Affinage

ALDH1A1

Aldehyde dehydrogenase 1A1 · UniProt P00352

Length
501 aa
Mass
54.9 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDH1A1 (RALDH1) is a cytosolic NAD+-dependent aldehyde dehydrogenase whose two principal catalytic outputs — biosynthesis of retinoic acid (RA) from retinaldehyde and detoxification of reactive lipid-peroxidation aldehydes — underlie roles in retinoid signaling, oxidative protection, and tumor biology (PMID:12851412, PMID:12941160). Genetic epistasis places ALDH1A1 downstream of ADH1 in the two-step oxidation of retinol, catalyzing the retinaldehyde→RA step, with non-redundant, region-specific RA synthesis in dorsal retina and liver (PMID:12851412, PMID:12808103); the enzyme oxidizes all-trans, 9-cis, and 13-cis retinal, generating 9-cis RA particularly efficiently (PMID:12576512). RA produced cell-autonomously drives downstream gene expression (PMID:23028851), and in vivo this enzyme→product axis is required for postsynaptic μ-opioid receptor expression in the striatum, where ALDH1A1+ nigrostriatal dopaminergic neurons are selectively lost in Parkinson's disease (PMID:30837649, PMID:34079441, PMID:39223183). In parallel, ALDH1A1 detoxifies 4-HNE, malondialdehyde, and hexanal, protecting the lens against cataract formation and contributing to corneal transparency (PMID:12941160, PMID:17567582, PMID:17724188). ALDH1A1 is also embedded in disease physiology: its loss in valvular interstitial cells, driven by TGF-β/SMAD2/3 repression, promotes osteoblast-like calcification reversible by retinoids (PMID:39989358), and in cancer its RA-generating and aldehyde-detoxifying activities feed multiple resistance and immune-evasion programs — PARP-inhibitor resistance via RA-driven POLQ/MMEJ DNA repair (PMID:31534014, PMID:37429899), multidrug resistance via 9-cis-RA→RXRα→NEK2 and ABCB1/AKT/BCL2 (PMID:25230277), ferroptosis suppression through CREB1/GPX4, lipid-droplet production, and FBXL12-controlled stability (PMID:39317105, PMID:40055736), and immune escape through a ZBTB7B/LDHA glycolysis axis (PMID:39107297). ALDH1A1 transcription is set by a wide array of regulators — β-catenin/TEAD-TAZ activation, STAT3, and C/EBP β-stabilizing EHMT1, opposed by ARID1A/HDAC1 (H3K27 deacetylation), DDB2/H3K27me3, and PBRM1-dependent chromatin states (PMID:24954508, PMID:31665232, PMID:29752431, PMID:28415606, PMID:30013043, PMID:34897678, PMID:35412614) — while its activity is directly inhibited by PRMT3 binding and its protein stability tuned by K260 2-hydroxyisobutyrylation-coupled chaperone-mediated autophagy (PMID:33495566, PMID:37867947).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2003 High

    Established ALDH1A1's place in retinoid metabolism by showing it catalyzes the committed retinaldehyde→RA oxidation step downstream of ADH1, answering where the enzyme acts in retinol clearance.

    Evidence Raldh1-/- knockout mice with serum RA/retinaldehyde quantification and genetic epistasis against Adh1

    PMID:12851412

    Open questions at the time
    • Whole-body metabolic readout does not resolve tissue-autonomous contributions
    • Does not address aldehyde detoxification role
  2. 2003 High

    Demonstrated non-redundant, region-specific RA synthesis, showing ALDH1A1 is required in the dorsal retina and adult liver despite ALDH1A3 covering the ventral retina.

    Evidence Raldh1-/- mice with RARE-lacZ RA reporter and orthogonal retinal assays

    PMID:12808103

    Open questions at the time
    • Does not define downstream RA target genes in these tissues
  3. 2003 High

    Defined the second catalytic function — detoxification of lipid-peroxidation aldehydes — by measuring direct kinetics on 4-HNE, malondialdehyde, and hexanal.

    Evidence Recombinant rabbit and human ALDH1A1 in vitro enzyme kinetics (Km values)

    PMID:12941160

    Open questions at the time
    • In vitro kinetics do not establish physiological aldehyde flux
    • No structural basis for substrate selectivity
  4. 2002 Medium

    Resolved retinal substrate preference, showing ALDH1A1 oxidizes multiple retinal isomers and produces 9-cis RA more efficiently than all-trans RA without isomerizing activity.

    Evidence Bacterially expressed recombinant RALDH1 kinetics plus live-cell HPLC retinoid analysis

    PMID:12576512

    Open questions at the time
    • Monkey/recombinant system; in vivo isomer balance not established
  5. 2007 High

    Connected aldehyde detoxification to organ protection, showing ALDH1A1 loss causes cataract via accumulated lipid aldehyde adducts and impaired proteostasis, and correlating expression with corneal transparency.

    Evidence Single/double Aldh1a1/Aldh3a1 knockout mice with UVB, oxidative markers, proteasome assays; corneal keratocyte imaging

    PMID:17567582 PMID:17724188

    Open questions at the time
    • Corneal data correlative without loss-of-function
    • Relative contributions of RA vs aldehyde-detox functions to lens protection not separated
  6. 2012 Medium

    Confirmed cell-autonomous RA generation, showing RALDH1 overexpression lets cells convert retinal into RA-responsive gene induction.

