Affinage

ALDH1A3

Retinaldehyde dehydrogenase 3 · UniProt P47895

Length
512 aa
Mass
56.1 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 38 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

ALDH1A3 is an NAD+-dependent retinaldehyde dehydrogenase that oxidizes retinaldehyde to retinoic acid and, through this activity, drives retinoic acid-dependent developmental patterning of the eye, inner ear, and ventral forebrain (PMID:11025231, PMID:11044606, PMID:17207476). It is expressed selectively in ventral retina, otic vesicle, and olfactory pit during embryogenesis, where its retinoic acid output is required for ventral forebrain RA signaling and dopamine receptor D2 expression (PMID:11025231, PMID:11044606, PMID:17207476). Loss-of-function mutations in ALDH1A3 cause human autosomal recessive anophthalmia/microphthalmia, with pathogenic alleles acting predominantly through reduced protein accumulation and impaired tetramer formation rather than loss of intrinsic catalysis (PMID:23312594, PMID:23591992, PMID:23646827, PMID:23881059, PMID:28590501); the developmental requirement is conserved, as aldh1a3 knockdown reduces eye size in zebrafish (PMID:23591992). Beyond its developmental role, ALDH1A3 is the dominant ALDH isoform underlying ALDH activity in breast cancer, glioma, and cardiac progenitor stem-cell populations and sustains their self-renewal and tumorigenicity (PMID:21280157, PMID:30087899). A nuclear, non-canonical function couples metabolism to chromatin: nuclear ALDH1A3 oxidizes acetaldehyde to acetate, generating acetyl-CoA — in partnership with the acetyl-CoA synthetase ACSS2 — that fuels H3K27/histone H3 acetylation at enhancers and promoters of cell-cycle, metabolic, and lineage genes, a mechanism required for smooth muscle proliferation in pulmonary hypertension, melanoma neural-crest gene programs, and ovarian and pancreatic cancer transcriptional networks (PMID:33764154, PMID:38963759, PMID:38211842, PMID:40781158). ALDH1A3 also acts independently of catalysis through direct protein interactions, binding and stabilizing PKM2 to promote aerobic glycolysis and, via enhanced PKM2 tetramerization and lactate production, driving lactylation-dependent nuclear import of XRCC1 and DNA-repair-mediated therapy resistance (PMID:33419984, PMID:39111285). Its abundance is set post-translationally by USP9X-mediated deubiquitination that stabilizes the protein and by p62/autophagy-mediated degradation (PMID:30958800, PMID:29306018), transcriptionally by FOXD1, CEBPβ (downstream of a STAT3-NFκB-DDIT3 axis), HIF-1α, PPARγ, the androgen receptor, and the chromatin remodeler CHD7 (PMID:27569208, PMID:25868979, PMID:38211842, PMID:29873276, PMID:17526768, PMID:29467333), and at the RNA level by Sam68-dependent suppression of intronic polyadenylation that permits full-length transcript expression (PMID:27845622). A crystal structure of human ALDH1A3 has enabled active-site-directed competitive inhibitors that phenocopy genetic loss (PMID:34934174).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Establishing ALDH1A3 as a discrete aldehyde dehydrogenase isozyme with defined gene structure and tissue distribution provided the molecular foundation for all subsequent functional study.

    Evidence cDNA cloning, Northern blot, and FISH chromosomal mapping

    PMID:7698756

    Open questions at the time
    • Did not define the physiological substrate or enzymatic specificity
    • No developmental or disease role assigned
  2. 2000 High

    Identifying retinaldehyde as the substrate and retinoic acid as the product, with spatially restricted embryonic expression, defined ALDH1A3 as a region-specific generator of the morphogen retinoic acid.

    Evidence cDNA cloning, in vitro enzymatic activity assay, in situ hybridization in mouse and chick embryos, Pax6 mutant analysis

    PMID:11025231 PMID:11044606

    Open questions at the time
    • Did not establish in vivo developmental requirement
    • Upstream regulators beyond Pax6 unresolved
  3. 2006 High

    Loss-of-function genetics demonstrated that ALDH1A3-derived retinoic acid is required for ventral forebrain patterning, moving the gene from a marker to a causal developmental signal.

    Evidence Raldh2/Raldh3 single and double null mouse epistasis with RA reporter and in situ readouts

    PMID:17207476

    Open questions at the time
    • Downstream transcriptional targets of RA in forebrain not fully mapped
  4. 2013 High

    Human genetics and zebrafish modeling established ALDH1A3 as a cause of autosomal recessive anophthalmia/microphthalmia, linking enzyme deficiency to congenital eye malformation.

    Evidence Homozygosity mapping, exome sequencing, mutant protein expression assays, in vitro enzymatic assay, zebrafish morpholino knockdown

    PMID:23312594 PMID:23591992 PMID:23646827 PMID:23881059

    Open questions at the time
    • Not all mutations impair catalysis (p.Val71Met retained activity), implicating stability/folding
    • Exact developmental window of pathogenesis unresolved
  5. 2016 Medium

    Native gel analysis of mutant alleles showed that pathogenic mutations impair tetrameric assembly and protein production, clarifying that protein stability, not always catalysis, underlies disease.

