ArticleCell death & disease2022
Ammonium tetrathiomolybdate triggers autophagy-dependent NRF2 activation in vascular endothelial cells.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 25 citations in OpenAlex.
- Systemic Copper Chelation Reduces Collagen Deposition and Preserves Secretory Function in Irradiated Mouse Salivary Glands.Advances in radiation oncology · 2026Article
- ASPP2 inhibits hepatocellular carcinoma growth by regulating cuproptosis via mitochondrial protein lipoylation.Cell death & disease · 2026Article
- Harnessing copper: Innovative approaches to combat neurodegenerative diseases and cancer (Review).International journal of molecular medicine · 2026Review
- Neuromodulation and Copper Chelation Reverse Sleep Fragmentation-Aggravated Myocardial Ischemia-Reperfusion Injury by Targeting NET-Induced Endothelial Cuproptosis.Research (Washington, D.C.) · 2026Article
- Cuproptosis in osteoarthritis: Exploring chondrocyte cuproptosis and therapeutic avenues.Journal of orthopaedic translation · 2025Article
- Nanomedicine strategies for cuproptosis: Metabolic reprogramming and tumor immunotherapy.Acta pharmaceutica Sinica. B · 2025Review
- An Up-to-Date Review of Traditional Chinese Medicine in the Treatment of Atherosclerosis: Components, Mechanisms, and Therapeutic Potentials.Phytotherapy research : PTR · 2025Review
- Bovine milk-derived extracellular vesicles reduce oxidative stress and ferroptosis induced by Klebsiella pneumoniae in bovine mammary epithelial cells.Journal of animal science and biotechnology · 2025Article
- Interaction of ferroptosis and cuproptosis in the perspective of pulmonary hypertension.Frontiers in cardiovascular medicine · 2025Review
- Nrf2 Connects Cellular Autophagy and Vascular Senescence in Atherosclerosis: A Mini-Review.Journal of lipid and atherosclerosis · 2024Review
- Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes.Nature communications · 2024Article
- Disulfidptosis, A Novel Cell Death Pathway: Molecular Landscape and Therapeutic Implications.Aging and disease · 2024Review
- ATG5 Knockdown Attenuates Ischemia‒Reperfusion Injury by Reducing Excessive Autophagy-Induced Ferroptosis.Translational stroke research · 2024Article
- Ammonium tetrathiomolybdate relieves oxidative stress in cisplatin-induced acute kidney injury via NRF2 signaling pathway.Cell death discovery · 2023Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ammonium tetrathiomolybdate (TTM) is a copper chelator in clinical trials for treatment of Wilson's disease, tumors and other diseases. In the current study, we innovatively discovered that TTM is a novel NRF2 activator and illustrated that autophagy contributed to TTM-induced NRF2 activation. We showed that TTM treatment promoted NRF2 nuclear translocation and upregulated transcription level of NRF2 target genes including HMOX1, GCLM, and SLC7A11 in vascular endothelial cells (HUVECs). Moreover, NRF2 deficiency directly hindered TTM-mediated antioxidative effects. Followingly, we revealed that overexpression of KEAP1, a negative regulator of NRF2, significantly repressed NRF2 activation induced by TTM. Further mutation analysis revealed that KEAP1 Cys151 is a major sensor responsible for TTM-initiated NRF2 signaling, suggesting that KEAP1 is involved in TTM-mediated NRF2 activation. Notably, we found that TTM can trigger autophagy as evidenced by accumulation of autophagosomes, elevation of LC3BI-II/I, increase of LC3 puncta and activation of AMPK/mTOR/ULK1 pathway. Autophagic flux assay indicated that TTM significantly enhanced autophagic flux in HUVECs. Inhibition of autophagy with knockout of autophagy key gene ATG5 resulted in suppression of TTM-induced NRF2 activation. TTM also induced phosphorylation of autophagy receptor SQSTM1 at Ser349, while SQSTM1-deficiency inhibited KEAP1 degradation and blocked NRF2 signaling pathway, suggesting that TTM-induced NRF2 activation is autophagy dependent. As the novel NRF2 activator, TTM protected against sodium arsenite (NaAsO
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