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Showing ALDH3A1 — ALDH3 is a alias.

ALDH3A1

Aldehyde dehydrogenase, dimeric NADP-preferring · UniProt P30838

Length
453 aa
Mass
50.4 kDa
Annotated
2026-06-09
74 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDH3A1 is a cytosolic NAD(P)+-dependent aldehyde dehydrogenase that detoxifies medium-chain (≥6 carbon) aliphatic and hydroxy-alkenyl aldehydes, most notably the lipid-peroxidation product 4-hydroxy-2-nonenal (4-HNE), oxidizing them to non-toxic carboxylic acids while short-chain aldehydes are poor substrates (PMID:12943535, PMID:11306050). Through this activity it protects cells from oxidative and UV-induced injury: it prevents 4-HNE-protein adduct formation, preserves glutathione homeostasis and proteasome function, and blocks caspase-3/PARP-mediated apoptosis in corneal and other cells (PMID:12706498, PMID:17023273, PMID:22406320). In vivo, Aldh3a1-null mice develop cataracts and accumulate 4-HNE/malondialdehyde adducts, and CRISPR knockout zebrafish establish ALDH3A1 as the primary 4-HNE detoxifier whose loss disrupts glucose homeostasis and ocular vasculature (PMID:17567582, PMID:32980661). Beyond catalysis, the abundant corneal protein protects co-incubated enzymes by directly absorbing UV energy and exhibits molecular chaperone-like activity against thermal aggregation, acting as a multifunctional 'corneal crystallin' (PMID:17158879, PMID:28526614). ALDH3A1 also restrains corneal epithelial proliferation through both enzymatic and non-enzymatic routes, promoting nuclear sequestration of p53 and suppressing NF-κB nuclear translocation (PMID:26751691, PMID:39652089). Catalysis depends on an active-site Cys243 that is the covalent target of selective inhibitors and dietary isothiocyanate adducts, and selective substrate-pocket inhibitors (CB7, CB29, EN40) confirm a druggable aldehyde-binding site (PMID:24387105, PMID:24677340, PMID:30004670, PMID:41672019). Expression is transcriptionally induced by the aryl hydrocarbon receptor via aromatic hydrocarbon response elements and by electrophile-responsive element signaling, and the SCF-FBXL12 E3 ligase targets ALDH3 proteins for proteasomal degradation to control trophoblast differentiation (PMID:10591537, PMID:11306049, PMID:26124079). In cancer, ALDH3A1 confers chemoresistance and ferroptosis resistance by detoxifying toxic aldehydes and limiting lipid peroxidation, with high expression in squamous carcinoma driven by TP63 binding to a super-enhancer (PMID:30429219, PMID:39863749, PMID:30004670).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1985 Medium

    Established the basic identity of the human enzyme—its chromosomal locus, dual NAD/NADP cofactor usage, and tissue distribution—providing the foundation for all later mechanistic work.

    Evidence Human-rodent somatic cell hybrids, enzyme activity assays, and antiserum immunoprecipitation

    PMID:4073832

    Open questions at the time
    • Did not define physiological substrate preference
    • No structural or active-site information
  2. 1999 Medium

    Defined how ALDH3A1 transcription is controlled, showing the gene is an AhR target driven by cooperative aromatic hydrocarbon response elements and that natural low-activity alleles arise from coding substitutions affecting the Rossmann fold and catalysis.

    Evidence Promoter deletion/reporter assays in AhR-deficient hepatoma cells; allelic cDNA sequencing and enzyme activity across inbred mouse strains with UV challenge

    PMID:10376761 PMID:10591537

    Open questions at the time
    • No site-directed mutagenesis confirmation of the allelic substitutions
    • Negative regulatory element factor not identified
  3. 2001 High

    Demonstrated the protective cellular function: ALDH3A1 oxidizes medium-chain aldehydes to confer resistance to aldehyde toxicity, distinguishing it from ALDH1A1, and linked its overexpression in cancer cells to EpRE-driven transcription.