    Evidence In vitro expression and tetramer formation assays of mutant alleles

    PMID:28590501

    Open questions at the time
    • Quaternary structure requirement not tested in vivo
    • Folding chaperone or degradation pathway for unstable mutants not identified
  6. 2011 High

    Isoform-specific knockdown revealed ALDH1A3 as the principal contributor to the ALDH activity that marks cancer stem cells, recasting the enzyme as a stem-cell functional determinant.

    Evidence Genome microarray, shRNA knockdown, Aldefluor assay across breast cancer cell lines and patient CSCs

    PMID:21280157

    Open questions at the time
    • Mechanism linking ALDH activity to stemness not defined at this stage
  7. 2016 High

    Multiple regulatory inputs were mapped — transcriptional control by FOXD1 and a STAT3-NFκB-DDIT3-CEBPβ axis, and RNA-level control by Sam68-dependent suppression of intronic polyadenylation — explaining how ALDH1A3 levels are tuned in stem and cancer cells.

    Evidence shRNA/RNAi, promoter and luciferase reporter assays, ChIP, co-IP, Khdrbs1 knockout mouse with pre-mRNA 3'-processing assays

    PMID:25868979 PMID:27569208 PMID:27845622

    Open questions at the time
    • Combinatorial integration of these regulators in a given tissue unresolved
    • Sam68-ALDH1A3 axis tested mainly in neural progenitors
  8. 2018 High

    Post-translational control was established through p62/autophagy-mediated degradation and CHD7-mediated transcriptional repression, expanding the regulatory layers governing ALDH1A3 abundance.

    Evidence Co-IP (ALDH1A3-p62), mRNA-vs-protein comparison, autophagy modulation; CHD7 chromatin binding and Chd7/Aldh1a3 double-mutant mouse rescue

    PMID:29306018 PMID:29467333

    Open questions at the time
    • E3 ligase upstream of autophagic turnover not identified
    • Direct vs indirect CHD7 repression mechanism only partly resolved
  9. 2019 High

    USP9X was identified as a deubiquitinase that stabilizes ALDH1A3, establishing the ubiquitin-proteasome counterbalance to its degradation and a node sustaining glioblastoma stem-cell self-renewal.

    Evidence Reciprocal co-IP, depolyubiquitylation assays, USP9X depletion with ALDH1A3 rescue, orthotopic xenografts, USP9X inhibitor

    PMID:30958800

    Open questions at the time
    • The opposing E3 ubiquitin ligase remains unidentified
    • Whether USP9X regulation is tissue-restricted unknown
  10. 2021 High

    The discovery that nuclear ALDH1A3 converts acetaldehyde to acetate to generate acetyl-CoA for histone H3K27 acetylation revealed a moonlighting metabolic-epigenetic function distinct from retinoic acid signaling.

    Evidence Nuclear fractionation, metabolic flux analysis, H3K27ac and NFYA ChIP, KAT2B acetyltransferase assay, SMC-specific Aldh1a3 knockout mouse in hypoxia

    PMID:33764154

    Open questions at the time
    • Determinants of nuclear vs cytoplasmic ALDH1A3 partitioning not defined
    • Generality across cell types established only later
  11. 2021 High

    Structure-guided inhibitor development produced a selective active-site competitive inhibitor that phenocopies ALDH1A3 knockout, providing a chemical tool and validating the active site as a target.

    Evidence Human ALDH1A3 crystal structure, in silico modeling, competitive inhibition assay, CETSA target engagement, knockout comparison

    PMID:34934174

    Open questions at the time
    • Inhibitor does not address non-catalytic protein-interaction functions
  12. 2021 Medium

    Identification of a direct ALDH1A3-PKM2 interaction that stabilizes PKM2 and promotes aerobic glycolysis revealed a non-enzymatic, scaffolding role in tumor metabolism.

    Evidence Co-IP/mass spectrometry, PKM2 ubiquitination assay, glycolysis assays, siRNA knockdown in colorectal cancer cells

    PMID:33419984

    Open questions at the time
    • Interaction interface and whether catalysis is required not defined
    • Single cancer context
  13. 2024 High

    Mechanistic dissection extended the nuclear acetyl-CoA/ACSS2 axis to melanoma lineage and ovarian/pancreatic cancer transcriptional networks, and connected the PKM2 interaction to lactate-driven XRCC1 lactylation and DNA-repair-mediated therapy resistance.

    Evidence Nuclear fractionation, ChIP for acetyl-H3/H3K27ac, metabolic flux, lactylated-proteome MS, XRCC1-importinα binding, zebrafish melanoma model, small-molecule disruptors

    PMID:38211842 PMID:38963759 PMID:39111285 PMID:40781158

    Open questions at the time
    • Quantitative contribution of nuclear vs cytosolic acetyl-CoA pools unresolved
    • How a single enzyme coordinates metabolic and chromatin functions in vivo not fully resolved
  14. 2023 High

    ALDH1A3 was implicated in beta-cell dedifferentiation, with inhibition reconverting dedifferentiated beta-cells to functional mature cells, revealing a role in cellular identity beyond cancer and development.

