{"gene":"ALDH1L2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2010,"finding":"ALDH1L2 (mtFDH) is a mitochondrial enzyme that converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in an NADP+-dependent reaction, homologous to cytosolic ALDH1L1. Mitochondrial localization was confirmed by GFP fusion constructs transfected into COS-7 and A549 cells. Purified pig liver mtFDH displayed dehydrogenase/hydrolase activities similar to cytosolic FDH.","method":"GFP fusion transfection/live imaging for localization; enzymatic assay of purified pig liver protein; sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic assay of purified protein plus live-cell localization imaging, replicated across two cell lines","pmids":["20498374"],"is_preprint":false},{"year":2011,"finding":"Recombinant human ALDH1L2 expressed in E. coli catalyzes the 10-formylTHF hydrolase reaction but does not produce detectable ALDH activity with short-chain aldehyde substrates. The enzyme requires post-translational modification by 4'-phosphopantetheinyl transferase (PPT) at Ser375 to perform the full 10-formylTHF dehydrogenase reaction. The isolated C-terminal ALDH-homologous domain (residues 413–923) forms a tetramer and catalyzes an esterase reaction.","method":"Recombinant protein expression and purification; in vitro enzymatic assays; site-directed mutagenesis of Ser375; domain expression and biochemical characterization","journal":"Chemico-biological interactions","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, active-site mutagenesis, and domain-level biochemical characterization in a single focused study","pmids":["21238436"],"is_preprint":false},{"year":2019,"finding":"Loss of ALDH1L2 (compound heterozygous mutations) impairs mitochondrial function: patient-derived fibroblasts showed distorted mitochondrial morphology, accumulation of acylcarnitine derivatives and Krebs cycle intermediates, lower ATP, and increased ADP/AMP ratio. Re-expression of functional ALDH1L2 restored mitochondrial morphology and metabolic profile.","method":"Patient fibroblast culture; metabolomics; mitochondrial morphology imaging; ATP/ADP/AMP measurement; rescue by re-expression of ALDH1L2","journal":"NPJ genomic medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (metabolomics, imaging, energy measurement) plus functional rescue experiment","pmids":["31341639"],"is_preprint":false},{"year":2020,"finding":"Aldh1l2 knockout in mice causes hepatic lipid accumulation (Oil Red O staining) and impaired β-oxidation, linked mechanistically to reduced mitochondrial NADPH → decreased glutathione → decreased cysteine → impaired CoA biosynthesis, leading to decreased mitochondrial ATP.","method":"Aldh1l2 knockout mouse model; liver histology (H&E, Oil Red O); untargeted metabolomics (liver, pancreas, plasma); folate pool measurements; NanoString inflammation panel","journal":"Human genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with multiple orthogonal metabolomic and histological readouts establishing the NADPH→GSH→CoA→β-oxidation pathway","pmids":["33168096"],"is_preprint":false},{"year":2020,"finding":"ALDH1L2 is required for UDCA-mediated protection against cisplatin-induced mitochondrial dysfunction in renal tubular cells; CRISPR/Cas9 knockout of ALDH1L2 abolished the protective effects of UDCA on mitochondrial function and apoptosis.","method":"CRISPR/Cas9 ALDH1L2 knockout in HK2/mPTCs; RNA-seq target identification; cisplatin injury model in vitro and in vivo; mitochondrial function and oxidative stress assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional phenotype readout, single lab, mechanism identified by RNA-seq but ALDH1L2 molecular role not fully reconstituted","pmids":["32004633"],"is_preprint":false},{"year":2022,"finding":"ALDH1L2 interacts with thioredoxin (TXN) by co-immunoprecipitation, and this interaction regulates the downstream NF-κB signaling pathway. Decreased ALDH1L2 expression leads to radioresistance in colorectal cancer cells by inhibiting ROS-mediated apoptosis; TXN inhibitor PX-12 overcomes this resistance.","method":"Co-immunoprecipitation; immunofluorescence; colony formation/comet assays; flow cytometry; xenograft animal models","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes interaction with TXN, multiple functional assays, single lab","pmids":["35597868"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9 knockout of ALDH1L2 in U251 glioblastoma cells reduces total cellular NADPH and increases ROS levels, impairing tumor sphere growth and rendering it methionine-independent.","method":"CRISPR/Cas9 knockout; NADPH measurement; ROS detection; tumor sphere formation assay","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with NADPH and ROS readouts, single lab, two orthogonal measurements","pmids":["35565854"],"is_preprint":false},{"year":2023,"finding":"ALDH1L2 is acetylated at Lys70, which inhibits its enzymatic activity (NADPH/GSH production); SIRT3 directly binds and deacetylates ALDH1L2 to increase its activity. 5-Fluorouracil inhibits SIRT3 expression, thereby increasing ALDH1L2 acetylation at K70, reducing NADPH and GSH, and inducing oxidative stress-driven apoptosis. The acetylation-mimicking K70Q mutant sensitizes cancer cells to 5-Fu in vitro and in vivo.","method":"Site-directed mutagenesis (K70Q); co-immunoprecipitation of SIRT3–ALDH1L2; enzymatic activity assays; NADPH/GSH measurement; in vivo xenograft tumor growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis, in vitro enzymatic assay, reciprocal Co-IP, and in vivo validation in a single focused study","pmids":["37507016"],"is_preprint":false},{"year":2023,"finding":"Reduction of ALDH1L2 expression in breast cancer cells increases ROS, formate, and formyl-methionine (fMet) production; elevated formate and fMet enhance cancer cell migration through formyl-peptide receptor (FPR)-dependent signaling. Increased ALDH1L2 expression in tumor models lowers formate/fMet and limits metastatic capacity.","method":"ALDH1L2 knockdown/overexpression in breast cancer cell lines; stable isotope metabolomics; cell migration assays; FPR-dependent signaling assays; in vivo tumor metastasis models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (metabolomics, functional