Affinage

ALDH1A1

Aldehyde dehydrogenase 1A1 · UniProt P00352

Length
501 aa
Mass
54.9 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDH1A1 is a cytoplasmic NAD⁺-dependent aldehyde dehydrogenase that catalyzes the oxidation of retinaldehyde to retinoic acid and detoxifies lipid peroxidation-derived aldehydes, thereby serving as a central node linking retinoid signaling, redox homeostasis, and cellular differentiation. As the principal retinaldehyde dehydrogenase acting downstream of ADH1, ALDH1A1 generates retinoic acid species including 9-cis-RA that activate RAR/RXRα transcriptional programs, driving processes as diverse as dorsal retinal patterning, spermatogonial differentiation, drug-efflux pump upregulation via RXRα/NEK2, and ferroptosis resistance through CREB1/GPX4 (PMID:12851412, PMID:12808103, PMID:25230277, PMID:35574006, PMID:39317105). Its transcription is regulated by multiple chromatin remodeling and signaling axes—repressed by EZH2/H3K27me3, ARID1A/HDAC1, DDB2/C/EBPβ competition, and PBRM1-containing PBAF, and activated by β-catenin, TAZ-TEAD, STAT3, and YAP—while protein stability is controlled by Cdk5 phosphorylation that blocks ubiquitylation and by FBXL12-mediated ubiquitin-dependent degradation and K260 2-hydroxyisobutyrylation-triggered chaperone-mediated autophagy (PMID:22144423, PMID:31665232, PMID:29752431, PMID:35412614, PMID:29948941, PMID:40055736, PMID:37867947). Beyond canonical aldehyde metabolism, ALDH1A1 enzymatic activity lowers intracellular pH to activate TAK1/NF-κB/GM-CSF immunosuppressive signaling, promotes MMEJ-dependent DNA repair, interacts with ZBTB7B to regulate glycolysis via LDHA, and functions as a GABA-synthetic enzyme in VTA GABAergic neurons where it controls inhibitory circuit-level regulation of impulsive behavior (PMID:34580061, PMID:31534014, PMID:39107297, PMID:34702328).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    ALDH1A1's biochemical identity as a retinaldehyde dehydrogenase and lipid aldehyde detoxifier was established, defining its dual enzymatic substrate repertoire and placing it in the retinol→retinaldehyde→retinoic acid pathway downstream of ADH1.

    Evidence Raldh1⁻/⁻ knockout mice with serum RA/retinaldehyde quantification and epistasis with Adh1⁻/⁻; recombinant enzyme kinetics for hexanal, 4-HNE, and MDA; RARE-lacZ reporter in dorsal retina of Raldh1⁻/⁻ mice

    PMID:12808103 PMID:12851412 PMID:12941160

    Open questions at the time
    • Crystal structure-based substrate selectivity determinants not resolved
    • Relative contribution of ALDH1A1 vs ALDH1A2/1A3 to systemic RA not fully quantified
    • Retinaldehyde vs lipid aldehyde preference in different tissues not systematically compared
  2. 2011 High

    The first transcriptional repression mechanism was identified: EZH2 deposits H3K27me3 at the ALDH1A1 locus to silence it, revealing that ALDH1A1 expression is under Polycomb-mediated epigenetic control.

    Evidence ChIP-seq for EZH2 and H3K27me3 at ALDH1A1 locus, EZH2 knockdown de-repression in ovarian cancer cells

    PMID:22144423

    Open questions at the time
    • Whether EZH2-mediated repression operates in non-cancer tissues unknown
    • Specific PRC2 recruitment mechanism to ALDH1A1 locus not defined
  3. 2014 High

    The downstream signaling output of ALDH1A1's RA product was delineated: 9-cis-RA activates RXRα to upregulate NEK2, which increases ABCB1 drug-efflux activity, establishing the first complete enzymatic product→receptor→effector pathway for ALDH1A1-mediated drug resistance.

    Evidence Enforced ALDH1A1 expression in myeloma cells, NEK2 shRNA, drug efflux assay, in vivo tumor model

    PMID:25230277

    Open questions at the time
    • Whether all-trans-RA contributes through RAR-dependent pathways in this context not excluded
    • NEK2 regulation of ABCB1 mechanism not fully resolved
  4. 2014 High

    β-catenin was identified as a direct transcriptional activator at the ALDH1A1 promoter, linking Wnt signaling to ALDH1A1 expression and cancer stemness.

    Evidence ChIP/co-IP of β-catenin at ALDH1A1 promoter, siRNA knockdown, spheroid formation assay in ovarian cancer

    PMID:24954508

    Open questions at the time
    • TCF/LEF binding site identity at ALDH1A1 promoter not mapped
    • Interplay between β-catenin activation and EZH2 repression at the same locus not tested
  5. 2017 High

    TAZ-TEAD was established as another transcriptional activator of ALDH1A1, expanding the set of oncogenic inputs that converge on ALDH1A1 transcription to include Hippo pathway effectors.