    Evidence Genetic ablation, lineage tracing, selective pharmacological inhibition, glycemia and insulin secretion assays in diabetic mice

    PMID:36732513

    Open questions at the time
    • Whether the metabolic-epigenetic or RA function drives dedifferentiation not separated
    • Mechanism of reversal incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALDH1A3's three modes — retinoic acid synthesis, nuclear acetyl-CoA generation for histone acetylation, and catalysis-independent protein stabilization of PKM2 — are partitioned and coordinated within a single cell remains unresolved.
  • No determinant identified that controls nuclear vs cytoplasmic localization
  • Relative weighting of enzymatic vs scaffolding functions across tissues unknown
  • No integrated structure-function model linking tetramerization, catalysis, and protein interactions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1430728 Metabolism 5 R-HSA-4839726 Chromatin organization 4 R-HSA-1643685 Disease 2
Partners
ACSS2KHDRBS1PKM2SQSTM1USP9X

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 RALDH3 (ALDH1A3) functions as a retinaldehyde dehydrogenase, catalyzing the oxidation of retinaldehyde to retinoic acid, and is expressed specifically in the ventral retina, otic vesicle, and olfactory pit during mouse embryonic development, with expression pattern distinct from RALDH1 and RALDH2. cDNA cloning, in situ hybridization, expression pattern analysis in mouse embryos Mechanisms of development High 11025231 11044606
1994 ALDH6 (ALDH1A3) encodes a 512 amino acid aldehyde dehydrogenase isozyme expressed highly in salivary gland, stomach, and kidney, and maps to chromosome 15q26; the gene spans ~37 kb with 13 exons. cDNA cloning, Northern blot analysis, fluorescence in situ hybridization for chromosomal localization Genomics High 7698756
2000 RALDH-3 (ALDH1A3) is the chick ortholog of human ALDH6, is specifically expressed in the ventral retina, and shows enzymatic activity to produce retinoic acid from retinaldehyde; its expression in the ventral retina is dependent on Pax6 transcription factor. Restriction landmark cDNA scanning, enzymatic activity assay, in situ hybridization, Pax6 mutant analysis Mechanisms of development High 11044606
2006 Raldh3 expression in the subventricular zone of the lateral ganglionic eminence (LGE) is required for retinoic acid signaling in the ventral forebrain; Raldh3 null mice lack RA signaling in the ventral forebrain and show essentially eliminated dopamine receptor D2 expression in the developing nucleus accumbens. Genetic epistasis using Raldh2/Raldh3 single and double null mouse mutants, RA signaling reporter assays, in situ hybridization Developmental biology High 17207476
2007 ALDH1A3 is an androgen-responsive gene in prostate cancer LNCaP cells: dihydrotestosterone (DHT) induces a ~4-fold increase in ALDH1A3 mRNA via the androgen receptor (AR) nuclear-translocation cascade, and DHT-upregulated ALDH1A3 increases retinaldehyde-dependent NAD+ reduction ~8-fold, leading to increased retinoic acid biosynthesis. qRT-PCR, siRNA knockdown of AR, pharmacologic inhibition of AR (bicalutamide) and kinases (PD98059, PP1), enzymatic activity assay (retinaldehyde-dependent NAD+ reduction), CYP26A1 mRNA induction Experimental biology and medicine High 17526768
2011 ALDH activity of breast cancer stem cells is primarily attributable to ALDH1A3 expression, not ALDH1A1; shRNA knockdown of ALDH1A3 (but not other isoforms) uniformly reduces ALDH activity in breast cancer cells. Genome microarray expression, immunofluorescence, qPCR, shRNA knockdown, Aldefluor assay Stem cells (Dayton, Ohio) High 21280157
2013 Loss-of-function mutations in ALDH1A3 cause autosomal recessive anophthalmia/microphthalmia in humans; missense mutations reduce accumulation of the enzyme, likely leading to altered retinoic acid synthesis during eye development. Homozygosity mapping, exome sequencing, Sanger sequencing, transitory expression of mutant ALDH1A3 ORFs to assess protein accumulation American journal of human genetics High 23312594 23591992 23646827 23881059
2013 Morpholino-mediated knockdown of aldh1a3 in zebrafish causes significant reduction in eye size and aberrant axonal projections to the tectum, confirming a conserved role in eye development. Antisense morpholino injection in Danio rerio, eye size measurement, axonal projection analysis Human molecular genetics Medium 23591992
2013 A missense mutation (p.Val71Met) in ALDH1A3 associated with isolated anophthalmia/microphthalmia showed no change in enzymatic activity in vitro, suggesting the pathogenic mechanism may involve altered protein stability or localization rather than catalytic impairment. In vitro enzymatic activity assay of wild-type vs. mutant ALDH1A3 protein European journal of human genetics Medium 23881059