    Evidence Stable transfection of V79 cells with viability/GSH/apoptosis/adduct readouts; RT-PCR and exclusion assays in MCF-7 oxazaphosphorine-resistant sublines

    PMID:11306049 PMID:11306050

    Open questions at the time
    • EpRE transactivating factor not directly identified
    • Did not address in vivo relevance
  4. 2003 High

    Quantified substrate specificity with purified recombinant enzyme and localized ALDH3A1 to corneal epithelium and keratocytes, while showing it protects corneal cells against UV- and 4-HNE-induced apoptosis with measurable kinetics.

    Evidence Recombinant Sf9 protein with kinetics and immunohistochemistry; stable transfection of HCE cells with caspase-3/PARP/NAD(P)H readouts; mouse corneal UV dose-response

    PMID:12604188 PMID:12706498 PMID:12943535

    Open questions at the time
    • UV downregulation mechanism (transcriptional vs post-translational) only partly resolved
    • No structural model of substrate binding
  5. 2006 High

    Revealed that ALDH3A1 is multifunctional—protecting other proteins both enzymatically (aldehyde clearance preserving G6PDH) and non-enzymatically by direct UV absorption—and that its downregulation by PPARγ underlies arachidonic-acid-induced tumor growth suppression.

    Evidence Co-incubation of purified ALDH3A1 with G6PDH under UVB/aldehyde stress; stable transfection of rabbit corneal fibroblasts; PPARγ antagonist epistasis in A549 cells

    PMID:16716894 PMID:17023273 PMID:17158879

    Open questions at the time
    • Mechanism of the chaperone-like structural transition not defined
    • Direct PPARγ binding to the gene not shown
  6. 2007 High

    Provided in vivo genetic proof that corneal ALDH3A1 protects the eye against oxidative damage, with knockout mice developing cataracts and accumulating aldehyde-protein adducts, partly redundant with lens ALDH1A1.

    Evidence Single and double Aldh1a1/Aldh3a1 knockout mice with ocular phenotyping, proteasome and adduct assays, and UVB challenge

    PMID:17567582

    Open questions at the time
    • Relative contribution of enzymatic vs UV-filtering function not separated genetically
    • Mechanism of cataractogenesis downstream of adducts unresolved
  7. 2010 High

    Showed that UV inactivation of ALDH3A1 results from aggregation and structural perturbation rather than direct active-site damage, since the catalytic cysteine remains intact in fully inactivated enzyme.

    Evidence UV irradiation of purified recombinant ALDH3A1 with activity assays, spectroscopy, and MALDI-TOF peptide mapping

    PMID:21203538

    Open questions at the time
    • Aggregation interface not mapped
    • In vivo relevance of these specific modifications not tested
  8. 2012 High

    Consolidated the corneal protective mechanism, showing ALDH3A1 metabolizes 4-HNE and its glutathione conjugate while preserving proteasome function and GSH homeostasis.

    Evidence Stable transfection of rabbit keratocytes with six orthogonal cellular and biochemical readouts

    PMID:22406320

    Open questions at the time
    • Single cell system
    • Did not address downstream signaling consequences
  9. 2014 High

    Defined a druggable aldehyde substrate-binding pocket by crystallizing selective small-molecule inhibitors (CB7, CB29) and validated that their inhibition sensitizes ALDH3A1-positive tumor cells to oxazaphosphorine chemotherapy.

    Evidence X-ray crystallography of inhibitor-bound ALDH3A1, enzyme kinetics, mutagenesis, and matched ALDH3A1-positive/negative cell proliferation assays

    PMID:24387105 PMID:24677340

    Open questions at the time
    • Inhibitor potency in vivo not established in these studies
    • Selectivity against full ALDH family not exhaustively profiled
  10. 2015 High

    Demonstrated mechanistic plasticity—both substrate scope (small molecule Alda-89 enabling acetaldehyde metabolism in vivo) and a free-standing molecular chaperone activity protecting model substrates from thermal aggregation—and clarified its FBXL12-dependent turnover controlling trophoblast differentiation.

    Evidence Pharmacological activation with Alda-89 and blood metabolite/behavioral assays in mice; in vitro chaperone assays with citrate synthase/SmaI; reciprocal Co-IP, ubiquitylation assay, FBXL12 knockout mice, and gossypol rescue

    PMID:25713355 PMID:26124079 PMID:28526614

    Open questions at the time
    • Structural basis of chaperone activity unresolved
    • FBXL12 specificity within ALDH3 family not fully dissected
  11. 2016 High

    Separated enzymatic from non-enzymatic roles in corneal homeostasis, showing only catalytically active ALDH3A1 drives nuclear p53 sequestration to restrict epithelial proliferation, validated by double-knockout epistasis.