    Evidence ALDH1A1 promoter-luciferase, TAZ-TEAD interaction assay, CRISPR KO of ALDH1A1, ALDH1A1 inhibitor A37, in vivo tumor formation

    PMID:28415606

    Open questions at the time
    • TEAD binding elements in ALDH1A1 promoter not mapped at base-pair resolution
    • Relative contribution of TAZ vs YAP at this promoter unclear
  6. 2018 High

    Post-translational regulation of ALDH1A1 was resolved: Cdk5 phosphorylation prevents ubiquitylation and stabilizes ALDH1A1 protein while converting it from an inactive tetramer to a highly active monomer, establishing the first kinase-dependent control of ALDH1A1 enzymatic output.

    Evidence In vitro kinase assay, phosphosite mutagenesis, ubiquitylation assay, native gel oligomeric state analysis, dehydrogenase activity measurement

    PMID:29948941

    Open questions at the time
    • Phosphorylation site identity not fully mapped across all Cdk5 sites
    • Identity of the E3 ubiquitin ligase counteracted by Cdk5 phosphorylation was unknown at that time
  7. 2018 High

    Additional chromatin-level repression mechanisms were defined: DDB2 competes with C/EBPβ for ALDH1A1 promoter occupancy and promotes H3K27me3, while ARID1A recruits HDAC1 to reduce H3K27 acetylation, revealing that multiple SWI/SNF and DNA-damage factors independently silence ALDH1A1.

    Evidence ChIP for DDB2, C/EBPβ competition, H3K27me3 enrichment; CRISPR KO of ARID1A with HDAC1 ChIP at ALDH1A1 promoter

    PMID:29752431 PMID:31665232

    Open questions at the time
    • Hierarchical relationship among EZH2, DDB2, and ARID1A repression at ALDH1A1 not dissected
    • Whether these mechanisms operate simultaneously or context-specifically unknown
  8. 2019 High

    A non-canonical function was uncovered: ALDH1A1 enhances microhomology-mediated end joining (MMEJ) DNA repair, contributing to PARP inhibitor resistance in BRCA2-deficient cells—the first link between ALDH1A1 and a specific DNA repair pathway.

    Evidence siRNA knockdown, intrachromosomal MMEJ reporter assay, selective ALDH1A1 inhibitor NCT-501, xenograft model

    PMID:31534014

    Open questions at the time
    • Biochemical mechanism by which ALDH1A1 promotes MMEJ is unknown—whether via RA signaling or direct protein interaction unresolved
    • Whether this extends to other alternative end-joining pathways not tested
  9. 2021 High

    ALDH1A1 enzymatic activity was shown to lower intracellular pH, triggering TAK1 phosphorylation, NF-κB activation, and GM-CSF secretion that expands myeloid-derived suppressor cells, establishing a metabolite-to-immune-evasion signaling axis.

    Evidence Disulfiram inhibition and siRNA/shRNA knockdown, intracellular pH measurement, TAK1 phosphorylation, GM-CSF ELISA, MDSC flow cytometry, syngeneic tumor models

    PMID:34580061

    Open questions at the time
    • Which ALDH1A1-generated metabolite lowers pH not identified
    • Whether this pH-dependent mechanism operates in non-breast-cancer contexts unknown
  10. 2021 High

    In the brain, ALDH1A1 was identified as a GABA-synthetic enzyme in VTA GABAergic interneurons; these Aldh1a1⁺ neurons project to the intermediate lateral septum and receive mPFC layer 5b input, forming a circuit whose dysfunction produces impulsive behavior.

    Evidence Aldh1a1-CRE knock-in mice, anterograde/retrograde tracing, optogenetic manipulation, LTP electrophysiology, genetic silencing and rescue in AD mice

    PMID:34702328

    Open questions at the time
    • Whether ALDH1A1-derived GABA synthesis is quantitatively significant vs GAD-mediated synthesis not measured
    • Mechanism of GABA synthesis by ALDH1A1 (substrate identity) not biochemically reconstituted
  11. 2021 High

    Cooperative RA synthesis by ALDH1A1 and ALDH1A2 in Sertoli cells was shown to be essential for spermatogonial differentiation; double knockout blocked spermatogenesis completely, establishing tissue-specific non-redundancy among ALDH1A isoforms.

    Evidence Aldh1a1 KO combined with Cre-loxP conditional Aldh1a2 deletion in Sertoli cells vs germ cells, histological analysis

    PMID:35574006

    Open questions at the time
    • Relative RA contribution of ALDH1A1 vs ALDH1A2 in Sertoli cells not quantified
    • Downstream RA target genes in spermatogonial differentiation not identified
  12. 2022 High

    PBAF SWI/SNF chromatin remodeling was linked to ALDH1A1: PBRM1 loss causes de novo H3K4me3 at the ALDH1A1 promoter, and residual ARID2 is required for this activation, distinguishing PBAF-dependent regulation from canonical BRG1-dependent remodeling.

