Affinage

ALDH2

Aldehyde dehydrogenase, mitochondrial · UniProt P05091

Length
517 aa
Mass
56.4 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 35 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

ALDH2 is a mitochondrial tetrameric aldehyde dehydrogenase that detoxifies reactive aldehydes — both ethanol-derived acetaldehyde and the lipid-peroxidation product 4-hydroxynonenal (4-HNE) — and thereby protects genomic integrity, mitochondrial function, and multiple downstream signaling pathways (PMID:19874182, PMID:26577527, PMID:37749090). The enzyme assembles into an active tetramer of homodimers stabilized by a Glu487-Arg475 hydrogen bond, and carries dehydrogenase, esterase, and reductase activities (PMID:26832618, PMID:23247008). By clearing acetaldehyde, ALDH2 prevents the formation of acetaldehyde-derived DNA adducts; the loss-of-function ALDH2*2 (Glu487Lys/E504K) variant produces an unstable, dominant-negative subunit that allows adduct accumulation, DNA damage, and accelerated carcinogenesis, establishing ALDH2 as a genome-protective tumor suppressor in liver, esophagus, and lung (PMID:1733836, PMID:17040107, PMID:26150517, PMID:26374466, PMID:31071657). By detoxifying 4-HNE, ALDH2 preserves mitochondrial respiration and constrains diverse stress pathways: it restrains cGAS-STING-driven inflammation, ERK1/2-Beclin1 autophagy, PPARγ/CD36 foam-cell formation, SP1/ACSL4 ferroptosis, and PAD4-dependent NETosis, while supporting AMPK and LKB1-AMPK-SIRT1 signaling (PMID:30853183, PMID:33767380, PMID:35770049, PMID:38124089, PMID:39178733, PMID:38666340, PMID:38472357, PMID:29463997, PMID:28027570). ALDH2 also acts through direct protein interactions independent of bulk aldehyde clearance, stabilizing Rac2 against K48-ubiquitination in macrophages, binding LIN28B to suppress ELK3 in endothelium, and promoting CHIP-mediated PAD4 degradation (PMID:35354308, PMID:37822152, PMID:38472357). Its activity is tuned by PKCε-mediated phosphorylation, transcriptionally by the VHL-HNF4α axis and EHMT2/NFYA, post-translationally by direct p53 binding that blocks tetramer formation, by mRNA stabilization through the CHKB-DT lncRNA, and by inhibitory mitochondrial HSPA8 binding (PMID:27575855, PMID:34944441, PMID:28643803, PMID:35477569, PMID:36825429, PMID:38299365, PMID:38247467). Beyond aldehyde detoxification, Aldh2 also feeds one-carbon metabolism by generating formate for nucleotide biosynthesis during stem-cell regeneration (PMID:35485397). Digenic ALDH2/ADH5 deficiency causes AMeD syndrome through failure of formaldehyde clearance (PMID:33355142).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1992 High

    Established the molecular basis of the East Asian alcohol-flushing phenotype by showing the ALDH2*2 allele produces a catalytically inactive subunit, defining ALDH2 as the dominant acetaldehyde-clearing enzyme in humans.

    Evidence Allele-specific oligonucleotide genotyping with phenotypic correlation across populations

    PMID:1733836

    Open questions at the time
    • Did not establish how a single substitution destabilizes the protein
    • No structural or mechanistic basis for the dominant-negative effect at this stage
  2. 2006 High

    Connected ALDH2 genotype to genotoxicity by demonstrating that deficient individuals accumulate acetaldehyde-derived DNA adducts in vivo, linking the enzyme's metabolic role to genome protection.

    Evidence LC/ESI-MS/MS quantification of DNA adducts in genotype-stratified human alcoholics

    PMID:17040107

    Open questions at the time
    • Correlative in blood DNA, not causal in target tissues
    • Did not test cancer outcomes directly
  3. 2009 High

    Confirmed in vivo essentiality of ALDH2 for acetaldehyde detoxification using a clean genetic loss-of-function model.

    Evidence Aldh2 knockout mice with ethanol feeding and acetaldehyde inhalation; blood acetaldehyde measurement

    PMID:19874182

    Open questions at the time
    • Acute toxicity readout did not address chronic disease or signaling roles
  4. 2015 High

    Established ALDH2 as a tumor suppressor that maintains genomic stability, and showed the E487K knockin is dominant-negative through increased protein turnover.

    Evidence Endogenous-locus knockin mice with carcinogen treatment, DNA damage assays, and human HCC tissue; KO/KD/OE in esophageal keratinocytes

    PMID:26150517 PMID:26374466

    Open questions at the time
    • Mechanism by which adducts drive transformation not fully resolved
    • Tissue-specific susceptibility determinants not defined
  5. 2016 Medium

    Defined the structural and enzymatic basis of ALDH2 function — tetramer assembly via Glu487-Arg475 and three catalytic activities — and the regulatory PKCε phosphorylation that activates the enzyme.

    Evidence Structural/biochemical characterization and computational modeling; siRNA and pharmacological activation in 3T3-L1 preadipocytes

    PMID:23247008 PMID:26832618 PMID:27575855

    Open questions at the time
    • ALDH1B1 heterotetramerization is computational prediction only
    • No high-resolution structure of the ALDH2*2 tetramer reported here
  6. 2017 High

    Identified upstream transcriptional control of ALDH2 through direct VHL-driven HNF4α activation at the ALDH2 promoter, linking expression to renal cancer drug response.