    Evidence Tet-On inducible wt vs catalytically-inactive ALDH3A1 cells, BrdU and p53 immunofluorescence, and Aldh1a1/Aldh3a1 double-KO mouse cornea phenotyping

    PMID:26751691

    Open questions at the time
    • Direct molecular link between catalysis and p53 trafficking not defined
    • Differentiation marker control mechanism unclear
  12. 2018 High

    Established ALDH3A1 as a cancer chemoresistance and survival factor across contexts—covalent active-site inhibition (DKM 3-42, EN40) impairs lung cancer pathogenicity, Wnt and PER2 circadian signaling converge on ALDH3A1 to drive resistance via ROS detoxification.

    Evidence Activity-based protein profiling and covalent inhibitors with lung cancer xenografts; porcupine inhibitor/TMZ epistasis with siRNA in glioma; Per2-mutant fibroblasts with shRNA and ROS readouts

    PMID:29854309 PMID:30004670 PMID:30429219

    Open questions at the time
    • Direct regulatory links between Wnt/PER2 and the ALDH3A1 promoter not shown
    • Single-lab pathway placements
  13. 2020 High

    Confirmed in a third species (zebrafish) that ALDH3A1 is the principal in vivo 4-HNE detoxifier, with loss causing 4-HNE accumulation, hyperglycemia, and retinal vascular changes rescuable by L-carnosine.

    Evidence CRISPR-Cas9 knockout zebrafish with reactive carbonyl metabolomics, glucose measurement, transgenic vascular/pancreas reporters, and pharmacological rescue

    PMID:32980661

    Open questions at the time
    • Mechanism linking 4-HNE to pancreatic/retinal phenotypes not fully resolved
    • Mammalian metabolic relevance inferred not demonstrated
  14. 2023 Medium

    Extended the cancer role to metabolic reprogramming, showing hypoxia-induced ALDH3A1 (via AHR/ARNT) promotes glycolysis and suppresses OXPHOS through the HIF-1α/LDHA axis to drive NSCLC proliferation.

    Evidence Hypoxia treatment, ALDH3A1 knockdown/overexpression, glycolysis/OXPHOS assays, pathway Western blots, and xenografts

    PMID:37730658

    Open questions at the time
    • Direct mechanism linking aldehyde dehydrogenase activity to HIF-1α/LDHA not established
    • Single-lab pathway placement
  15. 2025 High

    Defined the transcriptional control and therapeutic exploitation of ALDH3A1 in squamous carcinoma—TP63 drives high expression via a super-enhancer, and covalent inhibition (EN40) enzyme-dependently sensitizes cells to ferroptosis—and uncovered a Cys243-targeting dietary isothiocyanate adduct modulating odorant aldehyde metabolism, plus non-canonical NMN+ cofactor usage.

    Evidence ChIP-seq of TP63, covalent EN40 with ferroptosis/lipid peroxidation assays and SCC organoids/xenografts; crystallography and mass spectrometry of ITC-Cys243 adducts with GC-MS; in vitro kinetics with NMN+ (preprint)

    PMID:39863749 PMID:41672019 PMID:bio_10.1101_2025.08.01.668186

    Open questions at the time
    • Physiological significance of NMN+ cofactor usage not established (preprint)
    • Generality of TP63 regulation across SCC subtypes not fully tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the non-enzymatic functions (UV absorption, chaperone activity, p53 sequestration) are mechanistically coordinated with catalytic aldehyde clearance, and whether targeting ALDH3A1 in cancer can be achieved without compromising its protective corneal/ocular roles, remains unresolved.
  • No structural model linking catalysis to chaperone/UV-filtering functions
  • Tissue-selective therapeutic window not defined
  • Direct molecular partners mediating p53 and NF-κB effects unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0044183 protein folding chaperone 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3
Partners
FBXL12P53TP63