    Evidence RNA-seq, H3K4me3 ChIP-seq, ATAC-seq, PBRM1/ARID2/BRG1 knockdown in ccRCC cells

    PMID:35412614

    Open questions at the time
    • How ARID2 activates ALDH1A1 in the absence of PBRM1 mechanistically unclear
    • Whether this applies outside ccRCC not tested
  13. 2023 Medium

    A novel PTM-degradation axis was identified: K260 2-hydroxyisobutyrylation (regulated by HDAC2/3) triggers ALDH1A1 degradation via chaperone-mediated autophagy, providing a non-ubiquitin mechanism for ALDH1A1 protein turnover.

    Evidence K260hib-specific mutagenesis, HDAC2/3 inhibition, CMA pathway analysis in bladder cancer cells

    PMID:37867947

    Open questions at the time
    • The CMA receptor (LAMP2A) interaction with K260hib-modified ALDH1A1 not directly demonstrated
    • Writer enzyme for K260hib not identified
    • Single study awaiting independent replication
  14. 2024 Medium

    ALDH1A1's role in ferroptosis resistance was mechanistically dissected: ALDH1A1 detoxifies lipid aldehydes, generates NADH and RA, activates RARA and the CREB1/GPX4 axis, and promotes lipid droplet formation, collectively counteracting ferroptosis induced by KRAS inhibitors.

    Evidence ALDH1A1 knockout/inhibitor, GTF2I phosphorylation analysis, CREB1/GPX4 pathway assays, lipid droplet quantification, PDOs and xenografts

    PMID:39317105

    Open questions at the time
    • Whether ferroptosis suppression is RA-dependent or lipid-aldehyde-clearance-dependent not fully resolved
    • Single study with complex multi-pathway model
  15. 2025 Medium

    The E3 ubiquitin ligase FBXL12 was identified as the specific ubiquitin writer for ALDH1A1 degradation, regulated upstream by sorcin-PAX5 cytoplasmic sequestration; disruption of this axis depletes ALDH1A1 and promotes ferroptosis.

    Evidence Co-IP, ChIP, luciferase reporter, FBXL12 overexpression/knockdown, ubiquitylation assay, celastrol functional studies in pancreatic cancer

    PMID:40055736

    Open questions at the time
    • Whether FBXL12 is the same ligase antagonized by Cdk5 phosphorylation not tested
    • Sorcin-PAX5-FBXL12 axis validated only in pancreatic cancer
    • Celastrol target specificity beyond sorcin Cys194 not fully excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the biochemical mechanism by which ALDH1A1 promotes MMEJ DNA repair, the identity of the metabolite(s) responsible for intracellular pH reduction, how multiple chromatin-regulatory inputs at the ALDH1A1 promoter are hierarchically integrated, and whether ALDH1A1's GABA-synthetic activity in VTA neurons proceeds through a defined substrate.
  • MMEJ promotion mechanism (RA-dependent vs direct) unresolved
  • pH-lowering metabolite identity unknown
  • Integration of EZH2/ARID1A/DDB2/PBRM1 chromatin regulation hierarchy at ALDH1A1 not tested
  • GABA synthesis substrate and kinetics not biochemically reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0016787 hydrolase activity 1
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 4 R-HSA-4839726 Chromatin organization 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-112316 Neuronal System 1
Partners
ARID1AARID2CDK5DDB2EZH2FBXL12ZBTB7B