    Evidence Subtractive proteomics, promoter binding assay, RNAi/overexpression, and patient tissue correlation in ccRCC

    PMID:28643803

    Open questions at the time
    • Generalizability of this axis beyond renal cells unknown
  7. 2016 Medium

    Linked ALDH2 to anti-metastatic signaling by showing its control of acetaldehyde/redox status activates AMPK to suppress HCC migration and invasion.

    Evidence Reciprocal gain/loss-of-function in HCC lines and xenografts with AMPK pathway analysis

    PMID:28027570

    Open questions at the time
    • Direct mechanism connecting redox state to AMPK not fully defined
    • Single lab
  8. 2018 Medium

    Extended ALDH2's protective role to 4-HNE-driven cardiac pathology, defining the LKB1-AMPK-SIRT1 and mast-cell PKCε-ALDH2 axes in ischemia/reperfusion.

    Evidence Ex vivo I/R hearts, KO mice, AAV9 cardiac overexpression, SIRT1 carbonylation and LKB1-AMPK Co-IP

    PMID:29446730 PMID:29463997

    Open questions at the time
    • Single lab models
    • Quantitative contribution of each pathway to outcome unclear
  9. 2019 High

    Demonstrated that 4-HNE accumulation under ALDH2 deficiency drives vascular and metabolic disease through PPARγ/CD36 foam-cell formation, HIF-1α/Drp1 mitochondrial fission, and DNA damage in lung cancer.

    Evidence KO macrophages, cell-type-specific AAV overexpression in PASMCs, transgenic/KO mice, and reciprocal manipulation in lung adenocarcinoma cells

    PMID:30853183 PMID:31071657 PMID:31510791

    Open questions at the time
    • Cell-type-specific specificity of 4-HNE targets only partly mapped
    • Direct vs indirect effects on each pathway not always separated
  10. 2020 High

    Revealed non-catalytic and metabolic roles: ALDH2 interacts with the myocardin/miR-31-5p axis in VSMCs, generates formate for one-carbon metabolism in regeneration, and combined ALDH2/ADH5 deficiency causes AMeD syndrome; new disease variants beyond East Asian populations were also catalogued.

    Evidence Mouse AAD models and human VSMCs; zebrafish aldh2 loss-of-function with formate/purine rescue; patient genetics and Adh5/Aldh2 double-KO mice; in vitro variant enzymatic assays

    PMID:32403082 PMID:32428930 PMID:33355142 PMID:35485397

    Open questions at the time
    • Mechanism of ALDH2-myocardin interaction is Medium-confidence
    • Relevance of formate generation to mammalian tissues not established here
  11. 2022 High

    Established direct protein-stabilization functions: ALDH2 binds Rac2 and protects it from K48-ubiquitination to support macrophage efferocytosis, while epigenetic EHMT2/NFYA control of ALDH2 modulates RAS/RAF-driven chemoresistance, and autophagy is restrained via ERK1/2-Beclin1.

    Evidence Bone marrow transplant, Co-IP with ubiquitination site mapping, human carrier macrophages, microarray, and KO mouse PH models

    PMID:35354308 PMID:35477569 PMID:35770049

    Open questions at the time
    • Whether Rac2 stabilization is enzymatic-activity-dependent unclear
    • EHMT2/NFYA findings Medium-confidence
  12. 2023 High

    Mapped a multilayered regulatory network: p53 directly blocks ALDH2 tetramerization, CHKB-DT/FUS stabilizes ALDH2 mRNA, HSPA8 inhibits the enzyme in mitochondria, and LIN28B-ELK3 and cGAS-STING/HDAC3-HADHA axes mediate vascular, septic, and inflammatory protection; ALDH2*2 endothelial dysfunction was confirmed in isogenic CRISPR-corrected iPSC-ECs.

    Evidence Direct binding assays, genetic rescue mice, RNA pull-down, Co-IP/MS, subcellular fractionation, and CRISPR-corrected iPSC-EC and knockin models

    PMID:36696485 PMID:36825429 PMID:36992838 PMID:37749090 PMID:37822152 PMID:38124089 PMID:38247467 PMID:38299365

    Open questions at the time
    • Hierarchy and crosstalk among these regulators not integrated
    • Several downstream signaling links are Medium-confidence single-lab studies
  13. 2024 High

    Defined ALDH2's control of innate immunity and NETosis: it tunes cGAS stability via 4-HNE/USP14, promotes CHIP-dependent PAD4 degradation, and limits ER-stress/LTC4/NOX2-driven NETosis to protect against atherosclerosis, sepsis-ARDS, and myocardial I/R injury.

    Evidence Bone marrow transplant, K48-ubiquitination site mapping, CHIP Co-IP, double-KO (ALDH2/PAD4) epistasis, knockin mice, and human STEMI/ARDS cohorts