2015 A pSTAT3(tyr705)-NFkB(p65) complex represses DDIT3 mRNA, which ensures high CEBPβ-dependent ALDH1A3 promoter activity; inhibition of this STAT3-NFkB axis allows DDIT3 expression, which forms a DDIT3-CEBPβ complex that reduces CEBPβ occupancy at the ALDH1A3 promoter, thereby reducing ALDH1A3 expression in chemoresistant mesothelioma cells. RNAi, promoter activity assays, ChIP, co-immunoprecipitation, in vivo xenograft models Oncotarget Medium 25868979
2016 FOXD1 transcription factor directly regulates the transcriptional activity of ALDH1A3 in mesenchymal glioma stem cells (MES GSC); shRNA attenuation of FOXD1 ablates ALDH1A3-dependent clonogenicity in vitro and in vivo. shRNA knockdown, in vitro clonogenicity assays, in vivo xenograft models, RNAi in Drosophila brain tumor model (genetic conservation), luciferase reporter for ALDH1A3 transcription Cancer research Medium 27569208
2016 Sam68 (KHDRBS1) RNA-binding protein binds to an intronic polyadenylation site in Aldh1a3 pre-mRNA, preventing premature transcript termination and enabling expression of full-length functional ALDH1A3 enzyme; loss of Sam68 reduces ALDH1A3 expression and activity, leading to reduced glycolysis and clonogenicity in neural progenitor cells. Khdrbs1 knockout mouse, pre-mRNA 3'-end processing assay, clonogenicity, glycolysis assays, RNA-binding protein binding experiments eLife High 27845622
2017 ALDH1A3 regulates transcriptional expression of tissue transglutaminase (tTG) via its retinoic acid (RA) biosynthesis activity in mesenchymal glioma stem cells; enzymatic activity of ALDH1A3 and its product RA are necessary for tTG expression, and ectopic ALDH1A3 expression in proneural GSCs is sufficient to induce tTG. shRNA/siRNA knockdown, ectopic ALDH1A3 expression, RA supplementation rescue experiments, inhibitor treatment Oncotarget Medium 28423611
2018 CHD7 (an ATP-dependent chromatin remodeler) directly binds and represses the Aldh1a3 gene in the inner ear; loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects, placing CHD7 upstream of ALDH1A3 in a common genetic pathway regulating inner ear development. CHD7 chromatin binding assays, Chd7/Aldh1a3 double mutant genetic epistasis in mice, inner ear phenotypic rescue analysis JCI insight High 29467333
2018 ALDH1A3 protein is regulated post-translationally by autophagy: ALDH1A3 physically interacts with p62 (sequestosome 1/SQSTM1), an autophagosome adaptor protein, and temozolomide-induced autophagy leads to ALDH1A3 protein downregulation without affecting mRNA levels. Co-immunoprecipitation (ALDH1A3-p62 interaction), Western blot, qPCR (mRNA vs protein level comparison), autophagy induction/inhibition Cancer letters Medium 29306018
2019 USP9X (ubiquitin-specific protease 9X) acts as a bona fide deubiquitinase of ALDH1A3 in mesenchymal glioblastoma stem cells: USP9X interacts with ALDH1A3, depolyubiquitylates it, and stabilizes the protein; depletion of USP9X downregulates ALDH1A3, causing loss of self-renewal and tumorigenicity that can be rescued by ectopic ALDH1A3 expression. Co-immunoprecipitation, ubiquitination assays (depolyubiquitylation), USP9X depletion + ALDH1A3 rescue experiments, orthotopic xenograft models, USP9X inhibitor (WP1130) treatment The Journal of clinical investigation High 30958800
2019 ALDH1A3 regulates expression of lncRNA NRAD1 through retinoic acid signaling; NRAD1 is primarily nuclear-localized and functions downstream of ALDH1A3 to regulate gene expression via chromatin interactions, mediating part of ALDH1A3's effects on cancer stem cell gene expression. Cellular fractionation (nuclear localization), transcriptome profiling, ChIRP-seq (chromatin isolation by RNA purification + sequencing), antisense oligonucleotide knockdown, ALDH1A3 knockdown with NRAD1 measurement Cell death and differentiation Medium 31197235
2019 ALDH1A3 promotes vascular smooth muscle cell (VSMC) proliferation at least partially through upregulation of matricellular proteins TNC1 and ESM1, which activate AKT/mTOR and/or MEK/ERK pathways; ALDH1A3 silencing abolishes PDGF(BB)-stimulated VSMC total ALDH activity and proliferation. siRNA knockdown, ALDH activity assay, proliferation assay, pathway inhibition, in vivo angioplasty rat carotid model with ALDH inhibitor disulfiram iScience Medium 31513972
2010 Raldh3 (ALDH1A3) overexpression reduces insulin secretion from β-cells (MIN6) and increases glucagon secretion from α-cells (αTC1 clone 9); knockdown of Raldh3 decreases glucagon secretion; 13-cis retinoic acid (the product of Raldh3 catalysis of 13-cis retinal) reduces cell viability specifically in MIN6 and αTC1 cells. Overexpression, siRNA knockdown, insulin/glucagon secretion assays, 13-cis retinoic acid treatment, cell viability assays in multiple cell lines Biochemical and biophysical research communications Medium 20833146
