Affinage

ALDH3A1

Aldehyde dehydrogenase, dimeric NADP-preferring · UniProt P30838

Length
453 aa
Mass
50.4 kDa
Annotated
2026-04-28
74 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDH3A1 is a cytosolic NAD(P)⁺-dependent aldehyde dehydrogenase that serves as a central detoxification enzyme for medium-chain and lipid peroxidation-derived aldehydes—particularly 4-hydroxynonenal (4-HNE)—and functions as a corneal crystallin with UV-absorbing and chaperone-like properties. The enzyme preferentially oxidizes aldehydes of ≥6 carbons to their corresponding carboxylic acids, thereby preventing 4-HNE–protein adduct formation, glutathione depletion, proteasome dysfunction, and apoptosis triggered by oxidative stress, UV radiation, and cytotoxic drugs (PMID:12943535, PMID:11306050, PMID:22406320); Aldh3a1-knockout mice develop cataracts with elevated protein oxidation and lipid aldehyde adducts, and aldh3a1-null zebrafish accumulate 4-HNE and display hyperglycemia, confirming in vivo protective roles (PMID:17567582, PMID:32980661). Beyond catalysis, ALDH3A1 exhibits molecular chaperone activity protecting enzymes from thermal inactivation, regulates corneal epithelial proliferation partly by promoting p53 nuclear sequestration through an enzymatic-activity-dependent mechanism, and its turnover is controlled by the ubiquitin ligase FBXL12 to regulate trophoblast differentiation (PMID:28526614, PMID:26751691, PMID:26124079). Transcriptionally, ALDH3A1 is induced through AhR/XRE elements, NRF2 signaling, and TP63 super-enhancer binding in squamous cancers, where its enzymatic activity confers resistance to ferroptosis, chemotherapeutic agents, and glutathione depletion-induced cell death (PMID:10591537, PMID:28671577, PMID:39863749, PMID:30333913).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing the transcriptional control of ALDH3A1: the question of how ALDH3A1 expression is induced by xenobiotics was answered by identifying multiple cooperative AhR-responsive elements in the promoter, placing the gene squarely in the dioxin/xenobiotic-response pathway.

    Evidence Promoter deletion/reporter constructs and AhR-dependency assays in Hepa-1c1c7 mouse hepatoma cells

    PMID:10591537

    Open questions at the time
    • Whether NRF2/EpRE and AhR elements cooperate at the endogenous locus was not tested
    • Chromatin-level regulation not examined
    • Tissue-specific transcriptional mechanisms not addressed
  2. 1999 Medium

    Natural allelic variants in the mouse Aldh3a1c allele revealed that structural integrity of the Rossmann fold and a conserved β-strand are critical for enzymatic activity, since four substitutions abolished activity without altering mRNA levels.

    Evidence Sequencing of ALDH3A1 cDNA from multiple inbred mouse strains with enzymatic activity assays across tissues

    PMID:10376761

    Open questions at the time
    • Variants were not reconstituted individually in recombinant systems to assign causality to each substitution
    • Structural basis inferred from sequence analysis, not crystal structure
  3. 2001 High

    The cellular protective function of ALDH3A1 against lipid peroxidation-derived aldehydes was established: overexpression prevented aldehyde-induced glutathione depletion, protein adduct formation, and apoptosis, defining ALDH3A1 as an anti-apoptotic aldehyde scavenger.

    Evidence Stable transfection of ALDH3A1 in V79 and RAW 264.7 cells with viability, glutathione, adduct, and apoptosis assays

    PMID:11306050

    Open questions at the time
    • Endogenous loss-of-function not yet tested at this point
    • Relative contribution to total cellular aldehyde metabolism not quantified
  4. 2003 High

    Biochemical characterization of recombinant ALDH3A1 defined its substrate specificity as strongly favoring medium-chain (≥C6) aldehydes including 4-HNE, while excluding short-chain aldehydes and sugar phosphates, resolving the enzyme's metabolic niche.

    Evidence Recombinant protein expressed in Sf9 cells, purified and assayed with comprehensive substrate panel

    PMID:12943535

    Open questions at the time
    • In vivo substrate confirmation not performed at this stage
    • Cofactor preference (NAD⁺ vs. NADP⁺) kinetics not fully dissected
  5. 2003 High

    UV radiation was shown to inactivate ALDH3A1 through post-translational aggregation rather than direct active-site damage, establishing that ALDH3A1 acts as a sacrificial UV absorber in the cornea.

    Evidence In vivo UV exposure of C57BL/6J mouse corneas; in vitro UV irradiation of recombinant ALDH3A1 and stably transfected HCE cells with spectroscopic and aggregation analyses

    PMID:12604188 PMID:21203538

    Open questions at the time
    • Turnover and replacement kinetics of UV-damaged ALDH3A1 in vivo not determined
    • Whether aggregated ALDH3A1 retains chaperone function unknown
  6. 2006 High

    ALDH3A1 was shown to protect other enzymes from aldehyde-mediated inactivation and to absorb UVB shielding partner proteins; additionally, a structural transition near physiological temperature suggested intrinsic chaperone-like activity, expanding the functional repertoire beyond catalysis.