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 ALDH1A1 (Raldh1) functions as a retinaldehyde dehydrogenase in the second step of retinoic acid synthesis, acting downstream of alcohol dehydrogenase ADH1 to oxidize retinaldehyde to retinoic acid in adult mice. Raldh1-/- mice showed 72% reduction in serum RA levels and 2.5-fold accumulation of retinaldehyde after retinol dosing, establishing the enzymatic pathway position. Genetic knockout mouse model (Raldh1-/-), serum RA/retinaldehyde measurement, epistasis with Adh1-/- mice The Journal of biological chemistry High 12851412
2003 ALDH1A1 (Raldh1) is expressed in the dorsal neural retina and provides retinoic acid signaling required for dorsal retina development; Raldh1-/- mice lose RARE-lacZ RA reporter activity in dorsal retina at E16.5, demonstrating its non-redundant role in late dorsal RA synthesis when Raldh3 is absent from dorsal retina. Targeted gene disruption, RARE-lacZ transgenic reporter, retrograde ganglion cell labeling, electroretinography Molecular and cellular biology High 12808103
2003 Rabbit and human recombinant ALDH1A1 proteins efficiently oxidize lipid peroxidation aldehydes including hexanal (Km = 3.5 µM), 4-hydroxynonenal (Km = 2.1 µM), and malondialdehyde (Km = 14.0 µM), indicating a corneal cytoprotective function against UV-induced oxidative damage. Baculovirus expression and affinity purification of recombinant protein, in vitro enzymatic kinetic assay DNA and cell biology High 12941160
2002 ALDH1A1 possesses both dehydrogenase and esterase activities; the competitive irreversible inhibitor DIMATE acts via ALDH1A1 esterase activity to release methanethiol, which lowers mitochondrial glutathione and induces apoptosis in cells overexpressing BCL2. This identifies a mechanism by which ALDH1 enzymatic inhibition can overcome drug resistance. In vitro enzyme inhibition assay, ALDH1-transfected L1210 cells, DNA fragmentation apoptosis assay, intramitochondrial glutathione measurement Biochemical pharmacology Medium 12234608
2011 ALDH1A1 is a direct transcriptional target of EZH2 in epithelial ovarian cancer; EZH2 and H3K27Me3 bind the ALDH1A1 genomic locus, and EZH2 knockdown de-represses ALDH1A1 expression in a H3K27Me3-dependent manner, as validated by ChIP-seq and gene expression profiling. ChIP-seq for EZH2/H3K27Me3, EZH2 knockdown with gene expression microarray, ChIP validation Cancer prevention research (Philadelphia, Pa.) High 22144423
2014 ALDH1A1 in multiple myeloma generates the RXRα ligand 9-cis retinoic acid (not the RARα ligand ATRA), which activates RXRα to upregulate NEK2 kinase expression, which in turn increases drug-efflux pump activity (ABCB1) and promotes drug resistance. shRNA knockdown of NEK2 decreased drug efflux and resistance. Enforced ALDH1A1 expression in myeloma cells, shRNA knockdown of NEK2, mRNA/protein quantification, drug efflux assay, in vivo tumor formation Oncotarget High 25230277
2014 β-Catenin directly regulates ALDH1A1 transcription in ovarian cancer spheroids; β-catenin co-immunoprecipitates with the ALDH1A1 promoter, and β-catenin knockdown decreases ALDH1A1 expression and disrupts spheroid formation. Co-immunoprecipitation with ALDH1A1 promoter, siRNA knockdown, spheroid formation assay, small-molecule ALDH1A1 inhibitor (A37) Oncogene High 24954508
2018 DDB2 (DNA damage-binding protein 2) represses ALDH1A1 transcription by binding to the ALDH1A1 promoter, promoting H3K27me3 enrichment, and competing with the transcription factor C/EBPβ for promoter occupancy, thereby suppressing ovarian cancer cell dedifferentiation. ChIP assay, promoter binding competition assay, DDB2 knockdown/overexpression, H3K27me3 enrichment at ALDH1A1 promoter Cell death & disease High 29752431
2018 Cdk5 phosphorylates ALDH1A1, which prevents its ubiquitylation and increases protein stability; Cdk5-mediated phosphorylation also alters ALDH1A1 from a tetrameric to a highly active monomeric state, increasing dehydrogenase activity. Under sustained oxidative stress, Cdk5 ultimately inactivates ALDH1A1. In vitro kinase assay, phosphorylation-site mutagenesis, ubiquitylation assay, native gel analysis of oligomeric state, dehydrogenase activity assay Molecular neurobiology High 29948941
2020 ARID1A recruits HDAC1 to the ALDH1A1 promoter, decreasing histone H3K27 acetylation and suppressing ALDH1A1 transcription. ARID1A knockout via CRISPR/Cas9 increases H3K27 acetylation at the ALDH1A1 promoter and markedly upregulates ALDH1A1 expression and ALDH enzyme activity. CRISPR/Cas9 knockout, ChIP assay for ARID1A and HDAC1 at ALDH1A1 promoter, H3K27 acetylation ChIP, microarray gene expression Carcinogenesis High 31665232
2019 ALDH1A1 contributes to PARP inhibitor resistance in BRCA2-deficient ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) DNA repair. ALDH1A1 knockdown reduced MMEJ activity as measured by an intrachromosomal MMEJ reporter, and selective ALDH1A1 inhibitor NCT-501 synergized with olaparib in vitro and in vivo. siRNA knockdown, intrachromosomal MMEJ reporter assay, selective ALDH1A1 inhibitor (NCT-501), xenograft model Molecular cancer therapeutics High 31534014