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Recombinant human ALDH3A1 expressed in Sf9 insect cells demonstrates high substrate specificity for medium-chain (≥6 carbon) saturated and unsaturated aldehydes, including 4-hydroxy-2-nonenal (4-HNE); short-chain aldehydes (acetaldehyde, propionaldehyde, malondialdehyde) are very poor substrates. ALDH3A1 does not metabolize glucose-6-phosphate, 6-phosphoglucono-delta-lactone, or 6-phosphogluconate, ruling out roles in glycolysis or the pentose phosphate pathway. Immunohistochemistry localizes ALDH3A1 to corneal epithelial cells and stromal keratocytes, but not endothelial cells. Recombinant protein expression in Sf9 cells, affinity chromatography purification, enzyme kinetics (in vitro assay), immunohistochemistry with monoclonal antibodies The Biochemical journal High 12943535
2001 Stable transfection of ALDH3A1 in V79 cells confers high-level protection against medium-chain aliphatic aldehydes (hexanal, trans-2-hexenal, trans-2-octenal, trans-2-nonenal, 4-HNE) by oxidizing the aldehyde moiety to a carboxyl group, preventing glutathione depletion, HNE-protein adduct formation, and apoptosis. ALDH1A1, by contrast, provides only moderate protection against trans-2-nonenal and none against the other medium-chain aldehydes. Neither isoform protects against acrolein, acetaldehyde, or chloroacetaldehyde. Stable transfection of V79 cells; cell viability, glutathione measurement, apoptosis assay, protein adduct detection; comparison of ALDH3A1 vs ALDH1A1 expressing lines Chemico-biological interactions High 11306050
2003 Stable transfection of human ALDH3A1 in human corneal epithelial (HCE) cells protects against UV- and 4-HNE-induced cytotoxicity and apoptosis. Apoptosis in mock-transfected cells occurs via caspase-3 activation and PARP cleavage; ALDH3A1-expressing cells are protected. ALDH3A1 increases NAD(P)H levels upon 4-HNE treatment (Km for 4-HNE = 54 µM) and prevents 4-HNE-protein adduct formation. Stable transfection in HCE cells; cell viability assay, DNA fragmentation, caspase-3 activation, PARP cleavage by Western blot, NAD(P)H fluorescence, protein adduct detection Free radical biology & medicine High 12706498
2006 Stable transfection of human ALDH3A1 in rabbit corneal fibroblasts (TRK43) protects against H2O2-, mitomycin C-, and etoposide-induced oxidative damage. ALDH3A1 prevents apoptosis, maintains reduced glutathione (GSH) levels and redox balance, and reduces 4-HNE-protein adduct accumulation. Carbonylation of ALDH3A1 itself occurs after oxidative treatment but does not significantly reduce its enzymatic activity. Stable transfection; cell viability, apoptosis assay, GSH measurement, Western blot for 4-HNE adducts, enzymatic activity assay Free radical biology & medicine High 17023273
2006 ALDH3A1 protects other proteins from UV-induced inactivation through two mechanisms: (1) detoxification of reactive aldehydes (4-HNE, malondialdehyde) in the presence of NADP+, thereby protecting glucose-6-phosphate dehydrogenase (G6PDH) from aldehyde-mediated inactivation; and (2) direct UV-energy absorption, shielding other proteins from UVB damage through a competition mechanism. ALDH3A1 undergoes a structural transition at physiological temperatures suggestive of chaperone-like activity, though this transition alone does not account for protection. Co-incubation of purified ALDH3A1 with G6PDH under UVB and aldehyde stress; enzyme activity assays; spectroscopic studies of structural transitions The Journal of biological chemistry High 17158879
2007 Aldh3a1-null mice develop cataracts in anterior and posterior subcapsular regions and punctate cortical opacities by 1 month of age. Double knockout Aldh1a1/Aldh3a1 null mice show the same cataract phenotype with additive severity. Cataract formation is associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased 4-HNE- and malondialdehyde-protein adducts. UVB exposure accelerates lens opacification, more pronounced in Aldh3a1-null than Aldh1a1-null mice. These data demonstrate that corneal ALDH3A1 and lens ALDH1A1 protect the eye against oxidative damage through both nonenzymatic (UV-light filtering) and enzymatic (aldehyde detoxification) functions. Knockout mouse model (single and double KO); ocular phenotyping, proteasome activity assay, oxidized protein measurement, 4-HNE/MDA adduct Western blot, UVB exposure challenge The Journal of biological chemistry High 17567582