2021 Nuclear ALDH1A3 in pulmonary arterial smooth muscle cells (PASMC) converts acetaldehyde to acetate, producing acetyl-CoA that acetylates histone H3K27 at active enhancers; this enables KAT2B acetyltransferase-mediated chromatin modification at NFYA binding sites and NFY-mediated transcription of cell cycle and metabolic genes required for SMC proliferation and glycolysis. Mice with SMC-specific Aldh1a3 deletion did not develop hypoxia-induced pulmonary arterial muscularization or pulmonary hypertension. RNA sequencing, nuclear fractionation and localization, metabolic flux analysis (acetaldehyde→acetate→acetyl-CoA), H3K27 acetylation ChIP, KAT2B acetyltransferase assays, NFYA ChIP, SMC-specific Aldh1a3 knockout mouse (hypoxia model), siRNA knockdown Circulation High 33764154
2021 ALDH1A3 stabilizes PKM2 by reducing its ubiquitination, thereby promoting aerobic glycolysis (Warburg effect) in colorectal cancer cells; ALDH1A3 and PKM2 interact as identified by co-immunoprecipitation followed by mass spectrometry. Co-immunoprecipitation with mass spectrometry (PKM2 identification), ubiquitination assay (PKM2 stabilization), glycolysis assays, siRNA knockdown Oncogenesis Medium 33419984
2021 A selective, competitive inhibitor (MCI-INI-3) targeting the active site of human ALDH1A3 was developed using the crystal structure of ALDH1A3; mass spectrometry-based cellular thermal shift analysis confirmed ALDH1A3 as the primary cellular binding protein; MCI-INI-3 inhibits retinoic acid biosynthesis comparably to ALDH1A3 knockout. Crystal structure of human ALDH1A3, in silico modeling, in vitro competitive inhibition assay, mass spectrometry-based cellular thermal shift assay (CETSA), ALDH1A3 knockout comparison Communications biology High 34934174
2021 ALDH1A3 is the key isoform responsible for ALDH activity in cardiac atrial appendage progenitor cells; ALDH1A3 knockdown (but not ALDH1A1, ALDH1A2, ALDH2, ALDH4A1, or ALDH8A1) decreases ALDH activity and cell proliferation, while ALDH1A3 overexpression increases proliferation in ALDHlo cells. siRNA knockdown of individual ALDH isoforms, Aldefluor activity assay, retroviral overexpression, cell proliferation assay Frontiers in cardiovascular medicine Medium 30087899
2023 Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion; lineage tracing shows that ALDH1A3-positive β-cells (dedifferentiated) can be reconverted to functional mature β-cells upon ALDH1A3 inhibition, and ALDH1A3 inhibition reactivates differentiation and regeneration pathways. Somatic ALDH1A3 ablation (genetic), lineage tracing, selective pharmacological ALDH1A3 inhibitor treatment, glycemia measurement, insulin secretion assay, gene expression profiling Nature communications High 36732513
2024 ALDH1A3 interacts with PKM2 and enhances PKM2 tetramerization, promoting lactate accumulation in glioblastoma stem cells; accumulated lactate leads to lactylation of XRCC1 at K247, which increases XRCC1 affinity for importin α, enabling nuclear transposition of XRCC1 and enhanced DNA repair, thereby conferring chemoradiotherapy resistance. Co-immunoprecipitation (ALDH1A3-PKM2 interaction), lactylated proteome scanning by mass spectrometry, XRCC1-importin α binding assay, nuclear fractionation, high-throughput small molecule screening (D34-919 disrupts ALDH1A3-PKM2 interaction), in vitro and in vivo treatment Cell metabolism High 39111285
2024 ALDH1A3 forms an enzymatic partnership with ACSS2 (acetyl-CoA synthetase 2) in the nucleus of melanoma cells, coupling glucose metabolic flux with acetyl-histone H3 modification of neural crest lineage and glucose metabolism genes; acetaldehyde serves as a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner. Nuclear fractionation, ChIP for acetyl-H3 marks, metabolic flux analysis, ALDH1A3 inhibition/genetic manipulation, zebrafish melanoma residual disease model, ALDH1 suicide inhibitor (nifuroxazide) Cell reports High 38963759
2024 ALDH1A3 regulates the balance between two distinct breast cancer stem cell populations (ALDH+ and CD24-CD44+) via retinoic acid signaling-mediated gene expression; while ALDH1A3 increases ALDH+ cells, it inversely suppresses CD24-CD44+ cells. ALDH1A3 also increases oxidative phosphorylation and decreases glycolysis and ROS. ALDH1A3 knockdown/overexpression, Aldefluor assay, flow cytometry (CD44/CD24), metabolic assays (OXPHOS, glycolysis, ROS), retinoic acid signaling pathway inhibition, 2-DG (glycolysis inhibitor) rescue, xenograft tumor models Oncogene Medium 39251846
2023 ALDH1A3 promotes invasion and metastasis of triple-negative breast cancer by regulating the plasminogen activation pathway: ALDH1A3 increases levels and activity of tPA and uPA, leading to increased plasmin activity; this invasion is plasminogen-dependent, and the ALDH1A3 product all-trans-retinoic acid similarly increases tPA and plasmin activity. ALDH1A3 knockdown/overexpression, tPA/uPA activity assays, plasmin activity assay, plasminogen-dependent invasion assays, retinoic acid treatment, tPA knockdown in vivo (lymph node metastasis model) Molecular oncology Medium 37753740