    Evidence Adenoviral Raldh1 overexpression in INS-1 cells, qRT-PCR of RA-target genes

    PMID:23028851

    Open questions at the time
    • Gain-of-function only; endogenous contribution in this cell type untested
  7. 2019 High

    Established an in vivo enzyme→RA→receptor signaling circuit, showing ALDH1A1-derived RA transsynaptically sets striatal μ-opioid receptor expression and that dietary RA rescues the deficit.

    Evidence Aldh1a1 knockout mice with RA-supplementation rescue, immunofluorescence, Pitx3-null dyskinesia model

    PMID:30837649

    Open questions at the time
    • Molecular link between RA and MOR1 transcription not fully mapped
  8. 2021 Medium

    Identified the ALDH1A1+ dopaminergic neuron population as the major, selectively vulnerable nigrostriatal subtype controlling movement vigor.

    Evidence Whole-brain circuit mapping, marker-based identification, electrophysiology, motor behavior in mice; later extended to MPTP primate model

    PMID:34079441 PMID:39223183

    Open questions at the time
    • Whether ALDH1A1 enzymatic activity itself confers vulnerability vs being a marker is unresolved
  9. 2021 High

    Revealed direct post-translational control of enzyme activity, identifying PRMT3 as a physical binding partner that inhibits ALDH1A1 independent of methyltransferase activity.

    Evidence Yeast two-hybrid, Co-IP, docking, PRMT3 mutagenesis, in vitro ALDH activity assays

    PMID:33495566

    Open questions at the time
    • Physiological/disease contexts where PRMT3-ALDH1A1 regulation operates not defined
  10. 2021 Medium

    Linked ALDH1A1 activity to broad antioxidant cytoprotection, showing pharmacological activation preserves ALDH activity, limits lipid aldehyde accumulation, and protects mitochondrial respiration under H2O2 stress.

    Evidence Omeprazole activation and disulfiram inhibition with viability, lipid aldehyde, and respiration assays

    PMID:33400378

    Open questions at the time
    • Pharmacological tools have off-target liabilities; ALDH2-cross-protection mechanism unclear
  11. 2024 Medium

    Placed ALDH1A1 in a non-retinoid metabolic pathway, defining it as a sequential enzyme downstream of MAOB/SIRT2 in astrocytic GABA biosynthesis with elevated expression in Alzheimer's astrocytes.

    Evidence Transcriptomics, metabolite analysis, electrophysiology, ALDH1A1 inhibition in vitro/in vivo, APP/PS1 mice

    PMID:39815261

    Open questions at the time
    • Direct enzymatic identity of the GABA-pathway intermediate substrate not fully characterized
  12. 2022 High

    Demonstrated a protective physiological role in cardiovascular tissue, showing TGF-β/SMAD2/3 represses ALDH1A1 in valve cells and its loss drives RARα-dependent calcification reversible by retinoids.

    Evidence Human valve transcriptomics, siRNA/inhibitor in VICs, RA rescue, two in vivo animal models

    PMID:39989358

    Open questions at the time
    • Aldehyde-detox vs RA-signaling contributions to valve protection not dissected
  13. 2019 Medium

    Established ALDH1A1-driven DNA-repair-mediated drug resistance, showing it enhances MMEJ to confer PARP-inhibitor resistance, later traced to RA/RAR-driven POLQ transcription.

    Evidence MMEJ reporter assays, shRNA, NCT-501/NCT-505 inhibitors, RAR ChIP at POLQ RARE, xenografts and patient-derived organoids

    PMID:31534014 PMID:37429899

    Open questions at the time
    • Whether RA is the sole driver of POLQ induction vs aldehyde-related signals unresolved
    • Single-lab pathway
  14. 2014 Medium

    Defined RA-receptor-mediated multidrug resistance, showing ALDH1A1-generated 9-cis RA acts through RXRα to induce NEK2 and engage ABCB1/AKT/BCL2 survival programs.

    Evidence Enforced ALDH1A1 expression, NEK2 shRNA, drug-resistance assays, in vivo myeloma tumor models

    PMID:25230277

    Open questions at the time
    • RXRα vs RARα specificity in other tumor types untested
  15. 2024 Medium

    Connected ALDH1A1 to ferroptosis resistance and its ubiquitin control, showing it suppresses ferroptosis via aldehyde detox, NADH/RA-RARA, CREB1/GPX4, and lipid droplets, with FBXL12-mediated ubiquitination promoting degradation and ferroptosis.

    Evidence CRISPR knockout, inhibitors, ferroptosis assays, GTF2I phosphorylation analysis, organoids/xenografts; Co-IP, ChIP, ubiquitination assays for the sorcin-PAX5-FBXL12 axis

    PMID:39317105 PMID:40055736

    Open questions at the time
    • Multiple parallel mechanisms not individually weighted
    • Single-lab pathways
  16. 2021 Medium

    Linked ALDH1A1 to tumor immune evasion through metabolic and inflammatory signaling, via pH→TAK1→NF-κB→GM-CSF→MDSC expansion and via a ZBTB7B/LDHA glycolysis axis.

    Evidence Disulfiram/inhibitors, pH and NF-κB assays, MDSC expansion, immune-competent and nude mouse models; ChIP/luciferase for ZBTB7B-LDHA

    PMID:34580061 PMID:39107297

    Open questions at the time
    • Whether enzymatic activity per se drives intracellular pH changes mechanistically unclear
  17. 2024 Medium

    Showed ALDH1A1 cooperates with nuclear-receptor transcriptional programs in metastasis, regulating PLK3 oppositely to ALDH1A3 in an AR- and RAR-dependent manner to promote prostate cancer dissemination and radioresistance.