    Evidence In vitro co-incubation of recombinant ALDH3A1 with G6PDH under aldehyde/UV stress, spectroscopic structural analysis

    PMID:17158879

    Open questions at the time
    • Chaperone activity not yet demonstrated with dedicated chaperone assay clients
    • In vivo relevance of chaperone function not established
  7. 2007 High

    Genetic loss-of-function in vivo proved ALDH3A1's physiological importance: Aldh3a1-knockout mice developed cataracts with elevated protein oxidation and lipid aldehyde adducts, demonstrating that ALDH3A1 is essential for lens and corneal transparency through both enzymatic detoxification and UV absorption.

    Evidence Single and double (Aldh1a1/Aldh3a1) knockout mice with slit-lamp exam, histology, proteasome activity, protein carbonylation, and 4-HNE/MDA adduct measurements

    PMID:17567582

    Open questions at the time
    • Relative contributions of enzymatic vs. crystallin/UV-filter functions not separated in vivo
    • Corneal vs. lens-specific effects not fully delineated
  8. 2014 High

    Crystal structures of ALDH3A1 with selective inhibitors CB7 and CB29 mapped the aldehyde-binding pocket and enabled isoenzyme-selective pharmacology, demonstrating that ALDH3A1 inhibition sensitizes cancer cells to alkylating chemotherapy.

    Evidence X-ray crystallography, kinetic and mutagenesis studies, isoenzyme selectivity panels, mafosfamide sensitization assays in A549 and SF767 cells

    PMID:24387105 PMID:24677340

    Open questions at the time
    • In vivo chemosensitization not tested with these inhibitors
    • Structural basis for cofactor selectivity not resolved
  9. 2015 High

    FBXL12 was identified as the E3 ubiquitin ligase that targets ALDH3A1 for proteasomal degradation, and accumulation of ALDH3A1 in FBXL12-knockout placenta impaired trophoblast differentiation, revealing a developmental role for ALDH3A1 protein turnover.

    Evidence Co-immunoprecipitation, ubiquitylation assays, FBXL12-KO mice, trophoblast stem cell differentiation assays with forced ALDH3A1 expression

    PMID:26124079

    Open questions at the time
    • Whether FBXL12 regulation of ALDH3A1 operates in cornea or lung tissues unknown
    • Degron motif on ALDH3A1 not identified
  10. 2015 High

    Pharmacological expansion of ALDH3A1's substrate range was demonstrated: the small molecule Alda-89 enabled ALDH3A1 to metabolize acetaldehyde, reducing blood ethanol/acetaldehyde levels in mice, showing that ALDH3A1 can be therapeutically redirected.

    Evidence In vitro enzymatic assay and in vivo mouse models (wild-type and ALDH2*1/*2 knock-in) with blood alcohol/aldehyde measurement

    PMID:25713355

    Open questions at the time
    • Structural mechanism by which Alda-89 alters substrate acceptance not resolved
    • Long-term safety of ALDH3A1 substrate redirection not assessed
  11. 2016 High

    Dissection of enzymatic vs. non-enzymatic functions revealed that wild-type but not catalytically inactive ALDH3A1 promotes p53 nuclear sequestration and suppresses corneal epithelial proliferation, while DKO mice show corneal hyperproliferation with p53 loss.

    Evidence Tet-inducible wild-type and catalytic-mutant ALDH3A1 cell lines, proliferation assays, p53 nuclear fractionation, Aldh1a1/3a1 DKO mouse corneal analysis

    PMID:26751691

    Open questions at the time
    • Molecular mechanism linking ALDH3A1 catalytic activity to p53 nuclear retention unknown
    • Whether a metabolic product mediates the p53 effect not tested
  12. 2017 High

    Formal demonstration of ALDH3A1's chaperone activity was achieved: recombinant protein protected SmaI and citrate synthase from thermal inactivation in vitro, and overexpression in E. coli and corneal cells conferred stress resistance independent of catalysis.

    Evidence In vitro chaperone assays with multiple client proteins, E. coli thermal shock, HCE-2 cell oxidative stress assays

    PMID:28526614

    Open questions at the time
    • Whether chaperone and catalytic functions are structurally separable not resolved
    • Client specificity in vivo not defined
  13. 2018 Medium

    ALDH3A1 was placed at the nexus of cancer chemoresistance through multiple signaling axes: downstream of PER2 circadian regulation and Wnt/β-catenin signaling, and as a mediator of resistance to glutathione depletion-induced cell death via 4-HNE detoxification in HNSCC.

    Evidence shRNA knockdown in Per2-mutant fibroblasts and GBM cells with chemosensitivity/ROS assays; pharmacological Wnt inhibition; shRNA in sulfasalazine-resistant HNSCC with 4-HNE measurement and in vivo tumor assays

    PMID:29854309 PMID:30333913 PMID:30429219

    Open questions at the time
    • Direct transcriptional regulation by PER2 or β-catenin on ALDH3A1 promoter not confirmed by ChIP
    • Whether these pathways converge on shared regulatory elements unknown
    • Single-lab findings for each axis
  14. 2018 High

    Chemoproteomics identified the catalytic cysteine as the site of covalent inhibitor EN40 binding, and EN40 impaired lung cancer growth in vivo, validating ALDH3A1 as a druggable cancer target.

    Evidence Activity-based protein profiling in NSCLC cells, covalent ligand screen, in vitro and in vivo xenograft validation

    PMID:30004670

    Open questions at the time
    • Selectivity profile of EN40 across full ALDH superfamily not complete
    • Mechanism of anti-proliferative effect beyond ALDH3A1 inhibition not excluded
  15. 2020 High

    CRISPR-knockout zebrafish confirmed 4-HNE as the primary in vivo substrate of Aldh3a1 and revealed an unexpected role in glucose homeostasis, linking lipid aldehyde detoxification to pancreatic function.