2010 UV-light causes non-native aggregation of ALDH3A1 via both covalent and non-covalent interactions, leading to loss of enzymatic activity. Spectroscopic analysis shows secondary and tertiary structure perturbation upon aggregation. MALDI-TOF mass spectrometry of LysC peptides reveals UV-induced chemical modifications to Trp, Met, and Cys residues, but the conserved active-site Cys remains intact after UV exposure that completely inactivates the enzyme, indicating that UV-induced inactivation results from aggregation/structural changes rather than direct active-site damage. UV irradiation of purified recombinant ALDH3A1; enzyme activity assay, spectroscopy (secondary/tertiary structure), MALDI-TOF mass spectrometry peptide mapping PloS one High 21203538
2012 ALDH3A1 overexpression in rabbit corneal keratocytes (TRK43) protects cells from 4-HNE toxicity by: metabolizing 4-HNE and its glutathione conjugate, preventing 4-HNE-protein adduct formation, preventing apoptosis, maintaining glutathione homeostasis, and preserving proteasome function. Stable transfection; cell viability, morphology, Western blot for 4-HNE adducts, apoptosis assay, GSH measurement, proteasome activity assay Free radical biology & medicine High 22406320
2014 A selective submicromolar ALDH3A1 inhibitor, CB7 (1-[(4-fluorophenyl)sulfonyl]-2-methyl-1H-benzimidazole; IC50 0.2 µM), binds within the aldehyde substrate-binding pocket of ALDH3A1, as established by structural crystallography, kinetics, and mutagenesis. CB7 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2. Sensitization of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cells to mafosfamide occurs in the presence of CB7, while primary lung fibroblasts lacking ALDH3A1 are unaffected. X-ray crystallography (structure of inhibitor-bound ALDH3A1), enzyme kinetics, site-directed mutagenesis, cell proliferation assay Journal of medicinal chemistry High 24387105
2014 A selective ALDH3A1 inhibitor, CB29, binds within the aldehyde substrate-binding site of ALDH3A1 as shown by kinetics and crystallography, and enhances mafosfamide sensitivity in ALDH3A1-expressing A549 and SF767 tumor cells but not in ALDH3A1-negative CCD-13Lu fibroblasts. CB29 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 at up to 250 µM. X-ray crystallography, enzyme kinetics, cell proliferation assay Chembiochem : a European journal of chemical biology High 24677340
1999 The Aldh3a1 gene is regulated by the aromatic hydrocarbon receptor (AhR): at least four functional aromatic hydrocarbon response elements (AHREs) in the 5' flanking region act cooperatively to mediate dioxin (TCDD)-induced upregulation. A putative negative regulatory element (NRE) controls basal expression independently of dioxin inducibility. TCDD-mediated upregulation in Hepa-1c1c7 cells depends exclusively on the AhR. Deletion reporter gene constructs (CAT/luciferase) transiently transfected in mouse hepatoma cells; genomic cloning and sequencing; AhR-dependence assessed with AhR-deficient mutant cells Pharmacogenetics High 10591537
1999 The Aldh3a1c allele in SWR/J mice encodes a low-activity ALDH3A1 variant due to four amino acid substitutions (G88R, I154N, H305R, I352V). The I154N disrupts a potential alpha-helix in the Rossmann fold; H305R affects a beta-strand and likely directly impacts catalytic activity. Loss of ALDH3A1 activity in SWR/J mice is associated with extensive corneal clouding after UV exposure. RT-PCR and sequencing of cDNA; enzyme activity assay; comparison of allelic variants across inbred strains; UV challenge in vivo Pharmacogenetics Medium 10376761
2003 UVB radiation at ≥0.2 J/cm2 reduces corneal ALDH3A1 mRNA and protein levels (~80%) and enzymatic activity in C57BL/6J mice (transcriptional and/or post-translational downregulation). Lower doses (0.05–0.1 J/cm2) reduce enzymatic activity without altering mRNA or protein, indicating post-translational modification. In vitro experiments with purified recombinant ALDH3A1 show that UVR causes both covalent and non-covalent protein aggregation without detectable precipitation. Northern blot, Western blot, enzyme activity assay in mouse corneas; in vitro aggregation assay with purified recombinant ALDH3A1; dose-response UV exposure Chemico-biological interactions Medium 12604188
2015 A small molecule, Alda-89, enables ALDH3A1 to metabolize acetaldehyde—a substrate it normally does not efficiently process. In vivo, Alda-89 combined with the ALDH2 activator Alda-1 reduces blood ethanol and acetaldehyde levels and decreases acetaldehyde-induced behavioral impairment in both wild-type and ALDH2*1/*2 heterozygous knock-in mice after acute ethanol intoxication. Pharmacological activation with small molecule (Alda-89); blood ethanol/acetaldehyde measurement; behavioral assay in wild-type and ALDH2*2 knock-in mice Proceedings of the National Academy of Sciences of the United States of America High 25713355