    PMID:38472357 PMID:38666340 PMID:39178733

    Open questions at the time
    • Whether PAD4/cGAS regulation requires catalytic activity vs scaffolding not fully separated
    • Integration with the broader regulatory network unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALDH2's diverse non-catalytic protein-stabilization and signaling functions (Rac2, PAD4, cGAS, LIN28B) are mechanistically partitioned from its enzymatic aldehyde-clearance role, and how its many regulators are coordinated in vivo, remains unresolved.
  • No unified model distinguishing enzymatic vs scaffolding contributions
  • No high-resolution structural basis for partner interactions
  • Tissue-specific dominance of competing pathways undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016209 antioxidant activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0016787 hydrolase activity 1
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-168256 Immune System 4 R-HSA-73894 DNA Repair 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CGASFUSHSPA8LIN28BP53PAD4PRKCERAC2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The ALDH2*2 allele (Glu487Lys substitution) produces an inactive protein subunit that is unable to metabolize acetaldehyde, leading to acetaldehyde accumulation after alcohol consumption and associated flushing response. Allele-specific oligonucleotide hybridization of amplified genomic DNA; population genotyping with phenotypic correlation Human genetics High 1733836
2006 ALDH2-deficient alcoholics (ALDH2 1/2 genotype) accumulate significantly higher levels of acetaldehyde-derived DNA adducts (N2-ethyl-2'-deoxyguanosine, alpha-S- and alpha-R-methyl-gamma-hydroxy-1,N2-propano-2'-deoxyguanosine) in blood DNA compared to ALDH2 1/1 alcoholics, demonstrating that ALDH2 genotype directly affects acetaldehyde-induced genotoxic damage. LC/ESI-MS/MS quantification of acetaldehyde-derived DNA adducts in blood DNA from 44 Japanese alcoholic patients stratified by ALDH2 genotype Chemical research in toxicology High 17040107
2009 Aldh2 knockout mice are more susceptible to ethanol and acetaldehyde-induced toxicity than wild-type mice, showing increased mortality when fed ethanol and more severe toxic symptoms (weight loss, higher blood acetaldehyde levels) upon acetaldehyde inhalation, confirming ALDH2's essential role in acetaldehyde detoxification in vivo. Knockout mouse model with ethanol feeding and acetaldehyde inhalation exposure; blood acetaldehyde measurement Toxicology mechanisms and methods High 19874182
2015 The ALDH2(E487K) knockin mutation causes increased protein turnover and dominant-negative reduction of ALDH2 expression, impaired acetaldehyde clearance, increased sensitivity to alcohol-induced toxicity, increased DNA damage response in hepatocytes, and accelerated hepatocellular carcinoma development after carcinogen treatment, establishing ALDH2 as a tumor suppressor that maintains genomic stability. Knockin mice with E487K mutation at endogenous Aldh2 locus; carcinogen treatment; DNA damage assays; comparison with human HCC patient tissue Proceedings of the National Academy of Sciences of the United States of America High 26150517
2015 ALDH2 in esophageal keratinocytes protects against acetaldehyde-derived DNA damage (N2-ethylidene-2'-deoxyguanosine adducts): Aldh2-knockout mice show higher DNA adduct levels in esophagus after ethanol consumption; forced ALDH2 overexpression in human keratinocytes sharply reduces adduct levels; acetaldehyde induces ALDH2 expression in both mouse and human esophageal keratinocytes. Aldh2 knockout mice with ethanol exposure; ALDH2 knockdown and overexpression in human esophageal keratinocytes; DNA adduct quantification Scientific reports High 26374466
2015 4-Hydroxynonenal (4-HNE) impairs ALDH2 activity and reduces mitochondrial respiration in H9C2 cardiomyocytes; ALDH2 inhibition (by DSF or siRNA knockdown) also reduces mitochondrial respiratory reserve capacity and increases cell death, establishing that ALDH2 activity is required for normal mitochondrial function in cardiomyocytes. 4-HNE treatment, disulfiram inhibition, and siRNA knockdown of ALDH2 in H9C2 cells; Seahorse mitochondrial respiration assay; cell viability assays Cellular signalling Medium 26577527
2016 PKCε phosphorylates and activates ALDH2; PKCε-ALDH2 axis regulates adipogenesis through control of 4-HNE levels and PPARγ signaling. ALDH2 knockdown increases intracellular 4-HNE and attenuates adipocyte differentiation, while ALDH2 activation (Alda-1) or PKCε agonist treatment enhances adipogenesis. siRNA knockdown of ALDH2 and PKCε in 3T3-L1 preadipocytes; Alda-1 treatment; whole-genome microarray profiling; adipogenesis assays PloS one Medium 27575855
2016 ALDH2 inhibits hepatocellular carcinoma cell migration and invasion by altering redox status through regulation of acetaldehyde levels, which in turn activates the AMP-activated protein kinase (AMPK) signaling pathway; the ALDH2-acetaldehyde-redox-AMPK axis mediates the anti-metastatic function of ALDH2 in HCC. ALDH2 overexpression and knockdown in HCC cell lines and mouse xenografts; AMPK signaling analysis; migration/invasion assays Hepatology (Baltimore, Md.) Medium 28027570