    Evidence aldh3a1-null zebrafish with transgenic reporters, metabolomics, reactive carbonyl species measurement, transcriptomics

    PMID:32980661

    Open questions at the time
    • Mechanism linking 4-HNE accumulation to pancreatic disruption not molecularly defined
    • Whether mammalian ALDH3A1 has a similar metabolic role unknown
  16. 2024 Medium

    ALDH3A1 was identified as a mechanosensitive gene in corneal keratocytes: mechanical strain upregulates ALDH3A1, which inhibits NF-κB nuclear translocation to suppress proliferation and migration, linking biomechanical cues to ALDH3A1's anti-proliferative function.

    Evidence Flexcell tension system, RNAi, NF-κB immunofluorescence, BrdU proliferation, scratch wound, mouse injury models, scRNA-seq of keratoconus samples

    PMID:39652089

    Open questions at the time
    • Mechanotransduction pathway from strain to ALDH3A1 transcription not identified
    • Whether the NF-κB inhibition depends on catalytic activity or protein–protein interaction unknown
  17. 2025 Medium

    TP63 super-enhancer binding was shown to drive high ALDH3A1 expression in squamous cell carcinomas, and ALDH3A1 enzymatic activity was demonstrated to protect specifically against ferroptosis by mitigating lipid peroxidation-derived aldehydes.

    Evidence ChIP-seq, EN40 covalent inhibitor, viability assays, organoid models, xenograft, lipid peroxidation measurement

    PMID:39863749

    Open questions at the time
    • Whether ALDH3A1 is the primary or sole effector of TP63-driven ferroptosis resistance not excluded
    • Specific aldehyde substrates mediating ferroptosis protection not identified
  18. 2026 High

    Dietary isothiocyanates were shown to irreversibly inhibit ALDH3A1 by forming a covalent adduct at the catalytic Cys243, disrupting aldehyde metabolism in saliva—establishing a physiologically relevant environmental inhibitor of ALDH3A1.

    Evidence X-ray crystallography, mass spectrometry, enzymatic assays, ex vivo saliva assays, GC-MS aroma analysis

    PMID:41672019

    Open questions at the time
    • Systemic consequences of dietary ALDH3A1 inhibition beyond salivary function not explored
    • Whether chronic isothiocyanate exposure affects corneal or lung ALDH3A1 unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the molecular mechanism by which ALDH3A1 catalytic activity promotes p53 nuclear retention, the structural basis for its chaperone function and whether it can be genetically separated from catalysis, the identity of specific aldehyde products that mediate its anti-ferroptotic and anti-proliferative effects, and whether its metabolic roles in glucose homeostasis observed in zebrafish extend to mammals.
  • Mechanism of p53 nuclear sequestration by ALDH3A1 unknown
  • Chaperone vs. catalytic domains not structurally separated
  • Mammalian relevance of glucose homeostasis phenotype unconfirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 8 GO:0016209 antioxidant activity 6 GO:0044183 protein folding chaperone 2
Localization
GO:0005829 cytosol 4
Pathway
R-HSA-8953897 Cellular responses to stimuli 7 R-HSA-1430728 Metabolism 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1640170 Cell Cycle 2
Partners
AHRFBXL12NRF2TP53TP63