2016 ALDH3A1 decreases corneal epithelial cell proliferation through both enzymatic and non-enzymatic mechanisms. Inducible expression of wild-type (wt) but not catalytically-inactive (mu) ALDH3A1 promotes nuclear sequestration of tumor suppressor p53. In vivo, augmented proliferation is seen only in Aldh1a1/Aldh3a1 double-knockout mice (not Aldh3a1 single KO), and these hyper-proliferative corneas show near-complete loss of p53 expression. ALDH3A1 expression also modulates corneal differentiation markers. Tet-On inducible cell line expressing wt or catalytically-inactive ALDH3A1; BrdU proliferation assay; p53 nuclear localization by immunofluorescence; Aldh1a1/Aldh3a1 double-KO mouse cornea phenotyping; differentiation marker mRNA analysis PloS one High 26751691
2017 Recombinant human ALDH3A1 exhibits molecular chaperone-like activity in vitro, protecting SmaI restriction enzyme and citrate synthase from thermal stress-induced precipitation and inactivation. Overexpression of ALDH3A1 in E. coli confers resistance to thermal shock. ALDH3A1 overexpression in human corneal HCE-2 cells protects against H2O2- and tert-butyl hydroperoxide-induced cytotoxicity. In vitro chaperone assay with purified recombinant ALDH3A1 and model substrates (thermal aggregation assay); bacterial thermal shock survival; cell viability assay in HCE-2 cells The international journal of biochemistry & cell biology Medium 28526614
2018 Activity-based protein profiling (chemoproteomics) identified the catalytic cysteine of ALDH3A1 as the primary cellular target of covalent ligand DKM 3-42, which impairs lung cancer cell survival. A more potent and selective lead covalent inhibitor EN40, identified through direct ALDH3A1-targeted chemoproteomic screening, inhibits ALDH3A1 activity and impairs lung cancer pathogenicity both in situ and in vivo. Activity-based protein profiling (ABPP); covalent ligand library screen; in vitro ALDH3A1 activity assay; lung cancer cell viability and tumor xenograft (in vivo) ACS chemical biology High 30004670
2018 Pharmacological inhibition of the Wnt pathway (porcupine inhibitor LGK974) synergistically suppresses glioma cell growth with temozolomide; transcriptomic analysis revealed ALDH3A1 expression is significantly downregulated by this combination. Knockdown of ALDH3A1 alone increases TMZ efficacy and reduces clonogenic potential, indicating that Wnt signaling-mediated chemoresistance is at least partly mediated through ALDH3A1. Porcupine inhibitor treatment, TMZ combination; transcriptomic analysis; ALDH3A1 siRNA knockdown; clonogenic assay; stem cell marker expression Oncotarget Medium 29854309
2015 FBXL12, an F-box protein forming an SCF ubiquitin E3 ligase, interacts specifically with members of the ALDH3 family and mediates their polyubiquitylation, leading to proteasomal degradation. FBXL12 deficiency causes ALDH3 accumulation in placenta and impairs trophoblast stem cell differentiation. Forced expression of ALDH3 in wild-type trophoblast stem cells phenocopies the FBXL12-deficient differentiation defect; inhibition of ALDH3 activity by gossypol rescues the phenotype of FBXL12 deficiency. Co-immunoprecipitation (FBXL12-ALDH3 interaction); polyubiquitylation assay; FBXL12 knockout mice; forced ALDH3 overexpression in TSCs; gossypol pharmacological rescue Stem cells (Dayton, Ohio) High 26124079
2018 Mutation of the circadian clock component Per2 in oncogene-transformed mouse embryonic fibroblasts leads to ~7-fold elevated ALDH3A1 protein levels compared to wild-type oncogene-transformed cells. Elevated ALDH3A1 prevents chemotherapeutic drug-induced accumulation of reactive oxygen species, conferring resistance to methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin. shRNA-mediated suppression of Aldh3a1 relieves this chemoresistance. Per2-mutant mouse embryonic fibroblasts; Western blot for ALDH3A1; ROS measurement; cell viability with chemotherapy agents; shRNA knockdown of Aldh3a1 The Journal of biological chemistry Medium 30429219
2006 Arachidonic acid-induced growth suppression of A549 lung tumor cells is associated with reduced ALDH3A1 enzymatic activity, protein, and mRNA levels and increased lipid peroxidation. Activation of PPARγ mediates this downregulation; blockade of PPARγ with antagonist GW9662 prevents the arachidonic acid-mediated reduction of ALDH3A1 expression and the growth inhibition. PPARγ activation and ALDH3A1 reduction are also prevented by vitamin E co-treatment. Arachidonic acid treatment of A549 cells; PPARγ antagonist (GW9662) pharmacological blockade; vitamin E co-treatment; ALDH3A1 enzyme activity, protein, and mRNA measurement; NF-κB binding assay Free radical biology & medicine Medium 16716894