    Evidence Genetic silencing, RNA-seq, ChIP, zebrafish and murine xenografts, patient IHC

    PMID:38169509

    Open questions at the time
    • Mechanism of isozyme-divergent PLK3 regulation not resolved
  18. 2022 Medium

    Mapped the transcriptional and post-translational control network governing ALDH1A1 levels — activated by β-catenin/TEAD-TAZ, STAT3, and EHMT1-stabilized C/EBPβ, repressed by ARID1A/HDAC1, DDB2/H3K27me3, and PBRM1-dependent chromatin, with K260 2-hydroxyisobutyrylation routing it to chaperone-mediated autophagy.

    Evidence ChIP, promoter-luciferase, CRISPR/shRNA knockouts, ChIP-seq/ATAC-seq, PTM proteomics, CMA reporters across cancer models

    PMID:24954508 PMID:28415606 PMID:29752431 PMID:30013043 PMID:31665232 PMID:34897678 PMID:35412614 PMID:37867947

    Open questions at the time
    • Each regulatory arm shown in distinct cancer contexts; integrated hierarchy not established
    • Mostly single-lab mechanistic studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALDH1A1's dual catalytic outputs (RA synthesis vs aldehyde detoxification) are independently deployed across normal physiology and disease, and how its many transcriptional/post-translational regulators are integrated in vivo, remains unresolved.
  • No structural model relating substrate handling to disease-specific functions
  • Causal separation of RA-signaling vs aldehyde-detox roles in most tissues lacking
  • Regulatory network largely assembled from disparate single-context studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016740 transferase activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
FBXL12PRMT3