2017 VHL transcriptionally regulates ALDH2 expression by binding the ALDH2 promoter region (-130 bp to -160 bp) and activating HNF-4α transcription; VHL deficiency reduces ALDH2 expression, and decreased ALDH2 contributes to enhanced anthracycline cytotoxicity in clear cell renal cell carcinoma. Subtractive proteomics, RNAi/overexpression verification, promoter binding assay, patient tissue correlation in ccRCC Nature communications High 28643803
2018 Activation of Gi-coupled receptors (histamine H4, adenosine A3, sphingosine-1-phosphate S1P1) in cardiac mast cells sequentially activates PKCε and then ALDH2; increased ALDH2 enzymatic activity inhibits aldehyde-induced mast cell renin release, prevents local cardiac RAS activation, reduces norepinephrine release, and alleviates reperfusion arrhythmias. Ex vivo ischemia/reperfusion models in guinea pig and mouse hearts; human and murine mast cell lines; pharmacological receptor activation Current medicinal chemistry Medium 29446730
2018 Chronic pain-induced 4-HNE accumulation causes SIRT1 carbonylative inactivation and impairs LKB1-AMPK interaction, increasing myocardial ischemia/reperfusion susceptibility; cardiac-specific ALDH2 upregulation (via AAV9-cTNT delivery) detoxifies 4-HNE, prevents SIRT1 carbonylation, restores LKB1-AMPK interaction, and reduces MI/R injury. CCD chronic pain model; ALDH2 KO mice; AAV9-mediated cardiac-specific ALDH2 overexpression; SIRT1 carbonylation assay; LKB1-AMPK co-immunoprecipitation Theranostics Medium 29463997
2019 ALDH2 deficiency increases 4-HNE accumulation, which activates the 4-HNE/PPARγ/CD36 pathway: ALDH2-deficient macrophages show downregulated PPARγ and CD36 expression, suppressing foam cell formation induced by oxidized LDL (but not acetylated LDL). ALDH2-deficient and control mouse peritoneal macrophages; ox-LDL and ac-LDL treatment; CD36 inhibitor; Western blot; foam cell assay Biochemical and biophysical research communications Medium 30853183
2019 4-Hydroxynonenal (4-HNE), a lipid peroxidation product not detoxified in ALDH2-deficient conditions, drives pulmonary hypertension by stabilizing HIF-1α and increasing Drp1 (Ser616) phosphorylation, promoting mitochondrial fission and PASMC proliferation; ALDH2 overexpression specifically in pulmonary artery smooth muscle cells (but not endothelial cells) prevents HPH development. ALDH2 transgenic and KO mice; chronic hypoxia model; AAV-mediated cell-type-specific ALDH2 overexpression (ICAM2p vs. SM22αp); human PASMC in vitro; HIF-1α and Drp1 phosphorylation assays Arteriosclerosis, thrombosis, and vascular biology High 31510791
2019 ALDH2 repression in lung adenocarcinoma leads to acetaldehyde accumulation, which enhances DNA damage and promotes cell migration; ALDH2 knockdown increases and overexpression decreases proliferation, stemness, and migration of lung adenocarcinoma cells; Aldh2-KO mouse lung tissues show increased acetaldehyde and DNA damage in vivo. ALDH2 overexpression and knockdown in lung adenocarcinoma cells; Aldh2-KO mice; Alda-1 treatment; DNA damage assays Neoplasia (New York, N.Y.) Medium 31071657
2020 ALDH2 inhibition ablates pathological vascular smooth muscle cell (VSMC) phenotypic switch (contractile to synthetic) through interaction with myocardin; ALDH2 deficiency downregulates miR-31-5p (via increased Max expression), which relieves repression of myocardin mRNA, promoting contractile VSMC phenotype and protecting against aortic aneurysm/dissection. ALDH2 inhibitor treatment in mouse AAD models (BAPN and Ang II); microarray and bioinformatics; gain/loss-of-function for miR-31-5p; primary human VSMC experiments; interaction studies European heart journal Medium 32428930
2020 Digenic mutations in ALDH2 (rs671 defective allele) combined with ADH5 mutations cause AMeD syndrome through combined deficiency of formaldehyde clearance, leading to formaldehyde-induced DNA damage that saturates Fanconi anemia repair capacity and impairs hematopoietic stem cell differentiation and proliferation. Patient genetic analysis; cellular studies in patient-derived cells; Adh5/Aldh2 double-knockout mouse model recapitulating AMeD phenotypes Science advances High 33355142
2021 ALDH2 overexpression in APP/PS1 Alzheimer's mouse model attenuates cardiac dysfunction by suppressing ferroptosis via the SP1/ACSL4 pathway: ALDH2 reduces lipid peroxidation, decreases ACSL4 and SP1 expression, and prevents ferroptosis; Aβ-induced ferroptosis and cardiomyocyte injury in vitro is rescued by ALDH2 transgene or Alda-1 activator. ALDH2 transgenic crossed with APP/PS1 mice; in vitro Aβ treatment of cardiomyocytes; Alda-1 treatment; SP1 inhibitor (tolfenamic acid) and ACSL4 inhibitor (triacsin C) pharmacological validation Acta pharmacologica Sinica Medium 33767380