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Human ALDH3A1 expressed in Sf9 insect cells and purified demonstrates high substrate specificity for medium-chain (≥6 carbon) saturated and unsaturated aldehydes including 4-hydroxy-2-nonenal (4-HNE), while short-chain aldehydes (acetaldehyde, propionaldehyde, malondialdehyde) are very poor substrates; glyceraldehyde is metabolized poorly and glucose-6-phosphate, 6-phosphoglucono-delta-lactone, and 6-phosphogluconate are not metabolized at all. Recombinant protein expression in Sf9 cells, affinity chromatography purification, in vitro enzymatic assays with defined substrates The Biochemical journal High 12943535
2001 Stable transfection of human ALDH3A1 in V79 cells confers protection against growth inhibition and apoptosis induced by medium-chain aldehydes (hexanal, trans-2-hexenal, trans-2-octenal, trans-2-nonenal, 4-HNE) by oxidizing them to their corresponding carboxylic acids, preventing glutathione depletion and protein adduct formation; ALDH3A1 completely blocked HNE-induced apoptosis in both V79 and RAW 264.7 macrophage cells. Stable transfection, cell viability assays, glutathione measurement, protein adduct detection, apoptosis assays, in vitro enzymatic assays with crude cytosol Chemico-biological interactions High 11306050
2003 Stable transfection of ALDH3A1 in human corneal epithelial cells (HCE) protects against UV- and 4-HNE-induced cytotoxicity and apoptosis (via caspase-3/PARP pathway); ALDH3A1-expressing cells had 50% higher NAD(P)H levels upon 4-HNE treatment and prevented 4-HNE–protein adduct formation, with a Km for 4-HNE of 54 µM. Stable transfection, UV and 4-HNE cytotoxicity assays, DNA fragmentation assays, caspase-3/PARP Western blot, NAD(P)H measurement, 4-HNE protein adduct detection Free radical biology & medicine High 12706498
2006 ALDH3A1 stably transfected in rabbit corneal fibroblastic cells (TRK43) protects against H2O2-, mitomycin C-, and etoposide-induced apoptosis and oxidative damage by metabolizing 4-HNE, maintaining glutathione homeostasis, and sustaining redox balance; increased carbonylation of ALDH3A1 occurs after treatment without significant loss of enzymatic activity. Stable transfection, oxidative stress assays, apoptosis detection, GSH measurement, 4-HNE adduct Western blot Free radical biology & medicine High 17023273
2006 ALDH3A1 protects glucose-6-phosphate dehydrogenase (G6PDH) from inactivation by 4-HNE and malondialdehyde when co-incubated with NADP+, demonstrating enzymatic protection of other proteins; at large excess, ALDH3A1 directly absorbs UVB and shields G6PDH from UV inactivation. ALDH3A1 also undergoes a structural transition near physiological temperatures to a partially unfolded conformation suggestive of chaperone activity. In vitro co-incubation assays with recombinant proteins, G6PDH activity measurements, UV exposure experiments, spectroscopic analysis of structural transitions The Journal of biological chemistry High 17158879
2007 Aldh3a1−/− and Aldh1a1−/−/Aldh3a1−/− double knockout mice develop cataracts (anterior and posterior subcapsular and punctate cortical opacities) by 1 month of age; UVB exposure accelerates anterior lens opacification more in Aldh3a1−/− mice; cataract formation is associated with decreased proteasomal activity, increased protein oxidation, and increased 4-HNE and malondialdehyde-protein adducts, demonstrating that ALDH3A1 protects against cataract through both enzymatic and non-enzymatic (light-filtering) functions. Single and double knockout mouse models, UVB exposure, slit-lamp/histological evaluation, proteasome activity assay, protein carbonylation assay, 4-HNE/MDA adduct Western blots, GSH measurement The Journal of biological chemistry High 17567582
2012 ALDH3A1 overexpression in TRK43 corneal keratocyte cells protects from 4-HNE-induced cytotoxicity by metabolizing 4-HNE and its glutathione conjugate, preventing 4-HNE–protein adduct formation, blocking apoptosis, maintaining glutathione homeostasis, and preserving proteasome function. Stable transfection, cell viability assays, morphological evaluation, Western blot for 4-HNE adducts, glutathione assay, proteasome activity assay, apoptosis assays Free radical biology & medicine High 22406320
2014 Crystallographic and kinetic studies of ALDH3A1 with selective inhibitor CB7 (1-[(4-fluorophenyl)sulfonyl]-2-methyl-1H-benzimidazole, IC50 0.2 µM) show that CB7 binds within the aldehyde-binding pocket of ALDH3A1; mutagenesis confirmed this binding site; CB7 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2. ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cells are sensitized to mafosfamide by CB7, whereas fibroblasts lacking ALDH3A1 are not. X-ray crystallography, kinetic inhibition assays, active-site mutagenesis, isoenzyme selectivity panel, cell proliferation assays with mafosfamide Journal of medicinal chemistry High 24387105
2014 Crystal structure of ALDH3A1 with inhibitor CB29 shows it binds within the aldehyde substrate-binding site; CB29 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 at up to 250 µM, confirming isoenzyme selectivity; sensitizes ALDH3A1-expressing tumor cells (A549, SF767) but not ALDH3A1-negative fibroblasts to mafosfamide. X-ray crystallography, kinetic characterization, isoenzyme selectivity assays, cell proliferation assays Chembiochem : a European journal of chemical biology High 24677340
2015 Small molecule Alda-89 enables ALDH3A1 to metabolize acetaldehyde (a substrate it normally does not accept); when administered with ALDH2 activator Alda-1, Alda-89 reduced blood ethanol and acetaldehyde levels in vivo in wild-type and ALDH2*1/*2 knock-in mice, demonstrating pharmacological recruitment of ALDH3A1 to expand its substrate specificity. In vitro enzymatic assay, in vivo mouse model (wild-type and ALDH2*1/*2 knock-in), blood alcohol/aldehyde measurement, behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 25713355