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Genetic epistasis in mice demonstrated that Aldh1a1 (Raldh1) functions downstream of Adh1 in the two-step oxidative metabolism of excess retinol to retinoic acid: Adh1 catalyzes retinol→retinaldehyde, and Raldh1 catalyzes retinaldehyde→retinoic acid. Raldh1−/− mice showed 72% reduction in serum RA after retinol dosing and 2.5-fold increase in serum retinaldehyde, confirming the enzymatic step. Genetic knockout mouse model (Raldh1−/−), serum RA and retinaldehyde quantification, LD50 toxicity studies The Journal of biological chemistry High 12851412
2003 Aldh1a1 (Raldh1) is required for retinoic acid synthesis in the dorsal retina at late embryonic stages (E16.5) and in adult liver. Raldh1−/− mice lack RA signaling (RARE-lacZ reporter) in the dorsal retina at E16.5 despite normal ventral retinal RA signaling maintained by Raldh3, demonstrating non-redundant regional RA synthesis by Raldh1 in the dorsal retina and liver. Genetic knockout mouse model (Raldh1−/−), RARE-lacZ RA reporter transgene, retrograde axonal labeling, electroretinography Molecular and cellular biology High 12808103
2003 Recombinant rabbit ALDH1A1 expressed in baculovirus efficiently oxidizes lipid peroxidation aldehydes including hexanal (Km=3.5 µM), 4-hydroxynonenal (Km=2.1 µM), and malondialdehyde (Km=14.0 µM); similar kinetic constants were observed for human recombinant ALDH1A1, establishing catalytic activity in detoxifying toxic aldehydes produced during UV-induced lipid peroxidation. Baculovirus recombinant protein expression, affinity chromatography purification, in vitro enzymatic kinetics assay DNA and cell biology High 12941160
2007 Combined Aldh1a1−/−/Aldh3a1−/− double knockout and single Aldh1a1−/− mice develop cataracts (lens opacification) associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and elevated 4-HNE and malondialdehyde-protein adducts, demonstrating that ALDH1A1 protects the lens against cataract formation via enzymatic detoxification of lipid peroxidation aldehydes. Single and double knockout mouse models, UVB exposure, biochemical analysis of oxidative stress markers, proteasomal activity assays The Journal of biological chemistry High 17567582
2007 ALDH1A1 expression in rabbit corneal keratocytes markedly increases after eyelid opening postnatally, and combined ALDH1A1 and transketolase expression significantly correlates with reduction in light-scattering by stromal cells, supporting a role for ALDH1A1 in corneal transparency development. In vivo confocal microscopy, immunocytochemistry, Western blot, Northern blot, quantitative correlation analysis Investigative ophthalmology & visual science Medium 17724188
2012 Overexpression of RALDH1 (Aldh1a1) via recombinant adenovirus in INS-1 cells conferred the ability to convert retinal (not just retinoic acid) into RA-responsive Srebp-1c mRNA induction, directly demonstrating that RALDH1 enzymatic activity generates RA from retinal to regulate downstream gene expression in a cell-autonomous manner. Recombinant adenovirus overexpression of Raldh1 in INS-1 cells, qRT-PCR for Srebp-1c and Cyp26a1 reporter genes PloS one Medium 23028851
2014 ALDH1A1 enforced expression in multiple myeloma cells activates drug-efflux pump ABCB1 and survival proteins AKT and BCL2, and increases NEK2 mRNA and protein. The mechanism depends on ALDH1A1-generated 9-cis retinoic acid (9CRA) acting via RXRα (not RARα), and shRNA knockdown of NEK2 decreased drug efflux and resistance, defining an ALDH1A1→9CRA→RXRα→NEK2 drug resistance pathway. Enforced ALDH1A1 expression, shRNA knockdown of NEK2, in vitro drug resistance assays, in vivo mouse tumor models, mRNA/protein analysis Oncotarget Medium 25230277
2014 β-Catenin directly regulates ALDH1A1 transcription in ovarian cancer spheroids: β-catenin co-immunoprecipitated with the ALDH1A1 promoter, and β-catenin knockdown decreased ALDH1A1 expression levels. Pharmacological inhibition of ALDH1A1 (compound A37) or β-catenin knockdown disrupted spheroid formation and reduced cell viability. Co-immunoprecipitation (ChIP of promoter), siRNA knockdown, small-molecule ALDH1A1 inhibitor (A37), xenograft mouse model Oncogene Medium 24954508
2019 ALDH1A1-synthesized retinoic acid (RA) is required for postsynaptic μ-opioid receptor (MOR1) expression in the postnatal and adult dorsal striatum via transsynaptic RA signaling. Aldh1a1 knockout mice show severely decreased striatal MOR1 levels, and dietary RA supplementation restores MOR1 expression and alleviates L-DOPA-induced dyskinesia in ALDH1A1-deficient Pitx3-null mice. Aldh1a1 knockout mice, dietary RA supplementation rescue experiment, immunofluorescence, Pitx3-deficient mouse model, behavioral assays for dyskinesia Scientific reports High 30837649
2019 ALDH1A1 contributes to PARP inhibitor (olaparib) resistance in BRCA2-mutated ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) DNA repair activity. Olaparib-resistant cells showed elevated ALDH activity due to BRD4-induced ALDH1A1 expression, and selective ALDH1A1 inhibitor NCT-501 synergized with olaparib in vitro and in xenograft models. Intrachromosomal MMEJ reporter assay, shRNA knockdown, NCT-501 ALDH1A1-selective inhibitor, in vitro drug combination assays, in vivo xenograft model Molecular cancer therapeutics Medium 31534014
2021 ALDH1A1 enzymatic activity in breast tumor-initiating cells decreases intracellular pH, which promotes phosphorylation of TAK1, activates NFκB signaling, and increases GM-CSF secretion, leading to myeloid-derived suppressor cell (MDSC) expansion and immunosuppression to facilitate breast tumor growth. ALDH1A1 inhibitor (disulfiram), in vitro pH measurement, NFκB signaling assays, GM-CSF quantification, MDSC expansion assays, in vivo breast tumor models Cancer research Medium 34580061