2022 Wild-type ALDH2 directly interacts with Rac2 in macrophages and attenuates its K48-linked polyubiquitination at lysine 123, preventing Rac2 degradation; the rs671 mutant ALDH2 destabilizes Rac2, impairing macrophage efferocytosis and accelerating atherosclerosis. Bone marrow transplant experiments confirmed the macrophage-specific role. Bone marrow transplantation (APOE-/-ALDH2-/- to APOE-/-); RNA-seq, proteomics, co-immunoprecipitation; Rac2 ubiquitination assays; human macrophage studies from rs671 carriers Arteriosclerosis, thrombosis, and vascular biology High 35354308
2022 EHMT2 epigenetically represses ALDH2 expression (via H3K9 methylation); NFYA cooperatively regulates ALDH2 transcription; ALDH2 overexpression activates the RAS/RAF oncogenic pathway to confer paclitaxel resistance in non-small cell lung cancer; ALDH2 inhibition or EHMT2 inhibitor restores paclitaxel sensitivity. Gene microarray, cell line and xenograft functional studies, pharmacological ALDH2 inhibition, EHMT2 inhibition with JIB04, clinicopathological patient analysis Molecular cancer Medium 35477569
2022 ALDH2 deficiency increases autophagy in pulmonary artery smooth muscle cells via the ERK1/2-Beclin-1 pathway, contributing to PASMC migration/proliferation and pulmonary hypertension; ALDH2 knockout in mice exacerbates hypoxia/SU5416-induced PH with increased 4-HNE and autophagosomes. ALDH2 KO mice; lentiviral ALDH2 knockdown in human PASMCs; PDGF-BB stimulation; ERK1/2-Beclin-1 autophagy pathway analysis; electron microscopy; hemodynamic monitoring Oxidative medicine and cellular longevity Medium 35770049
2022 In zebrafish melanocyte stem cells, Aldh2 activity is required not only for aldehyde clearance but specifically to generate formate (a one-carbon building block for nucleotide biosynthesis) through formaldehyde metabolism, enabling McSC progeny generation during regeneration; disrupting the 1C cycle with methotrexate causes melanocyte regeneration defects; purines are sufficient to rescue Aldh2-deficient McSC regeneration. Live imaging coupled with scRNA-sequencing; aldh2 loss-of-function in zebrafish; metabolic rescue experiments with formate and purines; methotrexate treatment Development (Cambridge, England) Medium 35485397
2023 p53 directly binds to ALDH2 and prevents formation of its active tetramer; p53 also indirectly limits pyruvate production (a natural ALDH2 activator), thereby repressing ALDH2 enzymatic activity, reducing acetyl-CoA and histone acetylation, and suppressing SCD1 expression to protect against alcohol-induced fatty liver. Biochemical binding assay (p53-ALDH2 direct interaction); p53-deficient mice with ALDH2 depletion rescue; SCD1 overexpression/knockdown studies; acetyl-CoA and histone acetylation measurements The EMBO journal High 36825429
2023 ALDH2 directly binds LIN28B (an ELK3 mRNA stability regulator) in endothelial cells, hindering LIN28B binding to ELK3 mRNA and thereby suppressing ELK3 expression; ALDH2-specific knockout in endothelial cells increases ELK3 expression, enhances endothelial barrier integrity via focal adhesion/tight junction upregulation, and suppresses early aortic dilation in AAA. Endothelial cell-specific ALDH2 knockdown/knockout; single-cell RNA sequencing; mRNA sequencing; direct binding study (ALDH2-LIN28B); AAV-mediated ELK3 modulation; Ang II-induced AAA mouse model Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 37822152
2023 ALDH2 alleviates LPS-induced cardiac dysfunction, inflammation, and apoptosis through inhibition of the cGAS/STING signaling pathway; Alda-1 activation of ALDH2 suppresses cGAS/STING while daidzin inhibition exacerbates injury; cGAS siRNA knockdown abolishes the synergistic effect of daidzin, placing ALDH2 upstream of cGAS/STING. LPS-induced mouse and H9C2 cell cardiac injury models; Alda-1 and daidzin pharmacological modulation; cGAS siRNA knockdown; cardiac function by echocardiography; ELISA and flow cytometry Molecular medicine (Cambridge, Mass.) Medium 38124089
2023 ALDH2 inhibits myocardial pyroptosis in sepsis by preventing HDAC3 translocation from nucleus to mitochondria, thereby protecting HADHA acetylation; acetylated HADHA supports mitochondrial fatty acid β-oxidation; ALDH2 deficiency allows HDAC3 translocation → HADHA deacetylation → toxic lipid accumulation → mROS and ox-mtDNA release → NLRP3 inflammasome activation and GSDMD-dependent pyroptosis. LPS septic shock mouse model; ALDH2 knockout/knockdown; HDAC3 subcellular fractionation; HADHA acetylation assays; HDAC3 and HADHA siRNA epistasis experiments Frontiers in pharmacology Medium 36992838
2023 CHKB-DT lncRNA physically interacts with ALDH2 mRNA and FUS protein through a GGUG motif, protecting ALDH2 mRNA from degradation; CHKB-DT knockdown aggravates ALDH2 mRNA degradation and 4-HNE production; restoring ALDH2 in CHKB-DT+/- mice rescues cardiac dilation and dysfunction in dilated cardiomyopathy. RNA antisense purification; RNA pull-down; luciferase assay; CRISPR KO mouse model; quantitative proteomics and ribosome profiling; ALDH2 rescue in CHKB-DT+/- mice Circulation research High 38299365