2019 ALDH1A1 inhibition with CM37 increases intracellular ROS accumulation, which leads to DNA damage (γH2AX induction) and upregulation of DNA damage response genes (NEIL3), reducing ovarian cancer cell viability in ALDH+ cancer stem cell populations. ALDH1A1 small-molecule inhibitor CM37, siRNA knockdown, γH2AX immunofluorescence, ROS measurement, in vivo limiting dilution assay Cancers Medium 30965686
2021 ALDH1A1 enzymatic activity decreases intracellular pH in breast cancer tumor-initiating cells, promoting phosphorylation of TAK1, activating NF-κB signaling, and increasing GM-CSF secretion, which drives expansion of myeloid-derived suppressor cells and creates an immunosuppressive tumor microenvironment. ALDH1A1 enzymatic inhibitor (disulfiram), siRNA/shRNA knockdown, intracellular pH measurement, TAK1 phosphorylation assay, GM-CSF ELISA, MDSC flow cytometry, syngeneic tumor models Cancer research High 34580061
2022 S100A9 upregulates ALDH1A1 expression and activates the downstream retinoic acid (RA) signaling pathway in osimertinib-refractory EGFR-mutant lung cancer cells; genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) dramatically reduces brain metastasis. Genetic knockdown of S100A9/ALDH1A1/RARs, pan-RAR antagonist treatment, brain metastasis mouse models Cancer discovery High 35078784
2017 TAZ transcriptional co-activator induces ALDH1A1 transcription by activating the ALDH1A1 promoter through interaction with the TEAD transcription factor. CRISPR knockout or pharmacological inhibition of ALDH1A1 suppresses TAZ-induced lung cancer stem cell and tumorigenic phenotypes. RNA-seq, ALDH1A1 promoter-luciferase reporter assay, TAZ-TEAD interaction assay, CRISPR knockout, ALDH1A1 inhibitor (A37), in vivo tumor formation Oncotarget High 28415606
2018 STAT3 is a transcriptional activator of ALDH1 isozymes; TESC activates IGF1Rβ by direct recruitment of c-Src to the IGF1Rβ complex, leading to STAT3 activation that upregulates ALDH1 expression to maintain cancer stem cell properties and radioresistance. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, co-immunoprecipitation of c-Src/IGF1Rβ, TESC knockdown, IGF1R inhibitor (AG1024) Scientific reports Medium 30013043
2022 YAP (Yes-associated protein) transcriptionally activates ALDH1A1; ectopic expression of human ALDH1A1 in Yap1 hepatocyte-specific knockout mice reduces hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during alcohol/CCl4-induced liver damage, demonstrating a protective detoxification role downstream of YAP. AAV8-Cre-mediated hepatocyte-specific Yap1 knockout, whole-genome transcriptomics, ectopic ALDH1A1 expression rescue experiment, hyperactive YAP mutant transactivation assay FASEB journal Medium 35218575
2021 ALDH1A1 and ALDH1A2 together are required for RA synthesis in Sertoli cells to initiate spermatogonial differentiation; global double knockout of Aldh1a1 and Aldh1a2 blocks spermatogenesis completely, and remaining Aldh1a3 activity cannot compensate. Cell-specific deletion showed that Sertoli cell RA synthesis is required but germ cell RA synthesis is not. Global gene deletion (Aldh1a1 KO mouse), Cre-loxP conditional Aldh1a2 deletion in Sertoli cells and germ cells, histological analysis of spermatogenesis Frontiers in endocrinology High 35574006
2018 5-Nitrofuran nifuroxazide is selectively bio-activated by ALDH1A1/1A3 enzymes; it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. ALDH1A3 loss-of-function mutations confer resistance to nifuroxazide, confirming that ALDH1 enzymatic activity is required for drug activation. In vitro ALDH1A1 oxidation assay, ALDH1A3 loss-of-function mutagenesis, cytotoxicity assays, in vivo tumor xenograft Cell chemical biology High 30293938
2021 Omeprazole, after photoactivation, binds in the active site of ALDH1A1 and activates it, protecting eukaryotic cells from oxidative stress-induced lipid aldehyde accumulation. Disulfiram (ALDH inhibitor) blocks this protection, confirming ALDH1A1-mediated cell defense. ALDH total activity assay in cell suspensions, lipid aldehyde quantification, cell viability assay, disulfiram inhibition control, mitochondrial function assessment The FEBS journal Medium 33400378
2016 ALDH1A1 induces resistance to CHOP chemotherapy in diffuse large B-cell lymphoma through activation of the JAK2/STAT3 pathway; ALDH1A1 overexpression upregulates p-STAT3, and JAK2/STAT3 pathway inhibitor WP1066 negates the resistance conferred by ALDH1A1 overexpression. ALDH1A1 overexpression, shRNA knockdown, JAK2/STAT3 inhibitor (WP1066), caspase activity assay, western blot for p-STAT3 OncoTargets and therapy Medium 27621650
2022 EHMT1 methyltransferase does not directly bind the ALDH1A1 promoter but activates it by stabilizing C/EBPβ, a known transcriptional regulator of ALDH1A1 expression. EHMT1 depletion reduces ALDH1A1 expression, decreasing tumorsphere formation and tumor progression in rhabdomyosarcoma. RNA sequencing, EHMT1 knockdown, ChIP assay, C/EBPβ stabilization assay, ALDH1A1 inhibitor, tumorsphere assay, mouse xenograft 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 transcription. ARID2 (another PBAF subunit) remains bound after PBRM1 loss and is essential for ALDH1A1 upregulation, while BRG1 is dispensable. Increased ALDH1A1 enhances tumorigenic potential of ccRCC cells. RNA-seq, H3K4me3 ChIP-seq, ATAC-seq, PBRM1/ARID2 knockdown, BRG1 knockdown, ccRCC cell tumorigenicity assay Molecular cancer research : MCR High 35412614