migration assays, in vivo models) with both loss- and gain-of-function experiments","pmids":["37245210"],"is_preprint":false},{"year":2024,"finding":"ALDH1L2 deficiency (novel homozygous Pro133His missense variant) reduces enzyme activity in patient fibroblasts, lowers the NADPH/NADP+ ratio and mitochondrial ATP pool, and upregulates autophagy, establishing this reaction as essential for cellular redox and energy balance.","method":"Patient fibroblast assay; ALDH1L2 enzyme activity measured with 10-FDDF (stable 10-formyl-THF analog); NADPH/NADP+ ratio measurement; ATP measurement; metabolomics","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic assay in patient cells with multiple functional readouts, single case/lab","pmids":["38193334"],"is_preprint":false},{"year":2024,"finding":"FOXO1 acts as a transcription factor for ALDH1L2, binding its promoter to drive expression. Knockout of FOXO1 decreases ALDH1L2 and CPT1α protein levels, impairing fatty acid β-oxidation; overexpression of ALDH1L2 restores fatty acid oxidation in FOXO1-KO cells.","method":"Luciferase reporter assay of FOXO1-binding motifs at ALDH1L2 promoter; FOXO1 knockout; ALDH1L2 overexpression rescue; transcriptomic analysis; in vitro and in vivo experiments","journal":"Journal of gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter plus rescue experiment, single lab","pmids":["38923573"],"is_preprint":false},{"year":2024,"finding":"In hepatocellular carcinoma, ALDH1L2 promotes mitochondrial respiration and ATP production, activates NRF2 stabilization, and establishes a positive feedback loop in which NRF2 directly binds the ALDH1L2 promoter to increase its transcription. ALDH1L2 also drives IL-6/JAK2/STAT3 signaling and promotes tumor-associated macrophage polarization.","method":"In vitro and in vivo HCC assays; immunofluorescence; co-immunoprecipitation implied by NRF2 promoter binding (ChIP); Western blotting; knockdown/overexpression functional assays","journal":"JHEP reports : innovation in hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and NRF2 promoter binding, single lab, mechanistic details inferred from abstract","pmids":["39687603"],"is_preprint":false},{"year":2024,"finding":"MicroRNA-219a-5p directly targets ALDH1L2 (validated experimentally), suppressing its expression in renal cells. ALDH1L2 knockdown enhances PAI-1 induction during TGF-β1 treatment, reducing fibronectin degradation, linking ALDH1L2 to GSH/PAI-1-mediated fibronectin homeostasis.","method":"miRNA target identification and validation; ALDH1L2 knockdown in cultured renal cells; PAI-1 and fibronectin measurement; UUO mouse model","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA target validation plus KD functional readout, single lab, two orthogonal methods","pmids":["39295147"],"is_preprint":false},{"year":2025,"finding":"NXPH4 physically interacts with ALDH1L2 in mitochondria; androgen deprivation stimulates NXPH4 mitochondrial translocation and enhances its binding to ALDH1L2, promoting mitochondrial metabolic reprogramming and enzalutamide resistance in prostate cancer cells.","method":"Co-immunoprecipitation; subcellular fractionation/immunofluorescence for localization; gain- and loss-of-function studies in PCa cell lines; xenograft mouse models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes physical interaction, localization by immunofluorescence, functional KD/OE in vitro and in vivo, single lab","pmids":["41639054"],"is_preprint":false},{"year":2026,"finding":"ALDH1L2 expression decreases progressively during acinar-to-ductal metaplasia (ADM) in the pancreas and is absent in ductal cells. Loss of ALDH1L2 elevates ROS and formate, promotes ADM in a pancreatitis model, and accelerates tumor progression in pancreatic cancer models, identifying ROS as a driver of ADM.","method":"Aldh1l2 genetic mouse models of pancreatitis and PDAC; ROS and formate metabolite measurements; histological analysis; human/mouse PDAC metabolomics","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models with mechanistic metabolite readouts (ROS, formate), replicated across pancreatitis and PDAC contexts","pmids":["41922744"],"is_preprint":false},{"year":2026,"finding":"ALDH1L2 interacts with the TRX2-PRDX3 mitochondrial antioxidant network; high ALDH1L2 expression reduces hyperoxidized PRDX3 and oxidized PRDX3 dimers at the plasma membrane under cisplatin stress, suppressing lipid peroxidation and ferroptosis, thereby promoting chemoresistance in small cell lung cancer.","method":"Co-immunoprecipitation of ALDH1L2 with TRX2-PRDX3; lipid peroxidation assays; ferroptosis assays; cisplatin resistance models; PRDX3 inhibitor (thiostrepton) combination studies","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes protein interaction, functional assays with inhibitor, single lab","pmids":["41764940"],"is_preprint":false},{"year":2026,"finding":"In renal clear cell carcinoma (KIRC), ALDH1L2 knockdown increases ROS levels and reduces Akt/mTOR/S6K phosphorylation, suppressing cell proliferation and migration, mechanistically linking ALDH1L2-dependent NADPH/redox balance to the Akt/mTOR/S6K growth axis.","method":"siRNA knockdown; ROS detection; Western blotting of Akt/mTOR/S6K phosphorylation; EdU proliferation assay; wound-healing and Transwell migration assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with ROS and signaling readouts, multiple orthogonal assays, single lab","pmids":["41766916"],"is_preprint":false}],"current_model":"ALDH1L2 is a mitochondrial NADP+-dependent enzyme that catabolizes 10-formyltetrahydrofolate to tetrahydrofolate and CO2, producing NADPH; its activity requires 4'-phosphopantetheinyl transferase modification at Ser375 and is negatively regulated by SIRT3-reversible acetylation at Lys70. By sustaining mitochondrial NADPH, ALDH1L2 maintains glutathione and CoA pools to support fatty acid β-oxidation and ATP production, limits ROS and formate/fMet accumulation that would otherwise drive cell migration via formyl-peptide receptor signaling, and interacts with TXN/TRX2-PRDX3 antioxidant networks and signaling partners (NRF2, NXPH4) to control redox-dependent proliferation, metastasis, and cell-death sensitivity across multiple tissue contexts."