenesis, mammalian expression, enzymatic activity assay, RT-PCR of splice-site mutants\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — direct expression and activity assay with defined mutation in conserved catalytic domain\",\n      \"pmids\": [\"15241804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ALDH3A2 mutations in structural and functional domains (including the C-terminal α-helix, substrate-gating region, and catalytic domain) reduce fatty aldehyde-oxidizing activity; mammalian expression studies confirmed profound reduction in enzymatic activity for exon-9 mutants, and patient fibroblasts showed diminished aldehyde-oxidizing activity.\",\n      \"method\": \"Mammalian expression of mutant constructs, enzymatic activity assay, patient fibroblast assay, skin biopsy histology\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro expression assays with activity measurements, single lab\",\n      \"pmids\": [\"34082469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"During mesendoderm differentiation of human embryonic stem cells, Activin/Smad2 promotes EZH2 degradation reducing H3K27me3, and the forkhead protein FOXH1 integrates Activin/Smad2 and Wnt/β-catenin signals to activate ALDH3A2 expression; knockdown of ALDH3A2 greatly attenuates mesendoderm differentiation.\",\n      \"method\": \"ChIP-seq, knockdown experiments, differentiation assays, Western blot for histone modifications and EZH2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via KD phenotype with pathway placement and chromatin evidence, single lab\",\n      \"pmids\": [\"30282636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDH3A2 knockout in ovarian cancer cells elevates ferroptosis sensitivity, and its overexpression attenuates ferroptosis; ALDH3A2 knockout activates lipid metabolic, GSH metabolic, phospholipid metabolic, and aldehyde metabolic pathways as revealed by transcriptomic sequencing.\",\n      \"method\": \"ALDH3A2 knockout/overexpression, ferroptosis sensitivity assays, RNA sequencing\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss/gain of function with defined ferroptosis phenotype and transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"37247796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDH3A2 silencing in ccRCC cells promotes lipid accumulation by activating the PI3K-AKT pathway; ALDH3A2 expression is negatively regulated by miR-1182 which binds its transcript.\",\n      \"method\": \"siRNA knockdown, PI3K-AKT pathway western blot, lipid droplet staining, miRNA target validation\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic validation of PI3K-AKT pathway placement\",\n      \"pmids\": [\"38039946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDH3A2 overexpression in rat pulmonary artery smooth muscle cells suppresses proliferation, inhibits cell cycle progression, inhibits hypoxia-induced migration, and inhibits glycolytic enzymes (HK2, PGK1) and lactate dehydrogenase activity.\",\n      \"method\": \"ALDH3A2 overexpression in RPASMCs, proliferation assay, cell cycle analysis, migration assay, glycolytic enzyme activity measurement, MCT-induced PAH rat model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression with phenotypic readouts but limited mechanistic depth\",\n      \"pmids\": [\"40618980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDH3A2 impairs mitochondrial unfolded protein response (UPRmt) by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and ferroptosis in gastric cancer cells; ALDH3A2-induced ferroptosis promotes IL-6 release which drives M1 macrophage polarization.\",\n      \"method\": \"ALDH3A2 overexpression/knockdown, GPX4 rescue experiments, UPRmt rescue, NRF2 nuclear localization assay, co-culture with macrophages, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple pathway claims with rescue experiments but limited orthogonal validation\",\n      \"pmids\": [\"41444219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDH3A2 overexpression in TNBC cells drives arachidonic acid enrichment, increases lipid droplet formation and triglycerides, suppresses AMPK phosphorylation, and activates mTOR/SREBP1 signaling; mTOR inhibition attenuates ALDH3A2-induced lipid metabolic alterations.\",\n      \"method\": \"ALDH3A2 overexpression, lipidomic profiling, Western blot for AMPK/mTOR/SREBP1, lipid droplet quantification, murine metastasis model, mTOR inhibitor rescue\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway rescue with mTOR inhibitor supports mechanistic claim but limited orthogonal validation\",\n      \"pmids\": [\"41413590\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALDH3A2 encodes fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that oxidizes long-chain aliphatic aldehydes (including those from sphingolipid/fatty alcohol metabolism and lipid peroxidation products such as 4-HNE) to fatty acids; its loss causes toxic aldehyde accumulation leading to oxidative stress, keratinocyte hyperproliferation, impaired lipid/sphingolipid metabolism in skin, defective myelination, and insulin resistance, while its expression is regulated by PPAR signaling and, during development, by Activin/Smad2-Wnt/β-catenin-FOXH1-mediated epigenetic activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ALDH3A2 encodes fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that catalyzes the NAD⁺-dependent oxidation of long-chain aliphatic aldehydes—including lipid peroxidation-derived 4-hydroxynonenal (4-HNE) and intermediates of sphingolipid/fatty alcohol metabolism—to their corresponding fatty acids. Loss-of-function mutations in the catalytic domain, substrate-gating region, or C-terminal α-helix profoundly reduce enzymatic activity in patient fibroblasts and expression systems, causing Sjögren–Larsson syndrome characterized by ichthyosis and defective myelination [PMID:15931689, PMID:34082469]. In skin, ALDH3A2 is the predominant fatty aldehyde dehydrogenase in undifferentiated keratinocytes; its knockout leads to impaired long-chain base metabolism, keratinocyte hyperproliferation, oxidative stress gene upregulation, and delayed barrier recovery [PMID:27053112]. ALDH3A2 also protects against lipid peroxidation–driven damage: it detoxifies 4-HNE to preserve insulin receptor substrate signaling in adipocytes [PMID:18174527], and its loss sensitizes cells to ferroptosis by disrupting lipid and glutathione homeostasis [PMID:37247796].