2021 PRMT3 physically interacts with ALDH1A1 (identified by yeast two-hybrid screening and confirmed by multiple methods) and inhibits ALDH1A1 enzymatic activity, thereby negatively regulating expression of retinoic acid-responsive genes in a methyltransferase activity-independent manner. Specific residues in the PRMT3 catalytic domain facilitate interaction with the C-terminal region of ALDH1A1. Yeast two-hybrid screening, co-immunoprecipitation, molecular docking, site-directed mutagenesis of PRMT3, in vitro ALDH enzymatic activity assay, gene expression analysis of RA-responsive genes Communications biology High 33495566
2021 ALDH1A1 activation by omeprazole (requiring light exposure to activate at the active site) protects eukaryotic cells from H2O2-induced oxidative stress by preserving ALDH total activity and reducing lipid aldehyde accumulation; this protection is abolished by disulfiram-mediated ALDH inhibition. ALDH1A1 also protects mitochondrial respiration through preservation of ALDH2 activity. Cell viability assays in AS-30D and hepatocyte suspensions, ALDH enzymatic activity measurement, lipid aldehyde quantification, disulfiram inhibition, mitochondrial respiration assays The FEBS journal Medium 33400378
2022 Global deletion of both Aldh1a1 and Aldh1a2 in mice blocks spermatogenesis; cell-specific deletion showed that retinoic acid synthesis by Sertoli cells (via Aldh1a2) is required for the initial round of spermatogonial differentiation, while Aldh1a1 alone is dispensable for viability. Aldh1a3 activity could not compensate for the combined loss. Global and conditional (CRE-loxP) gene deletion in mice, histological analysis of spermatogenesis Frontiers in endocrinology Medium 35574006
2020 ARID1A recruits HDAC1 to the ALDH1A1 gene promoter, reducing histone H3K27 acetylation and repressing ALDH1A1 transcription in cholangiocarcinoma cells. ARID1A knockout (CRISPR/Cas9) increases H3K27 acetylation at the ALDH1A1 promoter and markedly increases ALDH enzymatic activity and stemness properties. CRISPR/Cas9 ARID1A knockout, chromatin immunoprecipitation (ChIP) for ARID1A, HDAC1, and H3K27ac at ALDH1A1 promoter, ALDH enzymatic activity assay, sphere formation assay Carcinogenesis High 31665232
2018 DDB2 binds to the ALDH1A1 gene promoter, facilitates enrichment of repressive histone H3K27me3, and competes with transcription factor C/EBPβ for promoter binding, thereby transcriptionally repressing ALDH1A1. DDB2 silencing de-represses ALDH1A1, driving non-CSC-to-CSC conversion in ovarian cancer. ChIP for DDB2, H3K27me3 at ALDH1A1 promoter; C/EBPβ competition assay; ALDH1A1 selective inhibitor blocking CSC expansion; orthotopic xenograft tumor model Cell death & disease Medium 29752431
2017 TAZ (Hippo pathway transcriptional co-activator) induces ALDH1A1 transcription by activating the ALDH1A1 promoter through interaction with the transcription factor TEAD. ALDH1A1 was identified as a critical TAZ downstream target mediating lung tumorigenesis and CSC phenotypes; CRISPR knockout or pharmacological inhibition of ALDH1A1 suppressed TAZ-induced tumorigenic phenotypes. RNA-seq, qRT-PCR, ALDH1A1 promoter-luciferase reporter assay, CRISPR knockout, ALDH1A1 inhibitor (A37), in vivo mouse tumor formation assay Oncotarget Medium 28415606
2018 TESC (tescalcin) activates STAT3 via direct recruitment of c-Src to the IGF1Rβ complex, and STAT3 directly transactivates ALDH1 isozyme promoters, increasing ALDH1 expression and CSC-like properties in NSCLC. Chromatin immunoprecipitation and luciferase assay demonstrated that STAT3 is a transcriptional activator of ALDH1 isozymes. ChIP assay, luciferase reporter assay, TESC knockdown, IGF1R inhibitor (AG1024), STAT3 phosphorylation analysis Scientific reports Medium 30013043
2022 ALDH1A1 in valvular interstitial cells (VIC) is downregulated by TGF-β in a SMAD2/3-dependent manner. Loss of ALDH1A1 promotes an osteoblast-like VIC phenotype and increases calcium deposition through inhibition of retinoic acid receptor alpha (RARα) signaling, driving aortic valve calcification. Retinoid treatment reverses calcification in human VIC cultures and two in vivo animal models. Transcriptome analysis of human calcified vs. control valves, ALDH1A1 siRNA/inhibitor in VIC cultures, osteogenic marker expression, calcium deposition assays, all-trans RA rescue, subcutaneous bovine pericardium rat model, sheep xenograft aortic valve model Circulation High 39989358
2022 EHMT1 activates ALDH1A1 expression not by direct promoter binding but by stabilizing C/EBPβ, a known transcriptional regulator of ALDH1A1. EHMT1 depletion reduces ALDH1A1 expression and activity, inhibits rhabdomyosarcoma tumorsphere formation, and reduces tumor progression in xenografts. RNA sequencing, EHMT1 shRNA depletion, ALDH1A1 inhibitor, ChIP (showing EHMT1 does NOT bind ALDH1A1 promoter), C/EBPβ stabilization assay, mouse xenograft model The Journal of pathology Medium 34897678
2022 Loss of PBRM1 (PBAF SWI/SNF subunit) results in de novo H3K4me3 gains at the ALDH1A1 promoter, activating ALDH1A1 expression in renal cell carcinoma. ARID2 (another PBAF subunit) remains bound to other PBAF components after PBRM1 loss and is essential for ALDH1A1 upregulation, while BRG1 (the ATPase subunit) is dispensable. RNA-seq, histone modification ChIP-seq (H3K4me3), ATAC-seq, PBRM1 and ARID2 knockdown biochemical studies, ccRCC cell lines and primary tumors Molecular cancer research : MCR Medium 35412614
2023 ALDH1A1 promotes PARP inhibitor resistance by enhancing expression of DNA polymerase θ (POLQ) via the retinoic acid (RA) signaling pathway. ALDH1A1 catalyzes RA biosynthesis, and RA receptor (RAR) binds the retinoic acid response element (RARE) in the POLQ promoter to activate transcription with accompanying histone modification changes. ALDH1A1 inhibition (NCT-505) combined with olaparib synergistically reduced viability of BRCA1/2-mutated patient-derived organoids. RAR ChIP at POLQ RARE promoter element, histone modification ChIP, ALDH1A1 inhibitor (NCT-505), POLQ expression analysis, patient-derived organoid model NPJ precision oncology Medium 37429899