2023 SGLT2 inhibitor empagliflozin ameliorates ALDH2*2-induced endothelial cell dysfunction by inhibiting Na+/H+-exchanger 1 (NHE-1) and activating AKT and eNOS pathways, reducing oxidative stress and restoring NO production; CRISPR-Cas9-corrected ALDH2*2 iPSC-ECs confirm the causal role of ALDH2*2 in EC dysfunction. iPSC-derived ECs from ALDH2*2 carriers; CRISPR-Cas9 correction; empagliflozin treatment; ALDH2*2 knock-in mice; human vasodilation clinical assessment; AKT/eNOS pathway analysis Science translational medicine High 36696485
2023 ALDH2 activator AD-9308 treatment in Aldh2 wild-type and Glu504Lys knock-in mice reduces 4-HNE-adducted proteins in brown adipose tissue mitochondria; ALDH2 deficiency in BAT leads to 4-HNE adduction of proteins involved in fatty acid oxidation and electron transport chain, decreasing fatty acid oxidation and mitochondrial respiration, impairing adaptive thermogenesis and promoting diet-induced obesity, glucose intolerance, and fatty liver. Aldh2 Glu504Lys knock-in mice; high-fat diet challenge; BAT proteomics (4-HNE-adducted proteins); mitochondrial respiration assays; AD-9308 pharmacological treatment Nature communications High 37749090
2024 ALDH2 deficiency increases cGAS stability in macrophages by reducing interaction between USP14 (a deubiquitinase) and cGAS; specifically, ALDH2 enzymatic activity reduces 4-HNE accumulation, which decreases USP14-cGAS interaction, allowing K48-linked polyubiquitination degradation of cGAS at lysine 282; ALDH2 deficiency therefore activates cGAS-STING pathway, promoting proinflammatory macrophage polarization and atherosclerosis. ALDH2-KO/ApoE-KO bone marrow transplantation; mechanistic Co-IP and ubiquitination assays; pharmacological cGAS inhibition (RU.521); USP14 knockdown; human macrophages from rs671 carriers Redox biology High 39178733
2024 ALDH2 deficiency exacerbates myocardial ischemia/reperfusion injury by promoting neutrophil extracellular trap (NETosis) formation via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4)/NOX2 pathway; PAD4 knockout or NETosis-inhibiting drugs (GSK484, DNase1) substantially attenuate myocardial damage in ALDH2 KO mice. ALDH2 KO, PAD4 KO, and ALDH2/PAD4 double KO mice; myocardial I/R model; human STEMI patient cohort (n=308); NETosis pathway mechanistic studies; pranlukast (LTC4 receptor antagonist) treatment European heart journal High 38666340
2024 ALDH2 promotes K48-linked polyubiquitination and degradation of PAD4 by facilitating PAD4 binding to the E3 ubiquitin ligase CHIP, thereby inhibiting NETosis in neutrophils; ALDH2 deficiency reduces PAD4 ubiquitination, increases NETosis, promotes vascular leakage, and exacerbates septic ARDS. Aldh2-KO and Aldh2rs671 knock-in mice; sepsis models; PAD4 ubiquitination assays; CHIP E3 ligase Co-IP; Alda-1 pharmacological rescue; human ARDS patient samples Cellular & molecular immunology High 38472357
2023 HSPA8 (Heat Shock 70-kDa Protein 8) translocates to mitochondria under oxygen-glucose deprivation and binds ALDH2, inhibiting its enzymatic activity and promoting fibroblast senescence; siRNA knockdown of HSPA8 increases ALDH2 activity and reduces OGD-induced senescence markers. Co-immunoprecipitation and mass spectrometry identification of ALDH2-HSPA8 interaction; HSPA8 siRNA knockdown; OGD fibroblast model; ALDH2 enzyme activity assays; mitochondrial fractionation Antioxidants (Basel, Switzerland) Medium 38247467
2021 PKCε activation promotes translocation to mitochondria and phosphorylation of ALDH2; activation of the mitochondrial PKCε-ALDH2 axis is required for recovery from 4-HNE-induced mechanical pain hypersensitivity; ALDH2-deficient knockin mice display increased 4-HNE nociceptive behavior and fail to respond to PKCε activator treatment. PKCε knockout mice; ALDH2-deficient knockin mice; PKCε activator peptide (ΨεHSP90); 4-HNE and carrageenan pain models; mechanical hypersensitivity measurements Biomolecules Medium 34944441
2016 ALDH2 forms homodimers through hydrogen bonding between Glu487 and Arg475 residues; two ALDH2 homodimers form an active tetramer. ALDH2 has dehydrogenase, esterase, and reductase activities with main substrates being aldehydes, 4-nitrophenyl acetate, and nitroglycerin, respectively. Computational modeling predicts that inactive ALDH2*2 mutant subunits can heterotetramerize with ALDH1B1, potentially explaining lack of compensatory ALDH1B1 activity in ALDH2*2 individuals. Structural analysis of ALDH2 homodimerization domains; enzymatic activity characterization; computational molecular modeling of ALDH2-ALDH1B1 heterotetramerization Nihon eiseigaku zasshi. Japanese journal of hygiene Medium 23247008 26832618
2020 Novel non-East Asian ALDH2 missense variants identified in Latino, African, South Asian, and Finnish populations show significantly reduced enzymatic activity in vitro and increased ethanol-induced toxicity in 3T3 cells; a new activator Alda-64 corrects loss of activity in most of these new variants where Alda-1 was ineffective. In vitro enzymatic activity assays; 3T3 cell overexpression of variants; Alda-1 and Alda-64 pharmacological activation screening EBioMedicine Medium 32403082

