Activation of lysosomal iron triggers ferroptosis in cancer DOI Creative Commons
Tatiana Cañeque, Leeroy Baron, Sebastian Müller

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Iron catalyses the oxidation of lipids in biological membranes and promotes a form cell death called ferroptosis1. Defining where this chemistry occurs can inform design drugs capable inducing or inhibiting ferroptosis various disease-relevant settings. Genetic approaches have revealed suppressors ferroptosis2-4; by contrast, small molecules provide spatiotemporal control at work5. Here we show that inhibitor liproxstatin-1 exerts cytoprotective effects inactivating iron lysosomes. We also inducer RSL3 initiates membrane lipid designed small-molecule activator lysosomal iron-fentomycin-1-to induce oxidative degradation phospholipids ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma pancreatic ductal adenocarcinoma cells, which promote metastasis fuel drug tolerance. In such regulates adaptation6,7 while conferring vulnerability ferroptosis8,9. Sarcoma cells exposed sublethal doses fentomycin-1 acquire ferroptosis-resistant state characterized downregulation mesenchymal markers activation membrane-damage response. This phospholipid degrader eradicate drug-tolerant persister cancer vitro reduces intranodal tumour growth mouse model breast metastasis. Together, these results reactivity confers therapeutic benefits, establish as druggable target highlight value targeting states10.

Language: Английский

Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis DOI Open Access
Luc Rochette,

Geoffrey Dogon,

Eve Rigal

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 449 - 449

Published: Dec. 27, 2022

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms RCD, ferroptosis is considered as type reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) lipid (L) membrane via formation radical L• induce peroxidation to form L-ROS. Ferroptosis triggered by an imbalance between hydroperoxide (LOOH) detoxification iron-dependent L-ROS accumulation. Intracellular iron accumulation are two central biochemical events leading ferroptosis. Organelles, including mitochondria lysosomes involved in regulation metabolism redox In this review, we will provide overview peroxidation, well key components ferroptotic cascade. The main mechanism that reduces ability glutathione (GSH). GSH, tripeptide includes glutamic acid, cysteine, glycine, acts antioxidant substrate peroxidase 4 (GPX4), which then converted into oxidized (GSSG). Increasing expression GSH inhibit We highlight role xc- GSH-GPX4 pathway regulate system xc-, composed subunit solute carrier family members (SLC7A11 SLC3A2), mediates exchange cystine glutamate across plasma synthesize GSH. Accumulating evidence indicates requires autophagy machinery for its execution. Ferritinophagy used describe removal major storage protein ferritin machinery. Nuclear receptor coactivator (NCOA4) cytosolic bind subsequent degradation ferritinophagy. During ferritinophagy, stored released becomes available biosynthetic pathways. dysfunctional response implicated variety pathological conditions. inducers or inhibitors targeting redox- metabolism-related proteins signal transduction have been developed. simultaneous detection intracellular extracellular markers may help diagnose treat diseases related damage.

Language: Английский

Citations

400
Molecular Engineering of pH-Responsive NIR Oxazine Assemblies for Evoking Tumor Ferroptosis via Triggering Lysosomal Dysfunction DOI
Wei Li,

Shulu Yin,

Yang Shen

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(6), P. 3736 - 3747

Published: Feb. 2, 2023

Ferroptosis, a newly discovered form of regulated cell death, is emerging as promising approach to tumor therapy. However, the spatiotemporal control cell-intrinsic Fenton chemistry modulate ferroptosis remains challenging. Here, we report an oxazine-based activatable molecular assembly (PTO-Biotin Nps), which capable triggering lysosomal dysfunction-mediated pathway with excellent resolution via near-infrared (NIR) light evoke ferroptosis. In this system, pH-responsive NIR photothermal oxazine molecule was designed and functionalized tumor-targeting hydrophilic biotin-poly(ethylene glycol) (PEG) chain engineer well-defined nanostructured assemblies within single-molecular framework. PTO-Biotin Nps possesses selective tropism lysosome accumulation inside cells, accommodated by its enhanced activity in acidic microenvironment. Upon activation, promoted dysfunction induced cytosolic acidification impaired autophagy. More importantly, photoactivation-mediated found markedly enhance cellular reactions ferroptosis, thereby improving antitumor efficacy mitigating systemic side effects. Overall, our study demonstrates that engineering enables modulation intrinsic mechanism, offering novel strategy for development metal-free inducers

Language: Английский

Citations

110
Ferroptosis: mechanisms and implications for cancer development and therapy response DOI
Ancély Ferreira dos Santos, Gholamreza Fazeli, Thamara Nishida Xavier da Silva

et al.

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 33(12), P. 1062 - 1076

Published: May 23, 2023

Language: Английский

Citations

75
TFEB regulates cellular labile iron and prevents ferroptosis in a TfR1-dependent manner DOI
Leilei Chen, Yue Ma,

Xizhen Ma

et al.