},"narrative":{"mechanistic_narrative":"ALDH1L2 is a mitochondrial NADP+-dependent 10-formyltetrahydrofolate dehydrogenase that converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 while generating NADPH, functioning as a central node in mitochondrial folate metabolism and redox homeostasis [PMID:20498374]. Full dehydrogenase activity requires 4'-phosphopantetheinyl transferase modification at Ser375, whereas the isolated C-terminal ALDH-homologous domain forms a tetramer and retains only esterase/hydrolase activity [PMID:21238436]. The NADPH it produces sustains mitochondrial glutathione, which feeds cysteine and CoA biosynthesis to support fatty acid β-oxidation and ATP production; loss of ALDH1L2 in mice and in patient fibroblasts collapses this NADPH→GSH→CoA axis, causing hepatic lipid accumulation, distorted mitochondrial morphology, metabolite accumulation, and energy failure [PMID:31341639, PMID:33168096, PMID:38193334]. Enzyme output is controlled post-translationally by acetylation at Lys70, which is reversed by SIRT3-mediated deacetylation to restore NADPH/GSH production [PMID:37507016], and transcriptionally by FOXO1 and NRF2, the latter forming a positive feedback loop by binding the ALDH1L2 promoter [PMID:38923573, PMID:39687603]. By limiting ROS and one-carbon byproducts such as formate and formyl-methionine, ALDH1L2 restrains cell migration through formyl-peptide receptor signaling and metaplastic transformation [PMID:37245210, PMID:41922744], and through interactions with the TXN/TRX2-PRDX3 antioxidant network it modulates apoptosis, ferroptosis, and redox-dependent proliferation and chemoresistance across colorectal, glioblastoma, lung, renal, and prostate cancers [PMID:35597868, PMID:35565854, PMID:41764940, PMID:41766916]. Compound heterozygous, homozygous missense, and other loss-of-function variants in ALDH1L2 cause a mitochondrial metabolic disorder rescued by re-expression of the functional enzyme [PMID:31341639, PMID:38193334].","teleology":[{"year":2010,"claim":"Established the basic identity and reaction of ALDH1L2 as a mitochondrial folate enzyme, answering where the protein acts and what chemistry it performs.","evidence":"GFP-fusion localization in COS-7/A549 cells and enzymatic assay of purified pig liver protein","pmids":["20498374"],"confidence":"High","gaps":["Did not resolve cofactor/PTM requirements of the human enzyme","No structural model of the full-length protein"]},{"year":2011,"claim":"Defined the post-translational and domain requirements for catalysis, showing the dehydrogenase reaction depends on phosphopantetheinylation at Ser375 while the C-terminal domain alone is only an esterase.","evidence":"Recombinant human protein, in vitro assays, Ser375 mutagenesis, and isolated domain characterization","pmids":["21238436"],"confidence":"High","gaps":["Identity and regulation of the PPT enzyme acting on ALDH1L2 not established","No full-length structure"]},{"year":2019,"claim":"Linked human ALDH1L2 loss to mitochondrial metabolic disease, establishing the enzyme as physiologically required for mitochondrial morphology and energetics.","evidence":"Compound-heterozygous patient fibroblasts with metabolomics, imaging, energy charge, and re-expression rescue","pmids":["31341639"],"confidence":"High","gaps":["Did not pinpoint the biochemical step bridging enzyme loss and morphology defects","Single patient context"]},{"year":2020,"claim":"Resolved the metabolic chain connecting ALDH1L2 activity to fat oxidation, defining the NADPH→GSH→cysteine→CoA→β-oxidation axis in vivo.","evidence":"Aldh1l2 knockout mice with liver histology, untargeted metabolomics, and folate pool measurement","pmids":["33168096"],"confidence":"High","gaps":["Tissue-specific contributions beyond liver not dissected","Did not address regulation of the enzyme"]},{"year":2020,"claim":"Implicated ALDH1L2 in protection against drug-induced mitochondrial injury, positioning it within nephroprotective redox responses.","evidence":"CRISPR knockout in renal tubular cells with UDCA/cisplatin injury models and RNA-seq","pmids":["32004633"],"confidence":"Medium","gaps":["ALDH1L2 molecular role in UDCA signaling not reconstituted","Single lab"]},{"year":2022,"claim":"Connected ALDH1L2 to antioxidant signaling partners and therapy resistance, showing a physical TXN interaction that tunes ROS-dependent apoptosis.","evidence":"Co-IP, colony/comet assays, flow cytometry, and xenografts in colorectal cancer; CRISPR KO with NADPH/ROS readouts in glioblastoma","pmids":["35597868","35565854"],"confidence":"Medium","gaps":["TXN interaction lacks reciprocal/structural validation","Whether NF-κB and methionine-dependence effects are direct vs. downstream of NADPH unresolved"]},{"year":2023,"claim":"Identified a reversible acetylation switch controlling enzyme output, establishing SIRT3-K70 as a regulatory axis exploited by 5-FU.","evidence":"K70Q mutagenesis, SIRT3–ALDH1L2 Co-IP, enzymatic and NADPH/GSH assays, and xenografts","pmids":["37507016"],"confidence":"High","gaps":["Acetyltransferase responsible for K70 acetylation not identified","Stoichiometry of acetylation in normal tissues unknown"]},{"year":2023,"claim":"Showed ALDH1L2 controls one-carbon byproduct levels that drive migration, linking formate/fMet accumulation to formyl-peptide receptor signaling and metastasis.","evidence":"Knockdown/overexpression in breast cancer, stable-isotope metabolomics, migration assays, and in vivo metastasis models","pmids":["37245210"],"confidence":"High","gaps":["FPR receptor subtype and downstream effectors not fully mapped","Generality across non-breast tumors not tested here"]},{"year":2024,"claim":"Extended disease evidence with a missense variant and added transcriptional/feedback regulators, framing ALDH1L2 within FOXO1- and NRF2-driven metabolic programs.","evidence":"Patient fibroblast enzyme assay (10-FDDF); FOXO1 luciferase/rescue; HCC NRF2 promoter binding and functional assays","pmids":["38193334","38923573","39687603"],"confidence":"Medium","gaps":["Direct vs. indirect nature of NRF2/FOXO1 promoter occupancy needs orthogonal confirmation","IL-6/JAK2/STAT3 and macrophage effects mechanistically