2023 ALDH1A1 is modified by 2-hydroxyisobutyrylation at lysine-260 (K260hib); higher K260hib modification promotes ALDH1A1 protein degradation through chaperone-mediated autophagy (CMA) and is regulated by HDAC2/3. Lower K260hib (as seen in bladder cancer) stabilizes ALDH1A1 protein and enhances its activity. Protein modification omics, K260hib-specific mutagenesis, HDAC2/3 inhibition assays, CMA pathway analysis, bladder cancer cell functional assays iScience Medium 37867947
2024 KRAS inhibitors dephosphorylate GTF2I at S784 via ERK, blocking its nuclear translocation and upregulating ALDH1A1 expression. Elevated ALDH1A1 suppresses KRAS inhibitor efficacy by detoxifying lipid aldehydes, boosting NADH and RA synthesis, activating RARA function and the CREB1/GPX4 pathway, stimulating lipid droplet production in a pH-dependent manner, and thereby counteracting ferroptosis. ALDH1A1 knockout/inhibitor, GTF2I phosphorylation analysis, CREB1/GPX4 pathway analysis, lipid droplet quantification, patient-derived organoids, xenograft models Redox biology Medium 39317105
2021 In the ventral tegmental area, Aldh1a1 neurons are a subtype of GABAergic inhibitory interneurons that synthesize GABA using ALDH1A1 rather than GAD, project inhibitory synapses onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS), and receive inputs from layer 5b medial prefrontal cortex pyramidal neurons. L5PN→Aldh1a1 synaptic transmission undergoes LTP, and dysfunction of this circuit produces impulsive behaviors. Aldh1a1-CRE knock-in mice, anterograde/retrograde synaptic tracing, optogenetic circuit manipulation, LTP electrophysiology, genetic silencing, exogenous Aldh1a1 rescue in AD mice Molecular neurodegeneration High 34702328
2024 ALDH1A1 interacts with the transcription factor ZBTB7B; ALDH1A1 promotes ZBTB7B SUMOylation to stabilize its activity, and ZBTB7B binds the LDHA promoter to regulate glycolysis. ALDH1A1 deficiency reduces ZBTB7B-dependent LDHA expression, decreasing tumor glycolysis and reducing immune evasion. RNA-seq, luciferase reporter assay, ChIP-qPCR for ZBTB7B at LDHA promoter, Co-IP, SUMOylation assay, xenograft in immune-normal mice, flow cytometry Cell death & disease Medium 39107297
2025 Labile hepatic copper (Cu) activity increases with age in mice and inversely correlates with ALDH1A1 activity. Treatment with copper chelator ATN-224 restores Cu homeostasis and preserves ALDH1A1 protective activity, establishing a direct mechanistic link between Cu dysregulation and ALDH1A1 functional decline in liver aging. Activity-based Cu(I) imaging probes, photoacoustic glutathione imaging, longitudinal aging mouse study, Cu chelator (ATN-224) treatment, ALDH1A1 activity assay Nature communications Medium 39979263
2025 The E3 ubiquitin ligase FBXL12 ubiquitinates ALDH1A1, targeting it for degradation. Sorcin normally sequesters PAX5 in the cytoplasm; disruption of the sorcin-PAX5 interaction (e.g., by celastrol binding Cys194 of sorcin) allows PAX5 nuclear translocation, which induces FBXL12 expression, increases ALDH1A1 ubiquitylation, depletes ALDH1A1 protein, and promotes ferroptosis in pancreatic cancer cells. Co-IP, ChIP assay, luciferase reporter, proteomics, FBXL12 overexpression/knockdown, ubiquitylation assay, celastrol docking and functional studies Journal of hematology & oncology Medium 40055736
2024 ALDH1A1 drives prostate cancer metastasis and radioresistance through interplay with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs; RNAseq and ChIP analyses identify PLK3 as a transcriptional target oppositely regulated by ALDH1A1 (activating) and ALDH1A3 (repressing) in RAR/AR-dependent manner, contributing to proliferation, migration, DNA repair, and radioresistance. ALDH1A1/ALDH1A3 genetic silencing, RNAseq, ChIP, zebrafish and murine xenograft models, comparative IHC of clinical specimens Theranostics Medium 38169509
2024 Melanoma cells overexpressing ALDH1A1 resist BRAF/MEK inhibitors (vemurafenib/trametinib) through activation of PI3K/AKT signaling rather than the MAPK axis; pharmacological inhibition of ALDH1A1 activity downregulates AKT phosphorylation and partially restores drug sensitivity, while PI3K/AKT inhibition also rescues sensitivity. ALDH1A1 overexpression, ALDH1A1 pharmacological inhibitor, PI3K/AKT inhibitor, western blot for p-AKT, drug sensitivity assays Biochemical pharmacology Medium 38701866
2022 ALDH1A1 inhibition with compound 974 suppresses platinum-induced cellular senescence and the senescence-associated secretory phenotype (SASP) in ovarian cancer stem cells, as demonstrated by transcriptomic sequencing and functional senescence assays, linking ALDH1A1 to regulation of chemotherapy-induced senescence. ALDH1A1 inhibitor (compound 974), transcriptomic RNA sequencing, functional senescence assays, in vivo limiting dilution assay Cancers Medium 35884498