2018 ALDH1A3 knockdown in glioblastoma reduces tumor cell invasion in vitro; ALDH1A3 is associated with mesenchymal transformation and drives changes in extracellular matrix organization and cell adhesion gene expression. siRNA/shRNA knockdown, Transwell invasion assay, Aldefluor flow cytometry, transcriptome analysis Cell death & disease Medium 30538217
2020 ALDH1A3 promotes pancreatic cancer metastasis via metabolic regulation: ALDH1A3 activates PI3K/AKT/mTOR signaling and downstream PPARγ, which increases HK2 (hexokinase 2) expression and enhances glycolysis; pharmacological inhibition of PPARγ in ALDH1A3-positive cells impairs glycolytic gene expression and PI3K/AKT/mTOR activity. ALDH1A3 shRNA knockdown, overexpression, RNA-seq, glycolysis assays (glucose uptake, lactate, ATP), PPARγ inhibitor treatment, in vitro metastasis assays, in vivo metastasis models Frontiers in oncology Medium 32612951
2020 ALDH1A3 depletion affects mTOR cell survival pathway gene expression, coinciding with decreased activating phosphorylation of S6 kinase, placing ALDH1A3 upstream of mTOR signaling in drug-tolerant gastric cancer persister cells. RNA interference, gene expression analysis, Western blot (S6 kinase phosphorylation), mTOR inhibitor (temsirolimus) treatment, single-cell analysis, xenograft tumor models Cancer science Medium 31960523
2017 miR-187 directly targets ALDH1A3 in prostate cancer cells; re-introduction of miR-187 in PC-3 cells downregulates ALDH1A3 protein and mRNA levels, identified by 2D-DIGE proteomics and validated by Western blot and qRT-PCR. 2D-DIGE proteomics, MALDI-TOF MS, LC-MS/MS, Western blot, qRT-PCR, miR-187 precursor transfection PloS one Medium 25969992
2018 PPARγ directly binds to a PPARγ response element (binding site 2) in the ALDH1A3 promoter and suppresses ALDH1A3 mRNA and protein expression upon ligand activation; ALDH1A3 suppression by PPARγ leads to accumulation of 4-HNE (lipid peroxidation marker) in PPARγ-positive lung cancer cells. NUBIscan in silico binding site prediction, ChIP assay (PPARγ binding to ALDH1A3 promoter BS2), QPCR, Western blot, PPARγ activator (TZD) treatment, 4-HNE Western blot Journal of receptor and signal transduction research Medium 29873276
2024 ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by increasing acetyl-CoA production, which leads to H3K27 acetylation at the PITX1 promoter and transcriptional activation of PITX1; ALDH1A3 knockdown reduces H3K27ac levels and PITX1 expression. ALDH1A3 expression is transcriptionally activated by HIF-1α. RNA-seq, siRNA knockdown, dual-luciferase reporter assay (HIF-1α→ALDH1A3 promoter), ChIP assay (H3K27ac at PITX1 promoter), exogenous acetate treatment (NaOAc), HDAC inhibitor (Pracinostat), HIF-1α inhibitor (KC7F2) Cellular signalling Medium 38211842
2023 ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network; ALDH1A3 affects acetylation of histone H3, mediating AP-1 activity (particularly FOS family members) and activating MAPK and TNF signaling; RUNX2 knockdown disrupted MAPK signaling and reduced tumor growth. Chromatin profiling (H3 acetylation), functional interaction studies (FAM3C, MCC, PMEPA1, IRS2), RUNX2 knockdown, MAPK pathway analysis, xenograft tumor models Oncogene Medium 40781158
2023 ALDH1A3 knockdown in prostate cancer promotes cellular senescence-like phenotype while reducing SASP pro-inflammatory factor secretion via inhibition of the cGAS-STING pathway. ALDH1A3 siRNA knockdown, senescence assays, SASP factor measurement, cGAS-STING pathway analysis, radiotherapy in vitro model Cancers Low 40227735
2016 Compound heterozygous mutations in ALDH1A3 (c.287G>A and c.709G>A) cause anophthalmia; in vitro expression analysis showed that mutated alleles are associated with decreased protein production and impaired tetrameric protein formation. Exome sequencing, Sanger sequencing, in vitro expression analysis, native protein gel/tetrameric protein formation assay Genetics and molecular biology Medium 28590501
2021 ALDH1A3 and ALDH1A1 paralogues are both pivotal for myogenic differentiation of skeletal muscle satellite cells (C2C12 myoblasts): CRISPR/Cas9 single-paralogue knockout impairs differentiation, and retinoic acid (RA) analogue TTNPB restores differentiation in knockout cells. ALDH1-paralogue knockout also impairs autophagic flux (p62 formation and LC3B-I to LC3B-II conversion). CRISPR/Cas9 knockout, recombinant ALDH1A3 re-expression rescue, RA analogue (TTNPB) treatment, RA receptor antagonist (AGN 193109) treatment, autophagy flux assays (p62, LC3B Western blot) Cell and tissue research Medium 37904003