inferred"]},{"year":2024,"claim":"Defined upstream microRNA control of ALDH1L2 and a role in fibrosis-related fibronectin homeostasis.","evidence":"miR-219a-5p target validation, ALDH1L2 knockdown, PAI-1/fibronectin measurement, UUO mouse model","pmids":["39295147"],"confidence":"Medium","gaps":["Mechanistic link from GSH to PAI-1 not fully resolved","Single lab"]},{"year":2025,"claim":"Identified NXPH4 as a stress-regulated mitochondrial binding partner, linking ALDH1L2 to metabolic reprogramming and antiandrogen resistance.","evidence":"Co-IP, fractionation/immunofluorescence, and gain/loss-of-function in prostate cancer xenografts","pmids":["41639054"],"confidence":"Medium","gaps":["Functional consequence of NXPH4 binding on enzyme activity not measured","Interaction not structurally defined"]},{"year":2026,"claim":"Consolidated ALDH1L2 as a ROS/ferroptosis gatekeeper across tissues, linking it to PRDX3 antioxidant defense, Akt/mTOR growth signaling, and suppression of metaplastic and tumor progression.","evidence":"TRX2-PRDX3 Co-IP with ferroptosis/cisplatin models (SCLC); siRNA with Akt/mTOR readouts (KIRC); Aldh1l2 genetic pancreatitis/PDAC mouse models with ROS/formate metabolomics","pmids":["41764940","41766916","41922744"],"confidence":"High","gaps":["Whether PRDX3 redox effects are direct or NADPH-mediated unresolved","Causal hierarchy among ROS, formate, and signaling outputs not separated"]},{"year":null,"claim":"How ALDH1L2's enzymatic NADPH/formate output is mechanistically converted into its diverse protein-protein interactions (TXN, NXPH4, PRDX3) and signaling outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length human ALDH1L2 or its complexes","Direct vs. metabolite-mediated nature of partner interactions undefined","Tissue-specific regulation by acetylation/transcription not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,8,14]}],"complexes":[],"partners":["TXN","SIRT3","NXPH4","PRDX3","TXN2","NRF2","FOXO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q3SY69","full_name":"Mitochondrial 10-formyltetrahydrofolate dehydrogenase","aliases":["Aldehyde dehydrogenase family 1 member L2"],"length_aa":923,"mass_kda":101.7,"function":"Mitochondrial 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q3SY69/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALDH1L2","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":[],"url":"https://opencell.sf.czbiohub.org/search/ALDH1L2","total_profiled":1310},"omim":[{"mim_id":"613584","title":"ALDEHYDE DEHYDROGENASE 1 FAMILY, MEMBER L2; ALDH1L2","url":"https://www.omim.org/entry/613584"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":38.3},{"tissue":"salivary gland","ntpm":12.2}],"url":"https://www.proteinatlas.org/search/ALDH1L2"},"hgnc":{"alias_symbol":["FLJ38508","mtFDH"],"prev_symbol":[]},"alphafold":{"accession":"Q3SY69","domains":[{"cath_id":"3.40.50.170","chopping":"25-208","consensus_level":"medium","plddt":92.531,"start":25,"end":208},{"cath_id":"3.10.25.10","chopping":"229-326","consensus_level":"high","plddt":89.7052,"start":229,"end":326},{"cath_id":"1.10.1200.10","chopping":"340-418","consensus_level":"medium","plddt":86.3144,"start":340,"end":418},{"cath_id":"3.40.605.10","chopping":"430-695","consensus_level":"high","plddt":97.682,"start":430,"end":695},{"cath_id":"3.40.309.10","chopping":"701-895","consensus_level":"high","plddt":98.4115,"start":701,"end":895}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3SY69","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q3SY69-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q3SY69-F1-predicted_aligned_error_v6.png","plddt_mean":92.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALDH1L2","jax_strain_url":"https://www.jax.org/strain/search?query=ALDH1L2"},"sequence":{"accession":"Q3SY69","fasta_url":"https://rest.uniprot.org/uniprotkb/Q3SY69.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q3SY69/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3SY69"}},"corpus_meta":[{"pmid":"20498374","id":"PMC_20498374","title":"ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20498374","citation_count":95,"is_preprint":false},{"pmid":"30362096","id":"PMC_30362096","title":"ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer.","date":"2018","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/30362096","citation_count":51,"is_preprint":false},{"pmid":"32004633","id":"PMC_32004633","title":"Ursodeoxycholic acid protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction through acting on ALDH1L2.","date":"2020","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32004633","citation_count":39,"is_preprint":false},{"pmid":"21238436","id":"PMC_21238436","title":"Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase.","date":"2011","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/21238436","citation_count":37,"is_preprint":false},{"pmid":"37245210","id":"PMC_37245210","title":"ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37245210","citation_count":36,"is_preprint":false},{"pmid":"35597868","id":"PMC_35597868","title":"TXN inhibitor impedes radioresistance of colorectal cancer cells with decreased ALDH1L2 expression via TXN/NF-κB signaling pathway.","date":"2022","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35597868","citation_count":29,"is_preprint":false},{"pmid":"33168096","id":"PMC_33168096","title":"Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder.","date":"2020","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33168096","citation_count":27,"is_preprint":false},{"pmid":"31341639","id":"PMC_31341639","title":"Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome.","date":"2019","source":"NPJ genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31341639","citation_count":17,"is_preprint":false},{"pmid":"35565854","id":"PMC_35565854","title":"ALDH1L2 Knockout in U251 Glioblastoma Cells Reduces Tumor Sphere Formation by Increasing Oxidative Stress and Suppressing Methionine Dependency.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/35565854","citation_count":13,"is_preprint":false},{"pmid":"39295147","id":"PMC_39295147","title":"Hypermethylation and suppression of microRNA219a-2 activates the ALDH1L2/GSH/PAI-1 pathway for fibronectin degradation in renal fibrosis.