2023 Lysine-260 2-hydroxyisobutyrylation (K260hib) of ALDH1A1 promotes its protein degradation through chaperone-mediated autophagy (CMA). Higher K260hib modification correlates with lower ALDH1A1 protein levels; this modification is regulated by HDAC2/3. Decreased K260hib in bladder cancer results in ALDH1A1 stabilization, enhanced activity, and chemoresistance. Protein modification proteomics, site-specific mutagenesis, HDAC2/3 inhibitor assays, CMA reporter, bladder cancer cell proliferation/migration/invasion assays iScience Medium 37867947
2024 ALDH1A1 suppresses ferroptosis induced by KRAS inhibitors by: (1) detoxifying deleterious aldehydes, (2) boosting NADH and retinoic acid (RA) synthesis to improve RARA function, (3) activating the CREB1/GPX4 pathway, and (4) stimulating lipid droplet production in a pH-dependent manner. GTF2I, dephosphorylated at S784 via ERK inhibition by KRAS inhibitors, mediates ALDH1A1 upregulation in response to KRAS inhibition. ALDH1A1 CRISPR knockout, loss-of-function inhibitors, ferroptosis assays, patient-derived organoids, xenograft models, GTF2I phosphorylation/nuclear translocation analysis Redox biology Medium 39317105
2024 ALDH1A1 positively regulates prostate cancer cell survival in circulation, extravasation, and metastatic dissemination via interplay with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 (up) vs ALDH1A3 (down) in an AR- and RAR-dependent manner, contributing to cancer cell proliferation, migration, DNA repair, and radioresistance. Genetic silencing in vitro, zebrafish xenograft model, murine xenograft model, RNA-seq, ChIP assay, comparative IHC in patient specimens Theranostics Medium 38169509
2025 FBXL12-mediated ubiquitination of ALDH1A1 promotes ferroptosis in pancreatic cancer cells. Sorcin inhibits PAX5 nuclear translocation (by cytoplasmic sequestration), which reduces FBXL12 expression and thus decreases ALDH1A1 ubiquitination, protecting cells from ferroptosis. Celastrol disrupts the sorcin-PAX5 interaction by binding sorcin Cys194, promoting PAX5 nuclear translocation, FBXL12 expression, ALDH1A1 ubiquitination, and ferroptosis. Co-immunoprecipitation, proteomics, ChIP (PAX5 binding FBXL12 promoter), luciferase reporter assay, ALDH1A1 ubiquitination assays, ferroptosis assays, celastrol binding to sorcin Cys194 Journal of hematology & oncology Medium 40055736
2024 ALDH1A1 promotes tumor immune escape through the ZBTB7B-glycolysis pathway. ALDH1A1 upregulates transcription factor ZBTB7B, which binds the LDHA promoter (rate-limiting glycolysis enzyme) to enhance glycolysis and immune evasion. ZBTB7B SUMOylation stabilizes its transcriptional activity. ALDH1A1 deficiency reduces tumor immune escape in immune-competent mice. RNA-seq, qPCR, Western blot, luciferase reporter (ZBTB7B binding LDHA promoter), ChIP-qPCR, xenograft models in immune-normal and nude mice, flow cytometry Cell death & disease Medium 39107297
2018 ALDH1A1 in melanoma cells promotes tumor angiogenesis by activating NF-κB-p65 via the retinoic acid pathway, leading to increased IL-8 secretion, which then activates Notch pathway gene expression in endothelial cells. ALDH1A1 pharmacological inhibition (CM037) significantly reduced IL-8 release, and IL-8 neutralization dampened endothelial angiogenic features. Gene array, ALDH1A1 overexpression, pharmacological inhibition (CM037), IL-8 neutralizing antibody, 3D co-culture multicellular spheroid assay, in vivo xenograft microvessel density, NF-κB-p65 activation assay International journal of molecular medicine Medium 35656893
2022 SIRT2 and ALDH1A1 act as critical sequential enzymes in the astrocytic GABA biosynthesis pathway downstream of MAOB, converting intermediates from putrescine degradation. Inhibition of ALDH1A1 reduced astrocytic GABA production. Elevated ALDH1A1 expression was found in hippocampal astrocytes of Alzheimer's disease patients and APP/PS1 mice. Transcriptomics, immunostaining, metabolite analysis, electrophysiology, ALDH1A1 inhibition in vitro and in vivo, APP/PS1 mouse model Molecular neurodegeneration Medium 39815261
2002 Monkey RALDH1 (ALDH1A1) from kidney proximal tubule cells (JTC12) catalyzes oxidation of all-trans, 9-cis, and 13-cis retinal with higher catalytic efficiency for 9-cis retinal than all-trans retinal, producing 9-cis retinoic acid more efficiently than all-trans retinoic acid in live cells, with no detectable retinal isomerizing activity. Bacterially expressed recombinant RALDH1, in vitro retinal oxidation kinetics, retinoid HPLC analysis from live JTC12 cells, Northern blot, RT-PCR cloning Journal of lipid research Medium 12576512
2021 ALDH1A1-positive nigrostriatal dopaminergic neurons represent ~70% of total nigrostriatal dopaminergic neurons in human and mouse brains, are selectively lost in Parkinson's disease, and project predominantly to the dorsal striatum. These ALDH1A1+ neurons are functionally essential for regulating the vigor of movement during motor skill acquisition. Whole-brain circuit mapping, ALDH1A1 reporter/marker-based neuron identification, in vivo electrophysiology, behavioral motor assays, mouse genetic models Frontiers in neural circuits Medium 34079441
2024 In a non-human primate (MPTP-treated monkey) model of Parkinson's disease, ALDH1A1+ neurons in the ventral SNc (nigrosome) are specifically lost in parallel with parkinsonism progression. ALDH1A1+ neurons constitute the main population of vulnerable dopaminergic nigrostriatal-projecting neurons, while ALDH1A1− neurons giving rise to nigropallidal projections remain relatively preserved. Histological analysis (immunofluorescence, immunohistochemistry), MPTP-treated primate model, retrograde tract tracing to define projection patterns, quantitative cell counting NPJ Parkinson's disease Medium 39223183