2016 Using tetracycline-inducible wild-type and catalytically-inactive ALDH3A1 human corneal epithelial cells (hTCEpi), ALDH3A1 was shown to decrease corneal cell proliferation through both enzymatic and non-enzymatic mechanisms; wild-type but not catalytically-inactive ALDH3A1 promotes p53 nuclear sequestration. In Aldh1a1−/−/Aldh3a1−/− DKO mice, hyperproliferative corneal epithelium shows nearly complete loss of p53 expression. Tet-inducible cell lines expressing wt or catalytically-inactive ALDH3A1, proliferation assays, p53 nuclear fractionation, DKO mouse corneal analysis, differentiation marker mRNA analysis PloS one High 26751691
2017 Recombinant human ALDH3A1 exhibits molecular chaperone-like activity in vitro: it protects SmaI and citrate synthase from thermal stress-induced precipitation and inactivation; overexpression of ALDH3A1 confers E. coli with enhanced resistance to thermal shock and protects HCE-2 corneal cells from H2O2 and tert-butyl hydroperoxide cytotoxicity. In vitro chaperone assays with recombinant protein and citrate synthase, E. coli thermal shock assays, cell viability assays in corneal cell line The international journal of biochemistry & cell biology High 28526614
2010 UV-light causes soluble, non-native aggregation of ALDH3A1 via covalent and non-covalent interactions, leading to loss of enzymatic activity; MALDI-TOF LysC peptide mapping shows UV-induced modifications to Trp, Met, and Cys residues, but the conserved catalytic Cys remains intact after UV exposure, indicating that inactivation results from structural changes rather than direct active-site damage. UV irradiation of recombinant ALDH3A1, spectroscopic analysis, MALDI-TOF mass spectrometry with LysC peptide mapping, aggregation assays PloS one High 21203538
2018 Chemoproteomics (activity-based protein profiling) identified the catalytic cysteine of ALDH3A1 as the primary target of the covalent ligand DKM 3-42 in non-small cell lung carcinoma cells; a more selective covalent inhibitor, EN40, inhibits ALDH3A1 activity at this catalytic cysteine and impairs lung cancer cell proliferation in vitro and tumor growth in vivo. Activity-based protein profiling (ABPP), covalent ligand library screen, in vitro cell proliferation assays, in vivo xenograft model ACS chemical biology High 30004670
2015 FBXL12 (F-box and leucine-rich repeat protein 12) interacts specifically with ALDH3-family members including ALDH3A1 and mediates their polyubiquitylation, leading to proteasomal degradation; FBXL12-deficient mice accumulate ALDH3 in the placenta and exhibit impaired trophoblast stem cell differentiation, and forced ALDH3A1 expression in wild-type TSCs phenocopies the differentiation defect. Co-immunoprecipitation, ubiquitylation assay, FBXL12 knockout mice, TSC differentiation assays, forced overexpression rescue experiments, ALDH inhibitor rescue Stem cells (Dayton, Ohio) High 26124079
1999 Deletion analysis and transient transfection of 5'-flanking region reporter constructs in mouse hepatoma Hepa-1c1c7 cells show that the Aldh3a1 promoter contains at least four functional aromatic hydrocarbon response elements (AHREs) that act cooperatively for dioxin (TCDD)-mediated induction, a negative regulatory element (NRE) controlling basal expression, and that TCDD-mediated upregulation depends exclusively on the aromatic hydrocarbon receptor (AhR). Promoter deletion/reporter gene (CAT/luciferase) constructs, transient transfection, AhR dependency assay in Hepa-1c1c7 cells Pharmacogenetics High 10591537
2018 Pharmacological Wnt pathway inhibition (LGK974) significantly downregulates ALDH3A1 expression in glioblastoma cells; shRNA-mediated ALDH3A1 knockdown increases TMZ efficacy and reduces clonogenic potential with decreased stem cell markers (CD133, Nestin, Sox2), placing ALDH3A1 downstream of Wnt/β-catenin signaling in glioblastoma chemoresistance. shRNA knockdown, pharmacological Wnt inhibition, transcriptomic analysis, clonogenic assay, proliferation assay, stem cell marker expression Oncotarget Medium 29854309
2018 In Per2-mutant oncogene-transformed fibroblasts, ALDH3A1 protein is ~7-fold higher than in wild-type transformed cells, correlating with chemoresistance; shRNA knockdown of Aldh3a1 in Per2-mutant cells relieves resistance to methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin by restoring chemotherapy-induced reactive oxygen species accumulation, placing ALDH3A1 downstream of the PER2 circadian clock component in drug resistance. Per2-mutant mouse embryonic fibroblasts, shRNA knockdown, chemotherapy cytotoxicity assays, ROS measurement, Western blot for ALDH3A1 The Journal of biological chemistry Medium 30429219
2006 Arachidonic acid treatment of A549 lung tumor cells reduces ALDH3A1 enzymatic activity, protein, and mRNA levels, associated with increased PPARγ expression and decreased NF-κB binding; selective PPARγ antagonist GW9662 prevents both ALDH3A1 reduction and A549 cell growth inhibition, identifying PPARγ activation as upstream repressor of ALDH3A1 expression. PPARγ antagonist treatment, ALDH3A1 mRNA/protein/activity measurement, NF-κB binding assay, cell growth assay, vitamin E co-treatment Free radical biology & medicine Medium 16716894
2017 NRF2 knockdown in pancreatic cancer cells markedly reduces ALDH3A1 expression, placing ALDH3A1 transcriptionally downstream of NRF2-mediated antioxidant signaling. siRNA knockdown of NRF2, RT-PCR/Western blot for ALDH3A1 expression, GCLC co-regulation analysis Antioxidants (Basel, Switzerland) Medium 28671577