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 208, P. 445 - 457

Published: Sept. 7, 2023

Language: Английский

Citations

61
Iron imbalance in neurodegeneration DOI Creative Commons
Sonia Levi, Maddalena Ripamonti, Andrea Stefano Moro

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(4), P. 1139 - 1152

Published: Jan. 12, 2024

Iron is an essential element for the development and functionality of brain, anomalies in its distribution concentration brain tissue have been found to be associated with most frequent neurodegenerative diseases. When magnetic resonance techniques allowed iron quantification vivo, it was confirmed that alteration homeostasis a common feature many However, whether main actor process, or consequence degenerative process still open question. Because different iron-related pathogenic mechanisms are specific distinctive diseases, identifying molecular various pathologies could represent way clarify this complex topic. Indeed, both overload deficiency profound consequences on cellular functioning, contribute neuronal death processes manners, such as promoting oxidative damage, loss membrane integrity, proteostasis, mitochondrial dysfunction. In review, attempt elucidate dyshomeostasis health, we summarize pathological couple death.

Language: Английский

Citations

60
Combined exposure of emamectin benzoate and microplastics induces tight junction disorder, immune disorder and inflammation in carp midgut via lysosome/ROS/ferroptosis pathway DOI
Xu Shi,

Tong Xu,

Meichen Gao

et al.

Water Research, Journal Year: 2024, Volume and Issue: 257, P. 121660 - 121660

Published: April 22, 2024

Language: Английский

Citations

49
Transformable Supramolecular Self‐Assembled Peptides for Cascade Self‐Enhanced Ferroptosis Primed Cancer Immunotherapy DOI
He Wang,

Di Jiao,

Dexiang Feng

et al.

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(21)

Published: Feb. 10, 2024

Abstract Immunotherapy has received widespread attention for its effective and long‐term tumor‐eliminating ability. However, immunogenic “cold” tumors, such as prostate cancer (PCa), the low immunogenicity of tumor itself is a serious obstacle to efficacy. Here, this work reports strategy enhance PCa by triggering cascade self‐enhanced ferroptosis in cells, turning from “hot”. This develops transformable self‐assembled peptide TEP‐FFG‐CRApY with alkaline phosphatase (ALP) responsiveness glutathione peroxidase 4 (GPX4) protein targeting. self‐assembles into nanoparticles under aqueous conditions transforms nanofibers response ALP during endosome/lysosome uptake promoting lysosomal membrane permeabilization (LMP). On one hand, released TEP‐FFG‐CRAY target GPX4 selectively degrade light irradiation, inducing ferroptosis; on other large amount leaked Fe 2+ further amplify through Fenton reaction. TEP‐FFG‐CRApY‐induced improves cell maturation dendritic cells (DCs) increasing intratumor T‐cell infiltration. More importantly, recovered T secreting amounts interferon‐gamma (IFN‐γ). provides novel molecular design synergistic molecularly targeted therapy tumors.

Language: Английский

Citations

33
Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications DOI Creative Commons
Yongxin Zheng, Junlu Sun,

Zhiting Luo

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(11)

Published: Nov. 26, 2024

Abstract Regulated cell death (RCD) refers to the form of that can be regulated by various biomacromolecules. Each modalities have their distinct morphological changes and molecular mechanisms. However, intense evidences suggest lipid peroxidation common feature initiates propagates death. Excessive alters property membrane further damage proteins nucleic acids, which is implicated in human pathologies. Here, we firstly review classical chain process peroxidation, clarify current understanding myriad roles mechanisms RCD types. We also discuss how involves diseases such intimate association between peroxidation-driven leveraged develop rational therapeutic strategies.

Language: Английский

Citations

19
Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases DOI Creative Commons
Leilei Chen, Qingqing Shen, Yingjuan Liu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 2, 2025

Language: Английский

Citations

12
Metal Ion Signaling in Biomedicine DOI Creative Commons
Raphaël Rodriguez, Sebastian Müller, Ludovic Colombeau

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species defined by their genomes, and differences between individuals within a given species directly result from variations in genetic codes. While alterations give rise to disease-causing acquisitions cell identities, it is now well-established biochemical imbalances also lead cellular dysfunction diseases. Specifically, nongenetic chemical events orchestrate metabolism transcriptional programs govern functional identity. Thus, signaling, which broadly defines the conversion extracellular signals into intracellular changes, contribute acquisition diseased states. Metal ions exhibit unique properties be exploited cell. For instance, metal maintain ionic balance cell, coordinate amino acid residues or nucleobases altering folding function biomolecules, catalyze reactions. metals essential signaling effectors normal physiology disease. Deciphering ion challenging endeavor illuminate pathways targeted for therapeutic intervention. Here, we review key processes where play roles describe how targeting has been instrumental dissecting biochemistry this led development effective strategies.

Language: Английский

Citations

4