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 ALDH1 as a functional marker of cancer stem and progenitor cells. Stem cells and development 262 18573038
2003 Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina. Molecular and cellular biology 190 12808103
2007 ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung cancer (Amsterdam, Netherlands) 172 17920722
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
2014 β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. Oncogene 154 24954508
2021 ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression. Cancer research 142 34580061
2003 Genetic evidence that retinaldehyde dehydrogenase Raldh1 (Aldh1a1) functions downstream of alcohol dehydrogenase Adh1 in metabolism of retinol to retinoic acid. The Journal of biological chemistry 123 12851412
2019 RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1. Leukemia 118 31768017
2022 ALDH1: A potential therapeutic target for cancer stem cells in solid tumors. Frontiers in oncology 85 36387165
2015 Differential Expression of Cancer Stem Cell Markers ALDH1 and CD133 in Various Lung Cancer Subtypes. Cancer investigation 80 26046383
2011 Expression of aldehyde dehydrogenase 1 (ALDH1) in endometrioid adenocarcinoma and its clinical implications. Cancer science 73 21231983
2022 ALDH1A1 in Cancers: Bidirectional Function, Drug Resistance, and Regulatory Mechanism. Frontiers in oncology 69 35814382
2012 High expression of ALDH1 and SOX2 diffuse staining pattern of oral squamous cell carcinomas correlates to lymph node metastasis. Pathology international 65 23005595
2022 Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer. Cancer discovery 62 35078784
2014 NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma. Oncotarget 62 25230277
2019 ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2-/- Ovarian Cancer Cells. Molecular cancer therapeutics 57 31534014
2018 Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1. Scientific reports 54 30013043
2007 Expression of zebrafish aldh1a3 (raldh3) and absence of aldh1a1 in teleosts. Gene expression patterns : GEP 52 18178530
2017 Aldehyde dehydrogenase 1 (ALDH1) isoform expression and potential clinical implications in hepatocellular carcinoma. PloS one 51 28792511
2015 Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma. Melanoma research 51 25643237
2010 Differential expression of aldehyde dehydrogenase 1a1 (ALDH1) in normal ovary and serous ovarian tumors. Journal of ovarian research 48 21176222
2018 ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. Cell chemical biology 47 30293938
2016 Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations. Scientific reports 46 27292183
2016 Comparative expression analysis of putative cancer stem cell markers CD44 and ALDH1A1 in various skin cancer subtypes. The International journal of biological markers 44 26391478
2012 Expression and functional role of ALDH1 in cervical carcinoma cells. Asian Pacific journal of cancer prevention : APJCP 44 22799327
2011 Hedgehog signaling pathway molecules and ALDH1A1 expression in early-stage non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 43 22115706
2003 Molecular cloning and baculovirus expression of the rabbit corneal aldehyde dehydrogenase (ALDH1A1) cDNA. DNA and cell biology 41 12941160
2017 MiR-23b controls ALDH1A1 expression in cervical cancer stem cells. BMC cancer 38 28449663
2020 Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma. Carcinogenesis 36 31665232
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
2021 Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson's Disease. Frontiers in neural circuits 35 34079441
2017 TAZ induces lung cancer stem cell properties and tumorigenesis by up-regulating ALDH1A1. Oncotarget 35 28415606
2024 ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. Theranostics 34 38169509
2021 Activation of ALDH1A1 by omeprazole reduces cell oxidative stress damage. The FEBS journal 34 33400378
2019 ALDH1A1 regulates postsynaptic μ-opioid receptor expression in dorsal striatal projection neurons and mitigates dyskinesia through transsynaptic retinoic acid signaling. Scientific reports 33 30837649
2011 The expression of ALDH1 in cervical carcinoma. Medical science monitor : international medical journal of experimental and clinical research 32 21804471
2022 ALDH1A1 overexpression in melanoma cells promotes tumor angiogenesis by activating the IL‑8/Notch signaling cascade. International journal of molecular medicine 29 35656893
2018 DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1. Cell death & disease 29 29752431
2017 ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells. Autophagy 29 28981387
2022 A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer. Cancers 27 35884498
2020 Silybin Prevents Prostate Cancer by Inhibited the ALDH1A1 Expression in the Retinol Metabolism Pathway. Frontiers in cell and developmental biology 27 32984354
2017 Correlation of ALDH1 and Notch3 Expression: Clinical implication in Ovarian Carcinomas. Journal of Cancer 26 29158806
2018 YAP regulates ALDH1A1 expression and stem cell property of bladder cancer cells. OncoTargets and therapy 25 30349299
2016 ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia. Oncology letters 25 28123562
2021 PRMT3 interacts with ALDH1A1 and regulates gene-expression by inhibiting retinoic acid signaling. Communications biology 24 33495566
2007 Postnatal corneal transparency, keratocyte cell cycle exit and expression of ALDH1A1. Investigative ophthalmology & visual science 24 17724188
2023 ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression. NPJ precision oncology 23 37429899
2017 The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma. Anticancer research 23 28476825
2024 Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson's disease model. NPJ Parkinson's disease 21 39223183
2024 Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis. Redox biology 21 39317105
2019 Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes. Chemico-biological interactions 21 31580832
2014 Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma. International journal of clinical and experimental pathology 21 25031716
2022 ALDH1-Mediated Autophagy Sensitizes Glioblastoma Cells to Ferroptosis. Cells 20 36552781
2013 Cancer stem cell characteristics, ALDH1 expression in the invasive front of nasopharyngeal carcinoma. Virchows Archiv : an international journal of pathology 20 24248285