2020 aldh3a1−/− zebrafish generated by CRISPR-Cas9 display retinal vasodilatory alterations and impaired glucose homeostasis; 4-HNE (but not methylglyoxal) was elevated in aldh3a1 mutants, establishing 4-HNE as the primary substrate of Aldh3a1 in vivo and linking impaired 4-HNE detoxification to pancreatic disruption and hyperglycemia. CRISPR-Cas9 knockout zebrafish, transgenic reporter lines for vasculature/pancreas, reactive carbonyl species measurement, transcriptome, metabolomics, ALDH activity assay, pdx1 silencing epistasis Redox biology High 32980661
2018 ALDH3A1 knockdown in sulfasalazine-resistant HNSCC cells sensitizes them to the xCT inhibitor sulfasalazine; dyclonine (a covalent ALDH inhibitor) combined with sulfasalazine induces intracellular 4-HNE accumulation synergistically, demonstrating that ALDH3A1-mediated 4-HNE detoxification is the mechanism of resistance to glutathione depletion-induced cell death. shRNA knockdown, drug combination assays, 4-HNE intracellular measurement, tumor growth assay in vivo Oncotarget Medium 30333913
2025 TP63 transcription factor binds to the super-enhancer of ALDH3A1 to drive its high expression in squamous cell carcinomas; ALDH3A1 enzymatic activity (not just protein presence) protects SCC cells against ferroptosis by catalyzing aldehyde oxidation and mitigating lipid peroxidation; the covalent inhibitor EN40 enhances ferroptosis sensitivity. ChIP-seq for TP63 super-enhancer binding, covalent inhibitor EN40, cell viability assays, organoid models, in vivo xenograft, lipid peroxidation measurement Oncogene Medium 39863749
2003 UV radiation decreases corneal ALDH3A1 mRNA, protein, and enzymatic activity in C57BL/6J mice; at lower UVB doses, enzymatic activity decreases without transcriptional changes, indicating post-translational modification; in vitro studies with purified recombinant ALDH3A1 and stably transfected HCE cells show UV causes covalent and non-covalent protein aggregation. Northern blot, Western blot, enzymatic activity assay, in vitro UV irradiation of recombinant protein and transfected cell lines Chemico-biological interactions Medium 12604188
2025 ALDH3A1 loss in FANCA-deficient keratinocytes causes synthetic lethality with DNA damage marker induction; loss of four functionally redundant ALDH3 isozymes causes lipid aldehyde accumulation; FA-deficient keratinocytes are more sensitive to 4-HNE than FA-competent cells, establishing ALDH3-family enzymes (including ALDH3A1) as a tier-1 defense against lipid aldehyde-induced DNA damage in keratinocytes. Systematic CRISPR/shRNA inactivation of ALDH/ADH genes in FANCA-deficient keratinocyte lines, DNA damage marker assays, 4-HNE sensitivity assays, NAC rescue bioRxivpreprint Medium bio_10.1101_2025.11.13.688345
2025 A conserved RH/QxxR sequence motif in ALDH3A1 (and other ALDH3 family members) enables activity with non-canonical redox cofactor NMN+ (nicotinamide mononucleotide); Bos taurus ALDH3A1 shows unprecedented turnover with NMN+, with kcat values matching or exceeding NAD+; structural analysis shows the motif reinforces cofactor positioning and pre-organizes the active site without requiring the adenosine monophosphate moiety of NAD+. Enzymatic kinetics, X-ray crystallography, molecular dynamics, mutagenesis of the RH/QxxR motif in diverse ALDH scaffolds bioRxivpreprint Medium bio_10.1101_2025.08.01.668186
2026 Dietary isothiocyanates (specifically allyl-isothiocyanate) form a covalent adduct with the ALDH3A1 catalytic cysteine residue (Cys243), causing irreversible inhibition of salivary ALDH3A1 activity both in vitro and ex vivo; this inhibition disrupts metabolic conversion of odorant aldehydes in saliva. X-ray crystallography, mass spectrometry adduct identification, in vitro enzymatic assay, ex vivo saliva assays, GC-MS aroma analysis Food chemistry High 41672019
1999 Four amino acid substitutions (G88R, I154N, H305R, I352V) in the Aldh3a1c allele of SWR/J mice are responsible for near-complete loss of ALDH3A1 enzymatic activity in all tissues; I154N disrupts a potential alpha helix in the Rossmann fold and H305R affects a beta strand potentially impacting catalytic activity; mRNA levels are unchanged between 'low-activity' and 'high-activity' variants, indicating post-translational/structural basis for activity differences. RT-PCR amplification and sequencing of ALDH3A1 cDNA from multiple inbred mouse strains, enzymatic activity assays across tissues, sequence analysis Pharmacogenetics Medium 10376761
2023 ALDH3A1 promotes glycolysis and suppresses oxidative phosphorylation (OXPHOS) in NSCLC cells by activating the HIF-1α/LDHA pathway; its expression is induced by hypoxia; β-elemene downregulates ALDH3A1 to inhibit glycolysis and enhance OXPHOS, suppressing NSCLC proliferation in vitro and in vivo. ALDH3A1 knockdown/overexpression, metabolic flux analysis (glycolysis/OXPHOS), HIF-1α/LDHA pathway analysis, β-elemene treatment, in vivo xenograft Cell death & disease Medium 37730658
2024 Mechanical strain (3%) applied to human keratocytes upregulates ALDH3A1 expression; increased ALDH3A1 inhibits NF-κB nuclear translocation, suppressing keratocyte proliferation and migration; ALDH3A1 knockdown promotes NF-κB nuclear translocation and enhances proliferation and migration, establishing ALDH3A1 as a mechanosensitive regulator of NF-κB signaling in corneal stroma. Flexcell tension system, RT-qPCR, Western blot, RNAi knockdown, NF-κB nuclear translocation immunofluorescence, BrdU proliferation assay, scratch wound healing assay, mouse injury models, single-cell RNA-seq of keratoconus patient samples FASEB journal Medium 39652089