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39295147","citation_count":10,"is_preprint":false},{"pmid":"37507016","id":"PMC_37507016","title":"Acetylation of aldehyde dehydrogenase ALDH1L2 regulates cellular redox balance and the chemosensitivity of colorectal cancer to 5-fluorouracil.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37507016","citation_count":10,"is_preprint":false},{"pmid":"39687603","id":"PMC_39687603","title":"ALDH1L2 drives HCC progression through TAM polarization.","date":"2024","source":"JHEP reports : innovation in hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39687603","citation_count":9,"is_preprint":false},{"pmid":"38923573","id":"PMC_38923573","title":"FOXO1 induced fatty acid oxidation in hepatic cells by targeting ALDH1L2.","date":"2024","source":"Journal of gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/38923573","citation_count":6,"is_preprint":false},{"pmid":"41922744","id":"PMC_41922744","title":"ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas.","date":"2026","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/41922744","citation_count":3,"is_preprint":false},{"pmid":"41764940","id":"PMC_41764940","title":"ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis.","date":"2026","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/41764940","citation_count":1,"is_preprint":false},{"pmid":"38193334","id":"PMC_38193334","title":"Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38193334","citation_count":1,"is_preprint":false},{"pmid":"37333081","id":"PMC_37333081","title":"Hypermethylation suppresses microRNA-219a-2 to activate the ALDH1L2/GSH/PAI-1 pathway for fibronectin degradation in renal fibrosis.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37333081","citation_count":1,"is_preprint":false},{"pmid":"41421227","id":"PMC_41421227","title":"DPEP1 mediates regulation of mitochondrial quality control via FOXO1/ALDH1L2 axis to attenuate ferroptosis in pulmonary endothelial cells to alleviate sepsis-associated acute lung injury.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41421227","citation_count":1,"is_preprint":false},{"pmid":"40005897","id":"PMC_40005897","title":"Early Enhancement in Contrast-Enhanced Computed Tomography Is an Index of DUSP9, SLPI, ALDH1L2, and SLC1A1 Expression in Canine Hepatocellular Carcinoma: A Preliminary Study.","date":"2025","source":"Veterinary sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40005897","citation_count":0,"is_preprint":false},{"pmid":"41639054","id":"PMC_41639054","title":"Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41639054","citation_count":0,"is_preprint":false},{"pmid":"41766916","id":"PMC_41766916","title":"ALDH1L2 orchestrates redox-growth coupling in renal carcinoma: pan-cancer evidence and mechanistic validation of the ROS-Akt/mTOR/S6K axis.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41766916","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13441,"output_tokens":4496,"usd":0.053881,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12583,"output_tokens":4016,"usd":0.081657,"stage2_stop_reason":"end_turn"},"total_usd":0.135538,"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\": 2010,\n      \"finding\": \"ALDH1L2 (mtFDH) is a mitochondrial enzyme that converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in an NADP+-dependent reaction, homologous to cytosolic ALDH1L1. Mitochondrial localization was confirmed by GFP fusion constructs transfected into COS-7 and A549 cells. Purified pig liver mtFDH displayed dehydrogenase/hydrolase activities similar to cytosolic FDH.\",\n      \"method\": \"GFP fusion transfection/live imaging for localization; enzymatic assay of purified pig liver protein; sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic assay of purified protein plus live-cell localization imaging, replicated across two cell lines\",\n      \"pmids\": [\"20498374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Recombinant human ALDH1L2 expressed in E. coli catalyzes the 10-formylTHF hydrolase reaction but does not produce detectable ALDH activity with short-chain aldehyde substrates. The enzyme requires post-translational modification by 4'-phosphopantetheinyl transferase (PPT) at Ser375 to perform the full 10-formylTHF dehydrogenase reaction. The isolated C-terminal ALDH-homologous domain (residues 413–923) forms a tetramer and catalyzes an esterase reaction.\",\n      \"method\": \"Recombinant protein expression and purification; in vitro enzymatic assays; site-directed mutagenesis of Ser375; domain expression and biochemical characterization\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, active-site mutagenesis, and domain-level biochemical characterization in a single focused study\",\n      \"pmids\": [\"21238436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of ALDH1L2 (compound heterozygous mutations) impairs mitochondrial function: patient-derived fibroblasts showed distorted mitochondrial morphology, accumulation of acylcarnitine derivatives and Krebs cycle intermediates, lower ATP, and increased ADP/AMP ratio. Re-expression of functional ALDH1L2 restored mitochondrial morphology and metabolic profile.\",\n      \"method\": \"Patient fibroblast culture; metabolomics; mitochondrial morphology imaging; ATP/ADP/AMP measurement; rescue by re-expression of ALDH1L2\",\n      \"journal\": \"NPJ genomic medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (metabolomics, imaging, energy measurement) plus functional rescue experiment\",\n      \"pmids\": [\"31341639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Aldh1l2 knockout in mice causes hepatic lipid accumulation (Oil Red O staining) and impaired β-oxidation, linked mechanistically to reduced mitochondrial NADPH → decreased glutathione → decreased cysteine → impaired CoA biosynthesis, leading to decreased mitochondrial ATP.