2012 The hepatic Raldh1 expression is elevated in Zucker fatty rats and its over-expression introduced the retinal-induced Srebp-1c expression in INS-1 cells. PloS one 20 23028851
2019 Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion. Biology open 19 31208996
2017 Low Retinal Dehydrogenase 1 (RALDH1) Level in Prepubertal Boys with Autism Spectrum Disorder: A Possible Link to Dopamine Dysfunction? Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 19 28783931
2011 Alcohol intake and folate antagonism via CYP2E1 and ALDH1: effects on oral carcinogenesis. Medical hypotheses 19 22100631
2024 ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway. Cell death & disease 17 39107297
2022 Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis. Frontiers in endocrinology 17 35574006
2018 Clinicopathological significance of cancer stem cell markers CD44 and ALDH1 expression in breast cancer. Breast cancer (Tokyo, Japan) 17 29845398
2012 ALDH1 immunohistochemical expression and its significance in salivary adenoid cystic carcinoma. Head & neck 17 22581680
2022 Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia. Molecular biology reports 16 35028852
2020 ALDH1A1 Inhibits Chicken Preadipocytes' Proliferation and Differentiation via the PPARγ Pathway In Vitro and In Vivo. International journal of molecular sciences 16 32365706
2014 Inflammation rapidly modulates the expression of ALDH1A1 (RALDH1) and vimentin in the liver and hepatic macrophages of rats in vivo. Nutrition & metabolism 16 25926859
2025 Disruption of the sorcin‒PAX5 protein‒protein interaction induces ferroptosis by promoting the FBXL12-mediated ubiquitination of ALDH1A1 in pancreatic cancer. Journal of hematology & oncology 14 40055736
2024 ALDH1A1 confers resistance to RAF/MEK inhibitors in melanoma cells by maintaining stemness phenotype and activating PI3K/AKT signaling. Biochemical pharmacology 14 38701866
2023 The Molecular Context of Oxidant Stress Response in Cancer Establishes ALDH1A1 as a Critical Target: What This Means for Acute Myeloid Leukemia. International journal of molecular sciences 14 37298333
2021 Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation. Cell reports 14 34758328
2020 Clinicopathological Significance of Tumor Stem Cell Markers ALDH1 and CD133 in Colorectal Carcinoma. Iranian journal of pathology 14 33391379
2017 Raldh1 promotes adiposity during adolescence independently of retinal signaling. PloS one 14 29095919
2015 Clinicopathological significance of ALDH1A1 in lung, colorectal, and breast cancers: a meta-analysis. Biomarkers in medicine 14 26230297
2022 Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors. Molecules (Basel, Switzerland) 13 35056791
2025 Aortic Valve Calcification Is Induced by the Loss of ALDH1A1 and Can Be Prevented by Agonists of Retinoic Acid Receptor Alpha: Preclinical Evidence for Drug Repositioning. Circulation 12 39989358
2023 Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression. iScience 12 37867947
2022 EHMT1 promotes tumor progression and maintains stemness by regulating ALDH1A1 expression in alveolar rhabdomyosarcoma. The Journal of pathology 12 34897678
2022 Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma. Molecular cancer research : MCR 12 35412614
2021 Discrimination of Cancer Stem Cell Markers ALDH1A1, BCL11B, BMI-1, and CD44 in Different Tissues of HNSCC Patients. Current oncology (Toronto, Ont.) 12 34287293
2020 Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer. Biomarkers in medicine 12 33064013
2018 Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer. International journal of cancer 12 30265376
2018 Androgen Receptor and ALDH1 Expression Among Internationally Diverse Patient Populations. Journal of global oncology 12 30307804
2019 Cancer stem cell markers ALDH1 and Bmi1 expression in oral erythroplakia revisited: Implication for driving the process of field cancerization. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 11 31444928
2017 Expression and associations of TRAF1, BMI-1, ALDH1, and Lin28B in oral squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 11 28381191
2022 Reliability of CD44, CD24, and ALDH1A1 immunohistochemical staining: Pathologist assessment compared to quantitative image analysis. Frontiers in medicine 10 36590957
2021 ALDH1 expression predicts progression of premalignant lesions to cancer in Type I endometrial carcinomas. Scientific reports 10 34099751
2020 Overexpression of ALDH1 and EMT marker profile are linked with unfavorable outcome in head and neck cancer. Medicina oral, patologia oral y cirugia bucal 10 32701933
2020 Increased expression of ALDH-1 is associated with clinical parameters of salivary glands neoplasms. Experimental and molecular pathology 10 33053323
2021 Fli1 deficiency suppresses RALDH1 activity of dermal dendritic cells and related induction of regulatory T cells: a possible role in scleroderma. Arthritis research & therapy 9 33964960
2016 SOX2 and ALDH1 as Predictors of Operable Breast Cancer. Anticancer research 9 27272809
2002 Cloning of monkey RALDH1 and characterization of retinoid metabolism in monkey kidney proximal tubule cells. Journal of lipid research 9 12576512
2025 SIRT2 and ALDH1A1 as critical enzymes for astrocytic GABA production in Alzheimer's disease. Molecular neurodegeneration 8 39815261
2022 Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression. Clinical and translational medicine 8 36504325
2020 Regulation of skin fibrosis by RALDH1-producing dermal dendritic cells via retinoic acid-mediated regulatory T cell induction: A role in scleroderma. Journal of dermatological science 8 31959382
2016 Detection of ALDH1 activity in rabbit hepatic VX2 tumors and isolation of ALDH1 positive cancer stem cells. Journal of translational medicine 8 26873175
2015 ALDH1 might influence the metastatic capability of HeLa cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 8 25864109
2025 ALDH1A1 in breast cancer: A prospective target to overcome therapy resistance (Review). Oncology letters 7 40093866
2024 ALDH1A1 as a marker for metastasis initiating cells: A mechanistic insight. Experimental cell research 7 39173941
2022 Vitamin A supplementation downregulates ADH1C and ALDH1A1 mRNA expression in weaned beef calves. Animal nutrition (Zhongguo xu mu shou yi xue hui) 7 35949197
2022 Targeting ALDH1A1 to induce Necroptosis in Nasopharyngeal Carcinoma. Journal of Cancer 7 36484016
2021 GLO 1 and PKCλ Regulate ALDH1-positive Breast Cancer Stem Cell Survival. Anticancer research 7 34848450

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