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung cancer (Amsterdam, Netherlands) 172 17920722
2002 Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study. Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Cancer chemotherapy and pharmacology 164 11914911
2007 Multiple and additive functions of ALDH3A1 and ALDH1A1: cataract phenotype and ocular oxidative damage in Aldh3a1(-/-)/Aldh1a1(-/-) knock-out mice. The Journal of biological chemistry 154 17567582
2003 Human aldehyde dehydrogenase 3A1 (ALDH3A1): biochemical characterization and immunohistochemical localization in the cornea. The Biochemical journal 138 12943535
2006 ALDH3A1: a corneal crystallin with diverse functions. Experimental eye research 121 16797007
2008 Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenetics and genomics 109 18496131
2003 Aldh3a1 protects human corneal epithelial cells from ultraviolet- and 4-hydroxy-2-nonenal-induced oxidative damage. Free radical biology & medicine 99 12706498
2001 Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells. Chemico-biological interactions 73 11306050
2018 Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells. Oncotarget 69 30333913
2017 Silencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells. Antioxidants (Basel, Switzerland) 64 28671577
2014 Selective ALDH3A1 inhibition by benzimidazole analogues increase mafosfamide sensitivity in cancer cells. Journal of medicinal chemistry 62 24387105
1985 Chromosome assignment, biochemical and immunological studies on a human aldehyde dehydrogenase, ALDH3. Annals of human genetics 58 4073832
2020 Exosomes carrying ALDOA and ALDH3A1 from irradiated lung cancer cells enhance migration and invasion of recipients by accelerating glycolysis. Molecular and cellular biochemistry 56 32297178
2006 Antioxidant function of corneal ALDH3A1 in cultured stromal fibroblasts. Free radical biology & medicine 55 17023273
2018 Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro. Oncotarget 52 29854309
2015 Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo. Proceedings of the National Academy of Sciences of the United States of America 51 25713355
2006 Mechanisms involved in the protection of UV-induced protein inactivation by the corneal crystallin ALDH3A1. The Journal of biological chemistry 51 17158879
2014 Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity. Chembiochem : a European journal of chemical biology 50 24677340
2019 ALDH3A1 Overexpression in Melanoma and Lung Tumors Drives Cancer Stem Cell Expansion, Impairing Immune Surveillance through Enhanced PD-L1 Output. Cancers 48 31817719
2006 Arachidonic acid suppresses growth of human lung tumor A549 cells through down-regulation of ALDH3A1 expression. Free radical biology & medicine 47 16716894
2023 Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming. Cell death & disease 45 37730658
2020 Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans. Redox biology 45 32980661
2012 Molecular mechanisms of ALDH3A1-mediated cellular protection against 4-hydroxy-2-nonenal. Free radical biology & medicine 43 22406320
2018 Chemoproteomics-Enabled Covalent Ligand Screening Reveals ALDH3A1 as a Lung Cancer Therapy Target. ACS chemical biology 41 30004670
1999 Mouse cytosolic class 3 aldehyde dehydrogenase (Aldh3a1): gene structure and regulation of constitutive and dioxin-inducible expression. Pharmacogenetics 38 10591537
2003 Ultraviolet radiation decreases expression and induces aggregation of corneal ALDH3A1. Chemico-biological interactions 36 12604188
1993 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced ethoxyresorufin-O-deethylase (EROD) and aldehyde dehydrogenase (ALDH3) activities in the brain and liver. A comparison between the most TCDD-susceptible and the most TCDD-resistant rat strain. Biochemical pharmacology 34 8363638
2013 Efficient E. coli expression strategies for production of soluble human crystallin ALDH3A1. PloS one 31 23451057
2010 Structural and functional modifications of corneal crystallin ALDH3A1 by UVB light. PloS one 27 21203538
1996 Induction of CYP1A1 and ALDH-3 in lymphoid tissues from Fisher 344 rats exposed to 2,3,7,8-tetrachlorodibenzodioxin (TCDD). Toxicology and applied pharmacology 27 8607142
2016 ALDH3A1 Plays a Functional Role in Maintenance of Corneal Epithelial Homeostasis. PloS one 24 26751691
2013 ALDH3A1 is overexpressed in a subset of hepatocellular carcinoma characterised by activation of the Wnt/ß-catenin pathway. Virchows Archiv : an international journal of pathology 24 24276407
2018 Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene. The Journal of biological chemistry 23 30429219
1999 Four amino acid changes are associated with the Aldh3a1 locus polymorphism in mice which may be responsible for corneal sensitivity to ultraviolet light. Pharmacogenetics 23 10376761
2020 Shikonin enhances the antitumor effect of cabazitaxel in prostate cancer stem cells and reverses cabazitaxel resistance by inhibiting ABCG2 and ALDH3A1. American journal of cancer research 22 33294267
2021 ALDH3A1 driving tumor metastasis is mediated by p53/BAG1 in lung adenocarcinoma. Journal of Cancer 18 34234849
2001 Three different stable human breast adenocarcinoma sublines that overexpress ALDH3A1 and certain other enzymes, apparently as a consequence of constitutively upregulated gene transcription mediated by transactivated EpREs (electrophile responsive elements) present in the 5'-upstream regions of these genes. Chemico-biological interactions 17 11306049
2015 FBXL12-Mediated Degradation of ALDH3 is Essential for Trophoblast Differentiation During Placental Development. Stem cells (Dayton, Ohio) 16 26124079