\",\n      \"method\": \"Aldh1l2 knockout mouse model; liver histology (H&E, Oil Red O); untargeted metabolomics (liver, pancreas, plasma); folate pool measurements; NanoString inflammation panel\",\n      \"journal\": \"Human genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with multiple orthogonal metabolomic and histological readouts establishing the NADPH→GSH→CoA→β-oxidation pathway\",\n      \"pmids\": [\"33168096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALDH1L2 is required for UDCA-mediated protection against cisplatin-induced mitochondrial dysfunction in renal tubular cells; CRISPR/Cas9 knockout of ALDH1L2 abolished the protective effects of UDCA on mitochondrial function and apoptosis.\",\n      \"method\": \"CRISPR/Cas9 ALDH1L2 knockout in HK2/mPTCs; RNA-seq target identification; cisplatin injury model in vitro and in vivo; mitochondrial function and oxidative stress assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional phenotype readout, single lab, mechanism identified by RNA-seq but ALDH1L2 molecular role not fully reconstituted\",\n      \"pmids\": [\"32004633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALDH1L2 interacts with thioredoxin (TXN) by co-immunoprecipitation, and this interaction regulates the downstream NF-κB signaling pathway. Decreased ALDH1L2 expression leads to radioresistance in colorectal cancer cells by inhibiting ROS-mediated apoptosis; TXN inhibitor PX-12 overcomes this resistance.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; colony formation/comet assays; flow cytometry; xenograft animal models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes interaction with TXN, multiple functional assays, single lab\",\n      \"pmids\": [\"35597868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9 knockout of ALDH1L2 in U251 glioblastoma cells reduces total cellular NADPH and increases ROS levels, impairing tumor sphere growth and rendering it methionine-independent.\",\n      \"method\": \"CRISPR/Cas9 knockout; NADPH measurement; ROS detection; tumor sphere formation assay\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with NADPH and ROS readouts, single lab, two orthogonal measurements\",\n      \"pmids\": [\"35565854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDH1L2 is acetylated at Lys70, which inhibits its enzymatic activity (NADPH/GSH production); SIRT3 directly binds and deacetylates ALDH1L2 to increase its activity. 5-Fluorouracil inhibits SIRT3 expression, thereby increasing ALDH1L2 acetylation at K70, reducing NADPH and GSH, and inducing oxidative stress-driven apoptosis. The acetylation-mimicking K70Q mutant sensitizes cancer cells to 5-Fu in vitro and in vivo.\",\n      \"method\": \"Site-directed mutagenesis (K70Q); co-immunoprecipitation of SIRT3–ALDH1L2; enzymatic activity assays; NADPH/GSH measurement; in vivo xenograft tumor growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis, in vitro enzymatic assay, reciprocal Co-IP, and in vivo validation in a single focused study\",\n      \"pmids\": [\"37507016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reduction of ALDH1L2 expression in breast cancer cells increases ROS, formate, and formyl-methionine (fMet) production; elevated formate and fMet enhance cancer cell migration through formyl-peptide receptor (FPR)-dependent signaling. Increased ALDH1L2 expression in tumor models lowers formate/fMet and limits metastatic capacity.\",\n      \"method\": \"ALDH1L2 knockdown/overexpression in breast cancer cell lines; stable isotope metabolomics; cell migration assays; FPR-dependent signaling assays; in vivo tumor metastasis models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (metabolomics, functional migration assays, in vivo models) with both loss- and gain-of-function experiments\",\n      \"pmids\": [\"37245210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALDH1L2 deficiency (novel homozygous Pro133His missense variant) reduces enzyme activity in patient fibroblasts, lowers the NADPH/NADP+ ratio and mitochondrial ATP pool, and upregulates autophagy, establishing this reaction as essential for cellular redox and energy balance.\",\n      \"method\": \"Patient fibroblast assay; ALDH1L2 enzyme activity measured with 10-FDDF (stable 10-formyl-THF analog); NADPH/NADP+ ratio measurement; ATP measurement; metabolomics\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic assay in patient cells with multiple functional readouts, single case/lab\",\n      \"pmids\": [\"38193334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXO1 acts as a transcription factor for ALDH1L2, binding its promoter to drive expression. Knockout of FOXO1 decreases ALDH1L2 and CPT1α protein levels, impairing fatty acid β-oxidation; overexpression of ALDH1L2 restores fatty acid oxidation in FOXO1-KO cells.\",\n      \"method\": \"Luciferase reporter assay of FOXO1-binding motifs at ALDH1L2 promoter; FOXO1 knockout; ALDH1L2 overexpression rescue; transcriptomic analysis; in vitro and in vivo experiments\",\n      \"journal\": \"Journal of gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter plus rescue experiment, single lab\",\n      \"pmids\": [\"38923573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In hepatocellular carcinoma, ALDH1L2 promotes mitochondrial respiration and ATP production, activates NRF2 stabilization, and establishes a positive feedback loop in which NRF2 directly binds the ALDH1L2 promoter to increase its transcription. ALDH1L2 also drives IL-6/JAK2/STAT3 signaling and promotes tumor-associated macrophage polarization.\",\n      \"method\": \"In vitro and in vivo HCC assays; immunofluorescence; co-immunoprecipitation implied by NRF2 promoter binding (ChIP); Western blotting; knockdown/overexpression functional assays\",\n      \"journal\": \"JHEP reports : innovation in hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and NRF2 promoter binding, single lab, mechanistic details inferred from abstract\",\n      \"pmids\": [\"39687603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MicroRNA-219a-5p directly targets ALDH1L2 (validated experimentally), suppressing its expression in renal cells. ALDH1L2 knockdown enhances PAI-1 induction during TGF-β1 treatment, reducing fibronectin degradation, linking ALDH1L2 to GSH/PAI-1-mediated fibronectin homeostasis.