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Distribution of ADH2 and ALDH2 genotypes in different populations. Human genetics 442 1733836
2007 ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism 275 17718397
2005 Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 173 16103445
2006 Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians. Psychological bulletin 169 16822169
2020 Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype. European heart journal 157 32428930
2011 ALDH2 in alcoholic heart diseases: molecular mechanism and clinical implications. Pharmacology & therapeutics 136 21664374
2021 Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer's disease via inhibition of ACSL4-dependent ferroptosis. Acta pharmacologica Sinica 120 33767380
2021 The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment. Acta pharmaceutica Sinica. B 119 34221859
2011 Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Human genetics 112 22102315
2006 Increased DNA damage in ALDH2-deficient alcoholics. Chemical research in toxicology 106 17040107
2015 ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 77 26150517
2020 Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. Science advances 73 33355142
2019 ALDH2 (Aldehyde Dehydrogenase 2) Protects Against Hypoxia-Induced Pulmonary Hypertension. Arteriosclerosis, thrombosis, and vascular biology 72 31510791
2024 Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition. European heart journal 71 38666340
2017 Aldehyde dehydrogenase-2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice. Hepatology (Baltimore, Md.) 67 28027570
2019 Activation of ALDH2 attenuates high glucose induced rat cardiomyocyte fibrosis and necroptosis. Free radical biology & medicine 62 31689484
2020 Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity. EBioMedicine 60 32403082
2019 ALDH2 Repression Promotes Lung Tumor Progression via Accumulated Acetaldehyde and DNA Damage. Neoplasia (New York, N.Y.) 59 31071657
2022 An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer. Molecular cancer 57 35477569
2017 Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. Experimental cell research 57 29155365
2023 ALDH2 mitigates LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING pathway. Molecular medicine (Cambridge, Mass.) 56 38124089
2023 ALDH2 as a potential stem cell-related biomarker in lung adenocarcinoma: Comprehensive multi-omics analysis. Computational and structural biotechnology journal 55 36936815
2019 ALDH2 and Cardiovascular Disease. Advances in experimental medicine and biology 55 31368097
2017 VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2. Nature communications 52 28643803
2016 The Role of Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) in Neuropathology and Neurodegeneration. Acta neurologica Taiwanica 52 28382610
2016 ALDH2 gene polymorphism in different types of cancers and its clinical significance. Life sciences 50 26804999
2019 ALDH2 Overexpression Alleviates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation. Journal of diabetes research 49 31871948
2023 SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant. Science translational medicine 48 36696485
2005 A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan. Carcinogenesis 47 16332725
1995 CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese. Alcoholism, clinical and experimental research 44 7573775
2023 A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators. Nature communications 42 37749090
2015 Protective role of ALDH2 against acetaldehyde-derived DNA damage in oesophageal squamous epithelium. Scientific reports 41 26374466
2022 Macrophage ALDH2 (Aldehyde Dehydrogenase 2) Stabilizing Rac2 Is Required for Efferocytosis Internalization and Reduction of Atherosclerosis Development. Arteriosclerosis, thrombosis, and vascular biology 38 35354308
2022 Impacts of ADH1B rs1229984 and ALDH2 rs671 polymorphisms on risks of alcohol-related disorder and cancer. Cancer medicine 35 35670037
2003 Effects of ALDH2 gene polymorphisms and alcohol-drinking behavior on micronuclei frequency in non-smokers. Mutation research 35 14568296
2010 Meta-analysis of ADH1B and ALDH2 polymorphisms and esophageal cancer risk in China. World journal of gastroenterology 34 21157980
2018 Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility. Theranostics 33 29463997
2024 ALDH2 polymorphism and myocardial infarction: From alcohol metabolism to redox regulation. Pharmacology & therapeutics 30 38763322
2021 Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis. Journal of clinical and translational hepatology 30 33604259
2015 Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes. Cellular signalling 30 26577527
2015 Association between Glu504Lys polymorphism of ALDH2 gene and cancer risk: a meta-analysis. PloS one 29 25680115
2014 ALDH2 and ADH1 genetic polymorphisms may contribute to the risk of gastric cancer: a meta-analysis. PloS one 29 24633362
2016 ADH1B and ALDH2 are associated with metachronous SCC after endoscopic submucosal dissection of esophageal squamous cell carcinoma. Cancer medicine 27 27038040
2009 Characteristics of aldehyde dehydrogenase 2 (Aldh2) knockout mice. Toxicology mechanisms and methods 27 19874182
2017 ALDH2---The Genetic Polymorphism and Enzymatic Activity Regulation: Their Epidemiologic and Clinical Implications. Current drug targets 26 26212265
2016 PKC-ALDH2 Pathway Plays a Novel Role in Adipocyte Differentiation. PloS one 26 27575855
2023 ALDH2 attenuates myocardial pyroptosis through breaking down Mitochondrion-NLRP3 inflammasome pathway in septic shock. Frontiers in pharmacology 25 36992838
2019 ALDH2 and Stroke: A Systematic Review of the Evidence. Advances in experimental medicine and biology 25 31368105
2024 LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2. Circulation research 24 38299365
2024 ALDH2 deficiency augments atherosclerosis through the USP14-cGAS-dependent polarization of proinflammatory macrophages. Redox biology 24 39178733
2022 Accumulation of acetaldehyde in aldh2.1-/- zebrafish causes increased retinal angiogenesis and impaired glucose metabolism. Redox biology 24 35114580
2019 Effect of ALDH2 polymorphism on cancer risk in Asians: A meta-analysis. Medicine 24 30921184
2017 ALDH2 restores exhaustive exercise-induced mitochondrial dysfunction in skeletal muscle. Biochemical and biophysical research communications 24 28249782
2016 miR-224 Affects Mammary Epithelial Cell Apoptosis and Triglyceride Production by Downregulating ACADM and ALDH2 Genes. DNA and cell biology 24 27918674