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 189 12808103
2014 β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. Oncogene 154 24954508
2012 ALDH1-bright epithelial ovarian cancer cells are associated with CD44 expression, drug resistance, and poor clinical outcome. The American journal of pathology 143 22222226
2021 ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression. Cancer research 133 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
2010 Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma--derived CD44(+)ALDH1(+) cells. Molecular cancer therapeutics 112 21062915
2009 Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer. British journal of cancer 82 20010944
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 78 28937653
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 64 35814382
2015 All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells. Carcinogenesis 62 25742746
2014 NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma. Oncotarget 62 25230277
2022 Targeting S100A9-ALDH1A1-Retinoic Acid Signaling to Suppress Brain Relapse in EGFR-Mutant Lung Cancer. Cancer discovery 59 35078784
2019 A Novel ALDH1A1 Inhibitor Targets Cells with Stem Cell Characteristics in Ovarian Cancer. Cancers 59 30965686
2019 ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2-/- Ovarian Cancer Cells. Molecular cancer therapeutics 55 31534014
2018 Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1. Scientific reports 52 30013043
2007 Expression of zebrafish aldh1a3 (raldh3) and absence of aldh1a1 in teleosts. Gene expression patterns : GEP 52 18178530
2015 Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma. Melanoma research 51 25643237
2017 Aldehyde dehydrogenase 1 (ALDH1) isoform expression and potential clinical implications in hepatocellular carcinoma. PloS one 50 28792511
2015 BMI1, ALDH1A1, and CD133 Transcripts Connect Epithelial-Mesenchymal Transition to Cancer Stem Cells in Lung Carcinoma. Stem cells international 48 26770215
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
2015 Cancer stem cell markers in prostate cancer: an immunohistochemical study of ALDH1, SOX2 and EZH2. Pathology 46 26517640
2012 Expression and functional role of ALDH1 in cervical carcinoma cells. Asian Pacific journal of cancer prevention : APJCP 44 22799327
2003 Molecular cloning and baculovirus expression of the rabbit corneal aldehyde dehydrogenase (ALDH1A1) cDNA. DNA and cell biology 41 12941160
2011 ALDH1A1 is a novel EZH2 target gene in epithelial ovarian cancer identified by genome-wide approaches. Cancer prevention research (Philadelphia, Pa.) 40 22144423
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
2017 TAZ induces lung cancer stem cell properties and tumorigenesis by up-regulating ALDH1A1. Oncotarget 35 28415606
2021 Function and Regulation of ALDH1A1-Positive Nigrostriatal Dopaminergic Neurons in Motor Control and Parkinson's Disease. Frontiers in neural circuits 34 34079441
2020 Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma. Carcinogenesis 34 31665232
2021 Activation of ALDH1A1 by omeprazole reduces cell oxidative stress damage. The FEBS journal 33 33400378
2011 The expression of ALDH1 in cervical carcinoma. Medical science monitor : international medical journal of experimental and clinical research 32 21804471
2024 ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. Theranostics 31 38169509
2020 How to conjugate the stemness marker ALDH1A1 with tumor angiogenesis, progression, and drug resistance. Cancer drug resistance (Alhambra, Calif.) 30 35582039
2015 The expression of aldehyde dehydrogenase 1 (ALDH1) in ovarian carcinomas and its clinicopathological associations: a retrospective study. BMC cancer 30 26148881
2018 DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1. Cell death & disease 29 29752431
2015 A Novel Approach for Overcoming Drug Resistance in Breast Cancer Chemotherapy by Targeting new Synthetic Curcumin Analogues Against Aldehyde Dehydrogenase 1 (ALDH1A1) and Glycogen Synthase Kinase-3 β (GSK-3β). Applied biochemistry and biotechnology 29 26113217
2018 Upregulation of stem cell markers ALDH1A1 and OCT4 as potential biomarkers for the early detection of cervical carcinoma. Oncology letters 28 30344706
2022 A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer. Cancers 27 35884498
2016 The utility of STAT6 and ALDH1 expression in the differential diagnosis of solitary fibrous tumor versus prostate-specific stromal neoplasms. Human pathology 27 27068523
2020 Silybin Prevents Prostate Cancer by Inhibited the ALDH1A1 Expression in the Retinol Metabolism Pathway. Frontiers in cell and developmental biology 26 32984354
2017 Correlation of ALDH1 and Notch3 Expression: Clinical implication in Ovarian Carcinomas. Journal of Cancer 26 29158806
2016 Complex Behavior of ALDH1A1 and IGFBP1 in Liver Metastasis from a Colorectal Cancer. PloS one 26 27152521
2012 High expression of stem cell marker ALDH1 is associated with reduced BRCA1 in invasive breast carcinomas. Asian Pacific journal of cancer prevention : APJCP 26 22938492
2018 Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas. Oncogene 25 30250298
2016 ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia. Oncology letters 25 28123562
2022 Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol-related hepatocyte damage. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 35218575
2011 Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer. Cellular oncology (Dordrecht, Netherlands) 24 21336637
2018 Immunolocalization of Cancer Stem Cells Marker ALDH1 and its Association with Tumor Budding in Oral Squamous Cell Carcinoma. Head and neck pathology 23 30430416
2016 Mining distinct aldehyde dehydrogenase 1 (ALDH1) isoenzymes in gastric cancer. Oncotarget 23 27015121
2021 Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet-induced mouse model of obesity. International journal of obesity (2005) 22 33934107