\",\n      \"method\": \"miRNA target identification and validation; ALDH1L2 knockdown in cultured renal cells; PAI-1 and fibronectin measurement; UUO mouse model\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA target validation plus KD functional readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"39295147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NXPH4 physically interacts with ALDH1L2 in mitochondria; androgen deprivation stimulates NXPH4 mitochondrial translocation and enhances its binding to ALDH1L2, promoting mitochondrial metabolic reprogramming and enzalutamide resistance in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation/immunofluorescence for localization; gain- and loss-of-function studies in PCa cell lines; xenograft mouse models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes physical interaction, localization by immunofluorescence, functional KD/OE in vitro and in vivo, single lab\",\n      \"pmids\": [\"41639054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ALDH1L2 expression decreases progressively during acinar-to-ductal metaplasia (ADM) in the pancreas and is absent in ductal cells. Loss of ALDH1L2 elevates ROS and formate, promotes ADM in a pancreatitis model, and accelerates tumor progression in pancreatic cancer models, identifying ROS as a driver of ADM.\",\n      \"method\": \"Aldh1l2 genetic mouse models of pancreatitis and PDAC; ROS and formate metabolite measurements; histological analysis; human/mouse PDAC metabolomics\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models with mechanistic metabolite readouts (ROS, formate), replicated across pancreatitis and PDAC contexts\",\n      \"pmids\": [\"41922744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ALDH1L2 interacts with the TRX2-PRDX3 mitochondrial antioxidant network; high ALDH1L2 expression reduces hyperoxidized PRDX3 and oxidized PRDX3 dimers at the plasma membrane under cisplatin stress, suppressing lipid peroxidation and ferroptosis, thereby promoting chemoresistance in small cell lung cancer.\",\n      \"method\": \"Co-immunoprecipitation of ALDH1L2 with TRX2-PRDX3; lipid peroxidation assays; ferroptosis assays; cisplatin resistance models; PRDX3 inhibitor (thiostrepton) combination studies\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes protein interaction, functional assays with inhibitor, single lab\",\n      \"pmids\": [\"41764940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In renal clear cell carcinoma (KIRC), ALDH1L2 knockdown increases ROS levels and reduces Akt/mTOR/S6K phosphorylation, suppressing cell proliferation and migration, mechanistically linking ALDH1L2-dependent NADPH/redox balance to the Akt/mTOR/S6K growth axis.\",\n      \"method\": \"siRNA knockdown; ROS detection; Western blotting of Akt/mTOR/S6K phosphorylation; EdU proliferation assay; wound-healing and Transwell migration assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with ROS and signaling readouts, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"41766916\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALDH1L2 is a mitochondrial NADP+-dependent enzyme that catabolizes 10-formyltetrahydrofolate to tetrahydrofolate and CO2, producing NADPH; its activity requires 4'-phosphopantetheinyl transferase modification at Ser375 and is negatively regulated by SIRT3-reversible acetylation at Lys70. By sustaining mitochondrial NADPH, ALDH1L2 maintains glutathione and CoA pools to support fatty acid β-oxidation and ATP production, limits ROS and formate/fMet accumulation that would otherwise drive cell migration via formyl-peptide receptor signaling, and interacts with TXN/TRX2-PRDX3 antioxidant networks and signaling partners (NRF2, NXPH4) to control redox-dependent proliferation, metastasis, and cell-death sensitivity across multiple tissue contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ALDH1L2 is a mitochondrial NADP+-dependent 10-formyltetrahydrofolate dehydrogenase that converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 while generating NADPH, functioning as a central node in mitochondrial folate metabolism and redox homeostasis [#0]. Full dehydrogenase activity requires 4'-phosphopantetheinyl transferase modification at Ser375, whereas the isolated C-terminal ALDH-homologous domain forms a tetramer and retains only esterase/hydrolase activity [#1]. The NADPH it produces sustains mitochondrial glutathione, which feeds cysteine and CoA biosynthesis to support fatty acid \\u03b2-oxidation and ATP production; loss of ALDH1L2 in mice and in patient fibroblasts collapses this NADPH\\u2192GSH\\u2192CoA axis, causing hepatic lipid accumulation, distorted mitochondrial morphology, metabolite accumulation, and energy failure [#2, #3, #9]. Enzyme output is controlled post-translationally by acetylation at Lys70, which is reversed by SIRT3-mediated deacetylation to restore NADPH/GSH production [#7], and transcriptionally by FOXO1 and NRF2, the latter forming a positive feedback loop by binding the ALDH1L2 promoter [#10, #11]. By limiting ROS and one-carbon byproducts such as formate and formyl-methionine, ALDH1L2 restrains cell migration through formyl-peptide receptor signaling and metaplastic transformation [#8, #14], and through interactions with the TXN/TRX2-PRDX3 antioxidant network it modulates apoptosis, ferroptosis, and redox-dependent proliferation and chemoresistance across colorectal, glioblastoma, lung, renal, and prostate cancers [#5, #6, #15, #16]. Compound heterozygous, homozygous missense, and other loss-of-function variants in ALDH1L2 cause a mitochondrial metabolic disorder rescued by re-expression of the functional enzyme [#2, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the basic identity and reaction of ALDH1L2 as a mitochondrial folate enzyme, answering where the protein acts and what chemistry it performs.\",\n      \"evidence\": \"GFP-fusion localization in COS-7/A549 cells and enzymatic assay of purified pig liver protein\",\n      \"pmids\": [\"20498374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve cofactor/PTM requirements of the human enzyme\", \"No structural model of the full-length protein\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the post-translational and domain requirements for catalysis, showing the dehydrogenase reaction depends on phosphopantetheinylation at Ser375 while the C-terminal domain alone is only an esterase.