2020 In aldh3a1-/- zebrafish larvae generated by CRISPR-Cas9, 4-HNE (but not methylglyoxal) accumulates, demonstrating that Aldh3a1 is the primary detoxifier of 4-HNE in vivo. 4-HNE accumulation disrupts pancreas morphology, impairs glucose homeostasis, and causes retinal vasodilatory alterations. The retinal and hyperglycemic phenotype can be rescued by L-Carnosine treatment. CRISPR-Cas9 knockout zebrafish; reactive carbonyl species measurement; glucose measurement; zebrafish transgenic reporter lines for vasculature and pancreas; transcriptomics; metabolomics; ALDH activity assay; pdx1 silencing epistasis Redox biology High 32980661
2023 In NSCLC, hypoxia induces ALDH3A1 expression via the AHR/ARNT pathway; ALDH3A1 promotes cell proliferation by enhancing glycolysis and suppressing OXPHOS through activation of the HIF-1α/LDHA pathway. β-elemene downregulates ALDH3A1, inhibiting glycolysis and enhancing OXPHOS to suppress NSCLC proliferation in vitro and in vivo. Hypoxia cell treatment; ALDH3A1 knockdown/overexpression; glycolysis and OXPHOS measurement; HIF-1α/LDHA pathway Western blot; β-elemene treatment; xenograft mouse model Cell death & disease Medium 37730658
2025 EN40 (covalent ALDH3A1 inhibitor targeting the catalytic cysteine) significantly enhances ferroptosis sensitivity in squamous cell carcinoma cells by its enzymatic activity-dependent inhibition of aldehyde catabolism and mitigation of lipid peroxidation. High ALDH3A1 expression in SCC is transcriptionally governed by TP63, which binds to a super-enhancer of ALDH3A1. The combination of EN40 and a ferroptosis inducer synergistically inhibits SCC proliferation in vitro and tumor growth in vivo. Covalent inhibitor (EN40) treatment; ferroptosis assay; lipid peroxidation measurement; ALDH3A1 overexpression/knockdown; ChIP-seq for TP63 binding to ALDH3A1 super-enhancer; SCC organoid and xenograft models Oncogene High 39863749
2024 Mechanical strain (3%) applied to human keratocytes upregulates ALDH3A1 expression, which suppresses NF-κB nuclear translocation and reduces keratocyte proliferation and migration. ALDH3A1 knockdown promotes NF-κB nuclear translocation and enhances proliferation and migration. Elevated ALDH3A1 is also observed in mouse corneal injury models and in keratoconus patient keratocytes. Flexcell Tension System (3% strain); RT-qPCR and Western blot for ALDH3A1; RNAi knockdown; NF-κB nuclear translocation by immunofluorescence; BrdU proliferation and scratch wound healing assay; mouse injury model; single-cell RNA-seq of keratoconus patient keratocytes FASEB journal Medium 39652089
1985 Human ALDH3 (ALDH3A1) gene is assigned to chromosome 17 using human-rodent hybrid cells. The enzyme shows optimal activity with benzaldehyde and can utilize either NAD or NADP as cofactor. It is expressed at highest levels in lung and stomach, with no expression in fetal tissues, blood, hair roots, or fibroblasts. Human-rodent somatic cell hybrids; enzyme activity assay; antiserum immunoprecipitation; chromosome assignment Annals of human genetics Medium 4073832
2025 Bos taurus ALDH3A1 exhibits unprecedented turnover with the non-canonical redox cofactor nicotinamide mononucleotide (NMN+), with kcat values matching or exceeding that of NAD+. A conserved RH/QxxR sequence motif in ALDH3A1 reinforces cofactor positioning and pre-organizes the active site without dependence on the adenosine monophosphate moiety of NAD+. Structural and dynamic analyses support this mechanism. In vitro enzyme kinetics (NMN+ and NAD+ comparison); structural analysis; sequence motif analysis; introduction of RH/QxxR motif into other ALDH scaffolds bioRxiv (preprint)preprint Medium bio_10.1101_2025.08.01.668186
2026 Dietary isothiocyanates (ITCs), specifically allyl-isothiocyanate, form a covalent adduct with the catalytic Cys243 residue of salivary ALDH3A1, causing irreversible inhibition. This inhibition, confirmed by X-ray crystallography and mass spectrometry, disrupts metabolic conversion of odorant aldehydes in saliva, modulating aroma release as confirmed by GC-MS. Enzymology (in vitro inhibition kinetics); X-ray crystallography of ITC-ALDH3A1 adduct; mass spectrometry; GC-MS analysis of odorant metabolites; ex vivo saliva assay Food chemistry High 41672019
2001 ALDH3A1 expression is constitutively elevated in stable MCF-7 breast cancer sublines due to constitutively upregulated transcription driven by transactivated electrophile responsive elements (EpREs) in the 5'-upstream region of the ALDH3A1 gene. Elevated ALDH3A1 mRNA is not due to gene amplification, DNA hypomethylation, or mRNA stabilization, pointing to altered EpRE signaling as the mechanism. RT-PCR for ALDH3A1 mRNA; Southern blot for gene amplification; methylation analysis; mRNA stability assay; comparison of MCF-7 sublines selected with oxazaphosphorines or polycyclic aromatic hydrocarbons Chemico-biological interactions Medium 11306049