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem cells (Dayton, Ohio) 380 21280157
2024 Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma. Cell metabolism 166 39111285
2000 RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development. Mechanisms of development 135 11025231
2016 FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells. Cancer research 128 27569208
2016 ALDH1A3, a metabolic target for cancer diagnosis and therapy. International journal of cancer 109 26991532
2019 ALDH1A3-regulated long non-coding RNA NRAD1 is a potential novel target for triple-negative breast tumors and cancer stem cells. Cell death and differentiation 95 31197235
2000 Identification of RALDH-3, a novel retinaldehyde dehydrogenase, expressed in the ventral region of the retina. Mechanisms of development 95 11044606
2021 ALDH1A3 Coordinates Metabolism With Gene Regulation in Pulmonary Arterial Hypertension. Circulation 90 33764154
2006 Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone. Developmental biology 85 17207476
2013 ALDH1A3 mutations cause recessive anophthalmia and microphthalmia. American journal of human genetics 83 23312594
2019 USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells. The Journal of clinical investigation 81 30958800
2017 Differential Functional Roles of ALDH1A1 and ALDH1A3 in Mediating Metastatic Behavior and Therapy Resistance of Human Breast Cancer Cells. International journal of molecular sciences 79 28937653
2016 Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3. Molecular oncology 72 27592281
2015 A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations. Oncotarget 69 25868979
2013 ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm. Human molecular genetics 63 23591992
2021 Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway. Oncogenesis 58 33419984
2015 MiR-187 Targets the Androgen-Regulated Gene ALDH1A3 in Prostate Cancer. PloS one 56 25969992
2016 Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing. eLife 55 27845622
2017 ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment. Oncogene 52 28581514
2007 Expression of zebrafish aldh1a3 (raldh3) and absence of aldh1a1 in teleosts. Gene expression patterns : GEP 52 18178530
2023 Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure. Nature communications 51 36732513
1994 Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6. Genomics 51 7698756
2017 ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status. British journal of cancer 50 29235568
2018 ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells. BMC cancer 49 30143021
2018 ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma. Cell death & disease 48 30538217
2017 The stem cell/cancer stem cell marker ALDH1A3 regulates the expression of the survival factor tissue transglutaminase, in mesenchymal glioma stem cells. Oncotarget 45 28423611
2020 ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism. Frontiers in oncology 41 32612951
2007 Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in the androgen-responsive human prostate cancer cell line LNCaP. Experimental biology and medicine (Maywood, N.J.) 41 17526768
2020 ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer. Cancer science 38 31960523
2018 Aldehyde dehydrogenase 1A3 (ALDH1A3) is regulated by autophagy in human glioblastoma cells. Cancer letters 38 29306018
2006 Expression of retinaldehyde dehydrogenase (RALDH)2 and RALDH3 but not RALDH1 in the developing anterior pituitary glands of rats. Cell and tissue research 36 17180597
2015 ALDH1A3: A Marker of Mesenchymal Phenotype in Gliomas Associated with Cell Invasion. PloS one 33 26575197
2023 The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond. Cancers 32 36672441
2021 A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells. Communications biology 32 34934174
2018 Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma. Molecular cancer research : MCR 32 29720480
2008 Expressions of Raldh3 and Raldh4 during zebrafish early development. Gene expression patterns : GEP 31 18262854
2020 Identification of ALDH1A3 as a Viable Therapeutic Target in Breast Cancer Metastasis-Initiating Cells. Molecular cancer therapeutics 29 32127468
2019 Inhibition of breast cancer growth via miR-7 suppressing ALDH1A3 activity concomitant with decreasing breast cancer stem cell subpopulation. Journal of cellular physiology 29 31347176
2013 A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia. Clinical genetics 29 24024553
2018 CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development. JCI insight 27 29467333
2016 Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1. Oncotarget 27 27286452
2004 Hair cycle-specific immunolocalization of retinoic acid synthesizing enzymes Aldh1a2 and Aldh1a3 indicate complex regulation. The Journal of investigative dermatology 27 15245423
2019 ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation. iScience 26 31513972
2015 Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders. PloS one 26 26352270
2013 Mutations in ALDH1A3 cause microphthalmia. Clinical genetics 26 23646827
2013 A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred. European journal of human genetics : EJHG 25 23881059
2020 MIR600HG suppresses metastasis and enhances oxaliplatin chemosensitivity by targeting ALDH1A3 in colorectal cancer. Bioscience reports 24 32270866
2019 Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes. Chemico-biological interactions 21 31580832
2018 ALDH1A3 Is the Key Isoform That Contributes to Aldehyde Dehydrogenase Activity and Affects in Vitro Proliferation in Cardiac Atrial Appendage Progenitor Cells. Frontiers in cardiovascular medicine 21 30087899
2016 Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam. International journal of cancer 21 27706811
2015 Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15. Journal of cancer research and clinical oncology 21 25656374
2014 Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families. Human mutation 21 24777706
2008 Expression patterns of Shh, Ptc2, Raldh3, Pitx2, Isl1, Lim3 and Pax6 in the developing chick hypophyseal placode and Rathke's pouch. Gene expression patterns : GEP 21 18647663
2022 circCYP24A1 promotes Docetaxel resistance in prostate Cancer by Upregulating ALDH1A3. Biomarker research 20 35831872
2021 microRNA-483 Protects Pancreatic β-Cells by Targeting ALDH1A3. Endocrinology 19 33564883
2014 Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia. The British journal of ophthalmology 19 24568872