1996 The human aldehyde dehydrogenase 3 gene (ALDH3): identification of a new exon and diverse mRNA isoforms, and functional analysis of the promoter. Gene expression 16 8979087
2022 ALDH3A1 overexpression in OSCC inhibits inflammation via phospho-Ser727 at STAT3 in tumor-associated macrophages. Oral diseases 15 35188323
2016 Corneal haze phenotype in Aldh3a1-null mice: In vivo confocal microscopy and tissue imaging mass spectrometry. Chemico-biological interactions 15 28038895
2011 Comparative studies of vertebrate aldehyde dehydrogenase 3: sequences, structures, phylogeny and evolution. Evidence for a mammalian origin for the ALDH3A1 gene. Chemico-biological interactions 15 21296057
2004 Alkali burn causes aldehyde dehydrogenase 3A1 (ALDH3A1) decrease in mouse cornea. Molecular vision 15 15547490
2017 Human aldehyde dehydrogenase 3A1 (ALDH3A1) exhibits chaperone-like function. The international journal of biochemistry & cell biology 14 28526614
2011 Importance of inverse correlation between ALDH3A1 and PPARγ in tumor cells and tissue regeneration. Chemico-biological interactions 13 21251908
1996 Hepatocyte expression of tumor associated aldehyde dehydrogenase (ALDH-3) and p21 Ras following diethylnitrosamine (DEN) initiation and chronic exposure to di(2-ethylhexyl)phthalate (DHEP). Carcinogenesis 13 8761421
2003 Acute-phase response to benzo[a]pyrene and induction of rat ALDH3A1. Chemico-biological interactions 12 12604189
2000 Changes of CYP1A1, GST, and ALDH3 enzymes in hepatoma cell lines undergoing enhanced lipid peroxidation. Free radical biology & medicine 12 11121727
1991 Aldehyde dehydrogenase (ALDH) isozymes in the gray short-tailed opossum (Monodelphis domestica): tissue and subcellular distribution and biochemical genetics of ALDH3. Biochemical genetics 12 1859355
2016 Development of Highly Selective Fluorescent Probe Enabling Flow-Cytometric Isolation of ALDH3A1-Positive Viable Cells. Bioconjugate chemistry 11 27976863
2024 ALDH3A1 upregulation inhibits neutrophils N2 polarization and halts oral cancer growth. Oral diseases 10 38225738
2006 Constitutive and 3-methylcholanthrene-induced rat ALDH3A1 expression is mediated by multiple xenobiotic response elements. Drug metabolism and disposition: the biological fate of chemicals 10 17151192
2003 An algorithm for identification and ranking of family-specific residues, applied to the ALDH3 family. Chemico-biological interactions 10 12604185
2021 Association with Corneal Remodeling Related Genes, ALDH3A1, LOX, and SPARC Genes Variations in Korean Keratoconus Patients. Korean journal of ophthalmology : KJO 8 33596621
2025 Targeting aldehyde dehydrogenase ALDH3A1 increases ferroptosis vulnerability in squamous cancer. Oncogene 5 39863749
2021 Common ALDH3A1 Gene Variant Associated with Keratoconus Risk in the Polish Population. Journal of clinical medicine 5 35011749
2009 The oxidation status of ALDH3A1 in human saliva and its correlation with antioxidant capacity measured by ORAC method. Acta poloniae pharmaceutica 5 19894643
2001 Inhibition of ALDH3A1-catalyzed oxidation by chlorpropamide analogues. Chemico-biological interactions 5 11306038
2024 Chronic restraint stress promotes oral squamous cell carcinoma development by inhibiting ALDH3A1 via stress response hormone. BMC oral health 4 38191346
2023 Identification of a peptide ligand for human ALDH3A1 through peptide phage display: Prediction and characterization of protein interaction sites and inhibition of ALDH3A1 enzymatic activity. Frontiers in molecular biosciences 4 37021113
2020 Generation and characterization of Aldh3-Cre transgenic mice as a tool for conditional gene deletion in postnatal cornea. Scientific reports 4 32493941
2001 Effects of 3-methylcholanthrene and aspirin co-administration on ALDH3A1 in HepG2 cells. Chemico-biological interactions 4 11306048
2001 Inhibition of ALDH3A1-catalyzed oxidation by chlorpropamide analogues. Chemico-biological interactions 4 11672702
2024 Corneal strain influences keratocyte proliferation and migration through upregulation of ALDH3A1 expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 39652089
2025 Aldehyde dehydrogenase ALDH3A1 rescues cigarette smoke-induced emphysema by conferring alveolar type 2 to type 1 cell transition. Free radical biology & medicine 1 41046948
2025 Multi-omics revealed GOT1/ALDH3A1 pathway attenuated head and neck squamous cell carcinoma and increased cisplatin sensitivity through ROS induced by mitochondrial dysfunction. Redox report : communications in free radical research 1 41327788
2026 ALDH3A1-dependent Nrf2/HO-1/GPX4 pathway supports AHR as a promising therapeutic target for ferroptosis and promotes imperatorin-mediated lung protection. Cell death discovery 0 41513604
2026 A viral-host redox axis: EBNA1-FOSL2-ALDH3A1 defines a targetable vulnerability in EBV-positive carcinomas. Redox biology 0 41564796
2026 Dietary isothiocyanates inhibit the oxidative activity of salivary aldehyde dehydrogenase ALDH3A1 and modulate aroma release. Food chemistry 0 41672019
2026 Novel benzophenones from the fibrous roots of Anemarrhena asphodeloides Bunge inhibit hepatocellular carcinoma activity by targeting ALDH3A1. Bioorganic chemistry 0 41724003
2026 Aldh3a1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to amyotrophic lateral sclerosis progression. Free radical biology & medicine 0 41831802
2025 Association of ALDH3A1 expression with tumor differentiation, pathological stage, and nodal status in oral squamous cell carcinoma. Journal of Taibah University Medical Sciences 0 40657474
2025 Sad from Proteobacteria is a Structurally Distinct ALDH3 Enzyme Specialized for the Oxidation of Steroidal Aldehydes. Biochemistry 0 40825534
2024 ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression. bioRxiv : the preprint server for biology 0 39677625