ArticleAntioxidants (Basel, Switzerland)2025
The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity.
Article in Antioxidants (Basel, Switzerland), 2025. 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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Who cites it
14 citing papers in PubMed.
- Subcellular regulation of ferroptosis: roles of individual intracellular organelles and cross talk.American journal of physiology. Cell physiology · 2026Review
- DDIT4 upregulation associates with gammadelta T Cells dysfunction in ART-suppressed people living with HIV-1.BMC infectious diseases · 2026Article
- Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death inHemaSphere · 2026Article
- Crossroads of iron, copper, and zinc in cancer: a paradox of toxicity and therapy.Molecular biology reports · 2026Review
- Article
- Dissecting Complex Interactions Between Ferroptosis and the Proteasome.bioRxiv : the preprint server for biology · 2026Article
- Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.Cell reports · 2026Article
- Ironing out mechanisms of ferroptotic death to tailor new stroke therapies.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- BIP orchestrates bidirectional ER protein trafficking via co-chaperone complexes.Cellular & molecular biology letters · 2026Article
- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Organelle-specific regulation of ferroptosis.Biology direct · 2026Review
- Ferroptosis: A Novel Mechanism and Therapeutic Target of Traditional Chinese Medicine for Metabolic Dysfunction-Associated Steatotic Liver Disease.Journal of inflammation research · 2026Review
- C/EBP-β Mediates the Reversal of Sorafenib Resistance by Tunicamycin in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2026Article
- Medium-Chain Fatty Acids Extracted from Black Soldier Fly (Animals : an open access journal from MDPI · 2025Article
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8 authors.
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Abstract
Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress.
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