2020 Association of ALDH1A1-NEK-2 axis in cisplatin resistance in ovarian cancer cells. Heliyon 22 33241139
2018 Multifaceted Regulation of ALDH1A1 by Cdk5 in Alzheimer's Disease Pathogenesis. Molecular neurobiology 22 29948941
2017 The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma. Anticancer research 22 28476825
2013 ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer. Human pathology 22 23332924
2019 Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes. Chemico-biological interactions 21 31580832
2016 ALDH1A1 induces resistance to CHOP in diffuse large B-cell lymphoma through activation of the JAK2/STAT3 pathway. OncoTargets and therapy 21 27621650
2014 Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma. International journal of clinical and experimental pathology 21 25031716
2002 Novel competitive irreversible inhibitors of aldehyde dehydrogenase (ALDH1): restoration of chemosensitivity of L1210 cells overexpressing ALDH1 and induction of apoptosis in BAF(3) cells overexpressing bcl(2). Biochemical pharmacology 21 12234608
2013 Cancer stem cell characteristics, ALDH1 expression in the invasive front of nasopharyngeal carcinoma. Virchows Archiv : an international journal of pathology 20 24248285
2024 Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis. Redox biology 19 39317105
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 Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson's disease model. NPJ Parkinson's disease 18 39223183
2015 Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression. Oncotarget 18 26305673
2021 ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype. Human genetics 17 34417872
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 17 27569851
2012 ALDH1 immunohistochemical expression and its significance in salivary adenoid cystic carcinoma. Head & neck 17 22581680
2022 Long non-coding ROR promotes the progression of papillary thyroid carcinoma through regulation of the TESC/ALDH1A1/TUBB3/PTEN axis. Cell death & disease 16 35173149
2022 Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis. Frontiers in endocrinology 16 35574006
2022 Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia. Molecular biology reports 15 35028852
2021 Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors. Molecular neurodegeneration 15 34702328
2024 ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway. Cell death & disease 14 39107297
2023 Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction. Proceedings of the National Academy of Sciences of the United States of America 14 37639589
2021 Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation. Cell reports 14 34758328
2020 L1CAM, CA9, KLK6, HPN, and ALDH1A1 as Potential Serum Markers in Primary and Metastatic Colorectal Cancer Screening. Diagnostics (Basel, Switzerland) 14 32630086
2019 UPLC-MS-based metabolomics reveals metabolic dysregulation in ALDH1A1-overexpressed lung adenocarcinoma cells. Metabolomics : Official journal of the Metabolomic Society 14 30911937
2015 Clinicopathological significance of ALDH1A1 in lung, colorectal, and breast cancers: a meta-analysis. Biomarkers in medicine 14 26230297
2025 Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion. Nature communications 13 39979263
2024 ALDH1A1 confers resistance to RAF/MEK inhibitors in melanoma cells by maintaining stemness phenotype and activating PI3K/AKT signaling. Biochemical pharmacology 13 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 13 37298333
2022 Novel Disulfiram Derivatives as ALDH1a1-Selective Inhibitors. Molecules (Basel, Switzerland) 13 35056791
2020 ALDH1A1+ ovarian cancer stem cells co-expressing surface markers CD24, EPHA1 and CD9 form tumours in vivo. Experimental cell research 13 32305326
2020 Clinicopathological Significance of Tumor Stem Cell Markers ALDH1 and CD133 in Colorectal Carcinoma. Iranian journal of pathology 13 33391379
2012 Psychotropics regulate Skp1a, Aldh1a1, and Hspa8 transcription--potential to delay Parkinson's disease. Progress in neuro-psychopharmacology & biological psychiatry 13 23046827
2022 Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma. Molecular cancer research : MCR 12 35412614
2022 KS10076, a chelator for redox-active metal ions, induces ROS-mediated STAT3 degradation in autophagic cell death and eliminates ALDH1+ stem cells. Cell reports 12 35858554
2018 Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer. International journal of cancer 12 30265376
2023 Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression. iScience 11 37867947
2022 EHMT1 promotes tumor progression and maintains stemness by regulating ALDH1A1 expression in alveolar rhabdomyosarcoma. The Journal of pathology 11 34897678
2021 Development of new disulfiram analogues as ALDH1a1-selective inhibitors. Bioorganic & medicinal chemistry letters 11 33744437
2021 Discrimination of Cancer Stem Cell Markers ALDH1A1, BCL11B, BMI-1, and CD44 in Different Tissues of HNSCC Patients. Current oncology (Toronto, Ont.) 11 34287293
2016 Characterization of CD44+ALDH1+Ki-67- Cells in Non-malignant and Neoplastic Lesions of the Breast. Anticancer research 11 27630305
2012 ALDH1 expression is correlated with pathologic grade and poor clinical outcome in patients with astrocytoma. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 11 23084350
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 10 40055736
2022 Reliability of CD44, CD24, and ALDH1A1 immunohistochemical staining: Pathologist assessment compared to quantitative image analysis. Frontiers in medicine 10 36590957
2021 The role of ALDH1A1 in contributing to breast tumour aggressiveness: A study conducted in an African population. Annals of diagnostic pathology 10 33460998
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
2014 ALDH1A1 mediates resistance of diffuse large B cell lymphoma to the CHOP regimen. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 10 25344211