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Defining the gene structure and transcriptional regulation of ALDH3A2 established it as a widely expressed, alternatively spliced gene with a TATA-less, GC-rich promoter, explaining how multiple FALDH isoforms with potentially distinct membrane-binding properties arise.\",\n      \"evidence\": \"Northern blot, S1 nuclease protection, primer extension, and in vitro transcription assays using HeLa nuclear extracts\",\n      \"pmids\": [\"9027499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of the alternatively spliced exon on membrane anchoring was not directly tested\",\n        \"Transcription factor identity at the GC-rich promoter elements was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Systematic mutation–activity correlation across >72 ALDH3A2 mutations demonstrated that missense changes throughout the catalytic domain profoundly reduce FALDH enzymatic activity, establishing the genotype–phenotype basis of Sjögren–Larsson syndrome.\",\n      \"evidence\": \"Expression studies in cultured patient fibroblasts with enzymatic activity assays and mutation analysis\",\n      \"pmids\": [\"15931689\", \"15241804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure to explain how individual mutations alter catalysis\",\n        \"Residual activity thresholds predicting disease severity were not defined\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of PPAR-dependent transcriptional induction of ALDH3A2 by bezafibrate revealed a druggable regulatory axis and suggested a pharmacological strategy to boost residual FALDH activity in patients.\",\n      \"evidence\": \"FALDH enzymatic activity and mRNA measurements in fibroblasts treated with bezafibrate\",\n      \"pmids\": [\"16837225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct PPAR binding to the ALDH3A2 promoter was not shown\",\n        \"In vivo efficacy and clinical relevance of bezafibrate-mediated induction were not established\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that FALDH detoxifies 4-HNE and thereby preserves IRS-1/IRS-2 from adduct formation expanded ALDH3A2 function beyond lipid metabolism to insulin signaling protection.\",\n      \"evidence\": \"Adenoviral FALDH overexpression in 3T3-L1 adipocytes with co-immunoprecipitation of HNE adducts, insulin-stimulated IRS-1 phosphorylation, PI3K activity, PKB activity, and glucose uptake assays\",\n      \"pmids\": [\"18174527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous FALDH loss-of-function effect on insulin signaling in vivo was not tested\",\n        \"Relative contribution of FALDH vs. other 4-HNE-metabolizing enzymes in adipocytes was not quantified\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Aldh3a2 knockout mice revealed that FALDH is the dominant aldehyde-oxidizing enzyme in undifferentiated keratinocytes and that its loss causes hyperproliferation, impaired sphingolipid metabolism, and defective skin barrier—recapitulating key features of Sjögren–Larsson syndrome.\",\n      \"evidence\": \"Aldh3a2 knockout mice with enzymatic activity assays, gene expression profiling, histology, and transepidermal water loss measurement\",\n      \"pmids\": [\"27053112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"CNS myelination defect was not characterized in this model\",\n        \"Identity of accumulating toxic aldehyde species in skin was not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placing ALDH3A2 downstream of Activin/Smad2–Wnt/β-catenin–FOXH1 signaling during mesendoderm differentiation revealed an unexpected developmental role, where ALDH3A2 knockdown severely attenuated differentiation of human embryonic stem cells.\",\n      \"evidence\": \"ChIP-seq, knockdown experiments, differentiation assays, and Western blot for H3K27me3/EZH2 in hESCs\",\n      \"pmids\": [\"30282636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which FALDH enzymatic activity promotes mesendoderm differentiation is unknown\",\n        \"Whether aldehyde detoxification or a non-canonical function drives the differentiation phenotype was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending structure–function mapping to the C-terminal α-helix and substrate-gating region refined understanding of FALDH domain architecture and confirmed that mutations outside the catalytic center also abolish activity.\",\n      \"evidence\": \"Mammalian expression of mutant constructs with enzymatic activity assays and patient fibroblast analysis\",\n      \"pmids\": [\"34082469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structural data to model substrate access or gating mechanism\",\n        \"Protein stability vs. catalytic defect was not distinguished for all mutants\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ALDH3A2 knockout in ovarian cancer cells elevated ferroptosis sensitivity while overexpression attenuated it, linking FALDH's aldehyde-detoxifying function to protection against lipid peroxidation-dependent cell death.\",\n      \"evidence\": \"CRISPR knockout and overexpression with ferroptosis sensitivity assays and RNA-seq pathway analysis in ovarian cancer cells\",\n      \"pmids\": [\"37247796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific lipid aldehyde substrates driving ferroptosis sensitization were not identified\",\n        \"Whether ferroptosis protection is a general or cancer cell-type-specific function is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The three-dimensional structure of FALDH, the identity of its full aldehyde substrate repertoire in vivo, and the mechanism by which its enzymatic activity supports mesendoderm differentiation and CNS myelination remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of FALDH\",\n        \"Substrate specificity in different tissues has not been systematically profiled\",\n        \"Mechanism linking FALDH loss to myelination failure in the CNS is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 3, 4, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FOXH1\",\n      \"IRS1\",\n      \"IRS2\",\n      \"NRF2\",\n      \"GPX4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}