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 156 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 101 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 70 30333913
2017 Silencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells. Antioxidants (Basel, Switzerland) 65 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 56 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 52 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
2023 Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming. Cell death & disease 48 37730658
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
2020 Elevated 4-hydroxynonenal induces hyperglycaemia via Aldh3a1 loss in zebrafish and associates with diabetes progression in humans. Redox biology 46 32980661
2012 Molecular mechanisms of ALDH3A1-mediated cellular protection against 4-hydroxy-2-nonenal. Free radical biology & medicine 45 22406320
2018 Chemoproteomics-Enabled Covalent Ligand Screening Reveals ALDH3A1 as a Lung Cancer Therapy Target. ACS chemical biology 42 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
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 24 30429219
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
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 23 33294267
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
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 18 11306049
2017 Human aldehyde dehydrogenase 3A1 (ALDH3A1) exhibits chaperone-like function. The international journal of biochemistry & cell biology 16 28526614
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
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 6 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
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 4 39652089
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
2026 A viral-host redox axis: EBNA1-FOSL2-ALDH3A1 defines a targetable vulnerability in EBV-positive carcinomas. Redox biology 1 41564796
2025 Association of ALDH3A1 expression with tumor differentiation, pathological stage, and nodal status in oral squamous cell carcinoma. Journal of Taibah University Medical Sciences 1 40657474
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 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 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

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