\",\n      \"evidence\": \"Recombinant human protein, in vitro assays, Ser375 mutagenesis, and isolated domain characterization\",\n      \"pmids\": [\"21238436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and regulation of the PPT enzyme acting on ALDH1L2 not established\", \"No full-length structure\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked human ALDH1L2 loss to mitochondrial metabolic disease, establishing the enzyme as physiologically required for mitochondrial morphology and energetics.\",\n      \"evidence\": \"Compound-heterozygous patient fibroblasts with metabolomics, imaging, energy charge, and re-expression rescue\",\n      \"pmids\": [\"31341639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint the biochemical step bridging enzyme loss and morphology defects\", \"Single patient context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the metabolic chain connecting ALDH1L2 activity to fat oxidation, defining the NADPH\\u2192GSH\\u2192cysteine\\u2192CoA\\u2192\\u03b2-oxidation axis in vivo.\",\n      \"evidence\": \"Aldh1l2 knockout mice with liver histology, untargeted metabolomics, and folate pool measurement\",\n      \"pmids\": [\"33168096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions beyond liver not dissected\", \"Did not address regulation of the enzyme\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated ALDH1L2 in protection against drug-induced mitochondrial injury, positioning it within nephroprotective redox responses.\",\n      \"evidence\": \"CRISPR knockout in renal tubular cells with UDCA/cisplatin injury models and RNA-seq\",\n      \"pmids\": [\"32004633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ALDH1L2 molecular role in UDCA signaling not reconstituted\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ALDH1L2 to antioxidant signaling partners and therapy resistance, showing a physical TXN interaction that tunes ROS-dependent apoptosis.\",\n      \"evidence\": \"Co-IP, colony/comet assays, flow cytometry, and xenografts in colorectal cancer; CRISPR KO with NADPH/ROS readouts in glioblastoma\",\n      \"pmids\": [\"35597868\", \"35565854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TXN interaction lacks reciprocal/structural validation\", \"Whether NF-\\u03baB and methionine-dependence effects are direct vs. downstream of NADPH unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a reversible acetylation switch controlling enzyme output, establishing SIRT3-K70 as a regulatory axis exploited by 5-FU.\",\n      \"evidence\": \"K70Q mutagenesis, SIRT3\\u2013ALDH1L2 Co-IP, enzymatic and NADPH/GSH assays, and xenografts\",\n      \"pmids\": [\"37507016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible for K70 acetylation not identified\", \"Stoichiometry of acetylation in normal tissues unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ALDH1L2 controls one-carbon byproduct levels that drive migration, linking formate/fMet accumulation to formyl-peptide receptor signaling and metastasis.\",\n      \"evidence\": \"Knockdown/overexpression in breast cancer, stable-isotope metabolomics, migration assays, and in vivo metastasis models\",\n      \"pmids\": [\"37245210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FPR receptor subtype and downstream effectors not fully mapped\", \"Generality across non-breast tumors not tested here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended disease evidence with a missense variant and added transcriptional/feedback regulators, framing ALDH1L2 within FOXO1- and NRF2-driven metabolic programs.\",\n      \"evidence\": \"Patient fibroblast enzyme assay (10-FDDF); FOXO1 luciferase/rescue; HCC NRF2 promoter binding and functional assays\",\n      \"pmids\": [\"38193334\", \"38923573\", \"39687603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of NRF2/FOXO1 promoter occupancy needs orthogonal confirmation\", \"IL-6/JAK2/STAT3 and macrophage effects mechanistically inferred\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined upstream microRNA control of ALDH1L2 and a role in fibrosis-related fibronectin homeostasis.\",\n      \"evidence\": \"miR-219a-5p target validation, ALDH1L2 knockdown, PAI-1/fibronectin measurement, UUO mouse model\",\n      \"pmids\": [\"39295147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from GSH to PAI-1 not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified NXPH4 as a stress-regulated mitochondrial binding partner, linking ALDH1L2 to metabolic reprogramming and antiandrogen resistance.\",\n      \"evidence\": \"Co-IP, fractionation/immunofluorescence, and gain/loss-of-function in prostate cancer xenografts\",\n      \"pmids\": [\"41639054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of NXPH4 binding on enzyme activity not measured\", \"Interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Consolidated ALDH1L2 as a ROS/ferroptosis gatekeeper across tissues, linking it to PRDX3 antioxidant defense, Akt/mTOR growth signaling, and suppression of metaplastic and tumor progression.\",\n      \"evidence\": \"TRX2-PRDX3 Co-IP with ferroptosis/cisplatin models (SCLC); siRNA with Akt/mTOR readouts (KIRC); Aldh1l2 genetic pancreatitis/PDAC mouse models with ROS/formate metabolomics\",\n      \"pmids\": [\"41764940\", \"41766916\", \"41922744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRDX3 redox effects are direct or NADPH-mediated unresolved\", \"Causal hierarchy among ROS, formate, and signaling outputs not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ALDH1L2's enzymatic NADPH/formate output is mechanistically converted into its diverse protein-protein interactions (TXN, NXPH4, PRDX3) and signaling outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length human ALDH1L2 or its complexes\", \"Direct vs. metabolite-mediated nature of partner interactions undefined\", \"Tissue-specific regulation by acetylation/transcription not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 8, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TXN\",\n      \"SIRT3\",\n      \"NXPH4\",\n      \"PRDX3\",\n      \"TXN2\",\n      \"NRF2\",\n      \"FOXO1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}