2015 Aldehyde dehydrogenase 2 (ALDH2) polymorphism gene and coronary artery disease risk: a meta-analysis. Genetics and molecular research : GMR 24 26782498
2023 ALDH2 ameliorates ethanol-induced gastric ulcer through suppressing NLPR3 inflammasome activation and ferroptosis. Archives of biochemistry and biophysics 23 37209766
2019 ALDH2 deficiency inhibits Ox-LDL induced foam cell formation via suppressing CD36 expression. Biochemical and biophysical research communications 23 30853183
2016 Roles of defective ALDH2 polymorphism on liver protection and cancer development. Environmental health and preventive medicine 23 27714678
2023 p53 protects against alcoholic fatty liver disease via ALDH2 inhibition. The EMBO journal 22 36825429
2023 Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2-LIN28B-ELK3 Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 37822152
2022 ALDH2 Hampers Immune Escape in Liver Hepatocellular Carcinoma through ROS/Nrf2-mediated Autophagy. Inflammation 22 35715591
2020 ALDH2 mutation promotes skeletal muscle atrophy in mice via accumulation of oxidative stress. Bone 21 33188956
2016 Role of ADH1B rs1229984 and ALDH2 rs671 gene polymorphisms in the development of Alzheimer's disease. Genetics and molecular research : GMR 21 27808372
2024 Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS. Cellular & molecular immunology 20 38472357
2019 The Bidirectional Effect of Defective ALDH2 Polymorphism and Disease Prevention. Advances in experimental medicine and biology 20 31368098
2008 SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan. Journal of gastroenterology and hepatology 20 18336671
2023 Impact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer's disease. Frontiers in aging neuroscience 19 37693648
2020 Association between ALDH2 and ADH1B Polymorphisms and the Risk for Colorectal Cancer in Koreans. Cancer research and treatment 19 33421985
2018 A comparison of CRISPR/Cas9 and siRNA-mediated ALDH2 gene silencing in human cell lines. Molecular genetics and genomics : MGG 19 29383448
2016 [Fundamental Properties of Aldehyde Dehydrogenase 2 (ALDH2) and the Importance of the ALDH2 Polymorphism]. Nihon eiseigaku zasshi. Japanese journal of hygiene 19 26832618
2014 Meta-analysis of association between ALDH2 rs671 polymorphism and essential hypertension in Asian populations. Herz 19 25403981
2019 ALDH2 and Cancer Therapy. Advances in experimental medicine and biology 18 31368107
2018 Salvaging the Ischemic Heart: Gi-Coupled Receptors in Mast Cells Activate a PKCε/ALDH2 Pathway Providing Anti-RAS Cardioprotection. Current medicinal chemistry 18 29446730
2011 Esophageal squamous cell carcinoma and ALDH2 and ADH1B polymorphisms in Chinese females. Asian Pacific journal of cancer prevention : APJCP 18 22292652
2023 ALDH2 deficiency exacerbates MCD-diet induced MASLD by modulating bile acid metabolism. Free radical biology & medicine 17 38104741
2022 Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy. Oxidative medicine and cellular longevity 17 35770049
2016 Aldehyde Dehydrogenase 2 (ALDH2) Polymorphism and the Risk of Alcoholic Liver Cirrhosis among East Asians: A Meta-Analysis. Yonsei medical journal 17 27189280
2014 Contribution of ALDH2 polymorphism to alcoholism-associated hypertension. Recent patents on endocrine, metabolic & immune drug discovery 17 25354396
2024 Deciphering the role of tryptophan metabolism-associated genes ECHS1 and ALDH2 in gastric cancer: implications for tumor immunity and personalized therapy. Frontiers in immunology 16 39328412
2023 ALDH2 promotes cancer stemness and metastasis in colorectal cancer through activating β-catenin signaling. Journal of cellular biochemistry 16 37183314
2023 Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis. Pharmacological research 16 37657657
2022 Association of ALDH2 rs671 and MTHFR rs1801133 polymorphisms with hypertension among Hakka people in Southern China. BMC cardiovascular disorders 15 35346052
2021 Origin and Spread of the ALDH2 Glu504Lys Allele. Phenomics (Cham, Switzerland) 15 36939783
2012 Comparative genomics, molecular evolution and computational modeling of ALDH1B1 and ALDH2. Chemico-biological interactions 15 23247008
2022 Association Study and Meta-Analysis of Polymorphisms and Blood mRNA Expression of the ALDH2 Gene in Patients with Alzheimer's Disease. Journal of Alzheimer's disease : JAD 14 35404279
2019 The Role of ALDH2 in Sepsis and the To-Be-Discovered Mechanisms. Advances in experimental medicine and biology 14 31368104
2024 ALDH2 alleviates inflammation and facilitates osteogenic differentiation of periodontal ligament stem cells in periodontitis by blocking ferroptosis via activating Nrf2. Functional & integrative genomics 13 39370484
2023 The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen-Glucose Deprivation-Induced Fibroblast Senescence. Antioxidants (Basel, Switzerland) 13 38247467
2020 Astaxanthin improves osteopenia caused by aldehyde-stress resulting from Aldh2 mutation due to impaired osteoblastogenesis. Biochemical and biophysical research communications 13 32446379
2019 Aldehyde Dehydrogenase 2 (ALDH2) and Aging: Is There a Sensible Link? Advances in experimental medicine and biology 13 31368109
2024 Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Protects against Binge Alcohol-Mediated Gut and Brain Injury. Cells 12 38891060
2024 Targeting ALDH2 to augment platinum-based chemosensitivity through ferroptosis in lung adenocarcinoma. Free radical biology & medicine 12 39216560
2024 Advances in Factors Affecting ALDH2 Activity and its Mechanisms. Cardiovascular toxicology 12 39365551
2023 SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway. Free radical biology & medicine 12 37406742
2022 Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells. Development (Cambridge, England) 12 35485397
2021 Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice. Biomolecules 12 34944441
2020 Folate, alcohol, ADH1B and ALDH2 and colorectal cancer risk. Public health nutrition 12 32223781
2020 Alcohol consumption is associated with glaucoma severity regardless of ALDH2 polymorphism. Scientific reports 12 33060820
2019 ALDH2 Polymorphism and Ethanol Consumption: A Genetic-Environmental Interaction in Carcinogenesis. Advances in experimental medicine and biology 12 31368108
2017 ALDH2*2 and peer drinking in East Asian college students. The American journal of drug and alcohol abuse 12 28471244

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