2016 Expression of retinoic acid-metabolizing enzymes, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1 and CYP26C1 in canine testis during post-natal development. Reproduction in domestic animals = Zuchthygiene 18 27569851
2023 Enhanced Sensitivity to ALDH1A3-Dependent Ferroptosis in TMZ-Resistant Glioblastoma Cells. Cells 17 37947601
2020 MicroRNA‑487b‑3p inhibits osteosarcoma chemoresistance and metastasis by targeting ALDH1A3. Oncology reports 17 33125503
2016 Incomplete penetrance of biallelic ALDH1A3 mutations. European journal of medical genetics 17 26873617
2020 ALDH1A3 serves as a predictor for castration resistance in prostate cancer patients. BMC cancer 15 32375698
2018 Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature. BMC medical genetics 15 30200890
2017 ALDH1A3 correlates with luminal phenotype in prostate cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 15 28443495
2016 Induced Expression of Cancer Stem Cell Markers ALDH1A3 and Sox-2 in Hierarchical Reconstitution of Apoptosis-resistant Human Breast Cancer Cells. Acta histochemica et cytochemica 15 27917009
2024 ALDH1A3 is the switch that determines the balance of ALDH+ and CD24-CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer. Oncogene 14 39251846
2018 PPARgamma-mediated ALDH1A3 suppression exerts anti-proliferative effects in lung cancer by inducing lipid peroxidation. Journal of receptor and signal transduction research 13 29873276
2010 Raldh3 expression in diabetic islets reciprocally regulates secretion of insulin and glucagon from pancreatic islets. Biochemical and biophysical research communications 13 20833146
2024 ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell reports 12 38963759
2021 ADP-Ribosylation Factor Like GTPase 4C (ARL4C) augments stem-like traits of glioblastoma cells by upregulating ALDH1A3. Journal of Cancer 12 33403039
2023 EGFRvIII Promotes the Proneural-Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis. Genes 11 36980923
2022 Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis. Life sciences 11 35598658
2021 Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors. Molecules (Basel, Switzerland) 11 34641313
2021 ALDH1A3 Segregated Expression and Nucleus-Associated Proteasomal Degradation Are Common Traits of Glioblastoma Stem Cells. Biomedicines 11 35052687
2023 MiR-4524b-5p-targeting ALDH1A3 attenuates the proliferation and radioresistance of glioblastoma via PI3K/AKT/mTOR signaling. CNS neuroscience & therapeutics 10 37551838
2023 In Vitro Evaluation of ALDH1A3-Affinic Compounds on Breast and Prostate Cancer Cell Lines as Single Treatments and in Combination with Doxorubicin. Current issues in molecular biology 9 36975509
2017 Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family. Genetics and molecular biology 9 28590501
2024 Luminal B Breast Cancer Coexpressing p62 and ALDH1A3 Is Less Susceptible to Radiotherapy. Anticancer research 8 38160009
2023 A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment. International journal of molecular sciences 8 37047661
2024 Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer. Cancer research communications 7 38669046
2023 ALDH1A3 promotes invasion and metastasis in triple-negative breast cancer by regulating the plasminogen activation pathway. Molecular oncology 7 37753740
2025 PPAR γ changing ALDH1A3 content to regulate lipid metabolism and inhibit lung cancer cell growth. Molecular genetics and genomics : MGG 6 40198404
2023 ALDH1A1 and ALDH1A3 paralogues of aldehyde dehydrogenase 1 control myogenic differentiation of skeletal muscle satellite cells by retinoic acid-dependent and -independent mechanisms. Cell and tissue research 6 37904003
2022 Curcumin-based-fluorescent probes targeting ALDH1A3 as a promising tool for glioblastoma precision surgery and early diagnosis. Communications biology 6 36050388
2022 ALDH1A3-Linc00284 Axis Mediates the Invasion of Colorectal Cancer by Targeting TGFβ Signaling via Sponging miR-361-5p. International journal of genomics 6 36275636
2025 Oral 7,8-Dihydroxyflavone Protects Retinal Ganglion Cells by Modulating the Gut-Retina Axis and Inhibiting Ferroptosis via the Indoleacrylic Acid-AhR-ALDH1A3-FSP1 Pathway. CNS neuroscience & therapeutics 5 40365730
2025 tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer. Translational oncology 5 40480147
2023 MiR-320b aberrant expression enhances the radioresistance of human glioma via upregulated expression of ALDH1A3. Aging 5 36996494
2023 Novel Function of Cancer Stem Cell Marker ALDH1A3 in Glioblastoma: Pro-Angiogenesis through Paracrine PAI-1 and IL-8. Cancers 5 37686698
2022 Identification of a novel ALDH1A3-selective inhibitor by a chemical probe with unrelated bioactivity: An approach to affinity-based drug target discovery. Chemical biology & drug design 5 36334047
2021 Knockdown of ALDH1A3 reduces breast cancer stem cell marker CD44 via the miR-7-TGFBR2-Smad3-CD44 regulatory axis. Experimental and therapeutic medicine 5 34504547
2024 ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification. Cellular signalling 4 38211842
2021 Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway. Biomedicines 4 34440089
2019 Deubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancer. The Journal of clinical investigation 4 30958802
2025 ALDH1A3 Regulates Cellular Senescence and Senescence-Associated Secretome in Prostate Cancer. Cancers 3 40227735
2023 ALDH1A3-related congenital microphthalmia-8 due to a novel frameshift variant. European journal of medical genetics 3 37339696
2009 Opossum aldehyde dehydrogenases: evidence for four ALDH1A1-like genes on chromosome 6 and ALDH1A2 and ALDH1A3 genes on chromosome 1. Biochemical genetics 3 19455414
2008 Regulation of RALDH-1, RALDH-3 and CYP26A1 by transcription factors cVax/Vax2 and Tbx5 in the embryonic chick retina. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 3 18406560
2025 ALDH1A3 promotes aggressive basal-like pancreatic cancer through an AP-1/RUNX2 enhancer network. Oncogene 2 40781158
2025 High p62 and ALDH1A3 Reduce the Effectiveness of Endocrine Therapy in Luminal B Breast Cancer. Cancer diagnosis & prognosis 2 41179310
2024 Expression of cancer stem cell markers (CD24, CD44 & ALDH1A3 isoform) in Breast Cancer in Indian population considering clinicopathological characteristics and response to neoadjuvant chemotherapy - a prospective analysis from a university hospital. Indian journal of surgical oncology 2 39555365

Missed literature

Know a paper Affinage missed for ALDH1A3? Flag it for the maintainers and the community.

No submissions yet.