Activation of lysosomal iron triggers ferroptosis in cancer

Nature, Год журнала: 2025, Номер unknown

Опубликована: Май 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.

Язык: Английский

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Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression

Pharmacology & Therapeutics, Год журнала: 2021, Номер 232, С. 107992 - 107992

Опубликована: Окт. 1, 2021

Язык: Английский

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Understanding Anthracycline Cardiotoxicity From Mitochondrial Aspect

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Фев. 8, 2022

Anthracyclines, such as doxorubicin, represent one group of chemotherapy drugs with the most cardiotoxicity. Despite that anthracyclines are capable treating assorted solid tumors and hematological malignancies, side effect inducing cardiac dysfunction has hampered their clinical use. Currently, mechanism underlying anthracycline cardiotoxicity remains obscure. Increasing evidence points to mitochondria, energy factory cardiomyocytes, a major target anthracyclines. In this review, we will summarize recent findings about mitochondrial during particular, focus on following aspects: 1) traditional view anthracycline-induced reactive oxygen species (ROS), which is produced by but in turn causes injury. 2) Mitochondrial iron-overload ferroptosis 3) Autophagy, mitophagy dynamics 4) Anthracycline-induced disruption metabolism.

Язык: Английский

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Iron-Sensitive Prodrugs That Trigger Active Ferroptosis in Drug-Tolerant Pancreatic Cancer Cells

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(26), С. 11536 - 11545

Опубликована: Июнь 13, 2022

Persister cancer cells represent rare populations of resistant to therapy. Cancer can exploit epithelial-mesenchymal plasticity adopt a drug-tolerant state that does not depend on genetic alterations. Small molecules interfere with cell or kill in state-dependent manner are highly sought after. Salinomycin has been shown the mesenchymal by sequestering iron lysosomes, taking advantage addiction this state. Here, we report chemo- and stereoselective synthesis series structurally complex small molecule chimeras salinomycin derivatives iron-reactive dihydroartemisinin. We show these accumulate lysosomes react release bioactive species, thereby inducing ferroptosis pancreatic biopsy-derived organoids ductal adenocarcinoma. This work paves way toward development new medicines acting through active ferroptosis.

Язык: Английский

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Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer

Science Advances, Год журнала: 2023, Номер 9(16)

Опубликована: Апрель 19, 2023

Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that inhibition alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression limiting availability labile pool. uses homeostasis, while other tumor types assessed require macropinocytosis, with being dispensable. We observed cancer-associated fibroblasts can provide bioavailable cells, promoting resistance ablation. To overcome this cross-talk, used low-iron diet demonstrated augmented response therapy PDAC-bearing mice. Our work highlights critical link between metabolism, may have implications for progression.

Язык: Английский

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Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription

Acta Pharmacologica Sinica, Год журнала: 2023, Номер 44(8), С. 1712 - 1724

Опубликована: Фев. 24, 2023

Язык: Английский

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Reactive Oxygen Species: A Crosslink between Plant and Human Eukaryotic Cell Systems

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13052 - 13052

Опубликована: Авг. 22, 2023

Reactive oxygen species (ROS) are important regulating factors that play a dual role in plant and human cells. As the first messenger response organisms, ROS coordinate signals growth, development, metabolic activity pathways. They also can act as an alarm mechanism, triggering cellular responses to harmful stimuli. However, excess cause oxidative stress-related damage oxidize organic substances, leading malfunctions. This review summarizes current research status mechanisms of eukaryotic cells, highlighting differences similarities between two elucidating their interactions with other reactive substances ROS. Based on similar regulatory pathways kingdoms, this proposes future developments provide opportunities develop novel strategies for treating diseases or creating greater agricultural value.

Язык: Английский

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Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 21, 2023

Ferroptosis, a newly characterized form of regulated cell death, is induced by excessive accumulation lipid peroxidation catalyzed intracellular bioactive iron. Increasing evidence has suggested that ferroptosis involved in the pathogenesis several human diseases, including acute liver injury. Targeted inhibition holds great promise for clinical treatment these diseases. Herein, we report simple and one-pot synthesis ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles (PAA@Mn3O4-NPs, PMO), which perform multiple antioxidant enzyme-mimicking activities can scavenge broad-spectrum reactive oxygen species. PMO could potently suppress ferroptosis. Mechanistically, after being absorbed mainly through macropinocytosis, are largely enriched lysosomes, where detoxify ROS, inhibit ferritinophagy-mediated iron mobilization preserve mTOR activation, collectively confer prominent Additionally, injection counteracts alleviates acetaminophen- ischaemia/reperfusion-induced injury mice. Collectively, our results reveal biocompatible act as potent inhibitors multifaceted mechanisms, ensures have translational potential ferroptosis-related

Язык: Английский

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Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death

Molecules, Год журнала: 2023, Номер 28(10), С. 4085 - 4085

Опубликована: Май 14, 2023

Energy transfer to ground state triplet molecular oxygen results in the generation of singlet (1O2), which has potent oxidizing ability. Irradiation light, notably ultraviolet A, a photosensitizing molecule 1O2, is thought play role causing skin damage and aging. It should also be noted that 1O2 dominant tumoricidal component generated during photodynamic therapy (PDT). While type II action generates not only but other reactive species, endoperoxides release pure upon mild exposure heat and, hence, are considered beneficial compounds for research purposes. Concerning target molecules, preferentially reacts with unsaturated fatty acids produce lipid peroxidation. Enzymes contain cysteine group at catalytic center vulnerable exposure. Guanine base nucleic susceptible oxidative modification, cells carrying DNA oxidized guanine units may experience mutations. Since produced various physiological reactions addition reactions, overcoming technical challenges related its detection methods used would allow potential functions biological systems better understood.

Язык: Английский

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Revealing Mitochondrion–Lysosome Dynamic Interactions and pH Variations in Live Cells with a pH-Sensitive Fluorescent Probe

Analytical Chemistry, Год журнала: 2023, Номер 95(45), С. 16609 - 16617

Опубликована: Ноя. 2, 2023

Mitochondrion–lysosome interactions have garnered significant attention in recent research. Numerous studies shown that mitochondrion–lysosome interactions, including contact (MLC) and mitophagy, are involved various biological processes pathological conditions. Single fluorescent probes termed a pivotal chemical tool unraveling the intricate spatiotemporal interorganelle interplay live cells. However, current tools insufficient to deeply understand dynamic related diseases, Moreover, rational design of dual-targeting is intractable. Herein, we designed synthesized pH-sensitive probe called INSA, which could simultaneously light up mitochondria (red emission) lysosomes (green for their internal pH differences. Employing successfully recorded long-term between mitochondria. More importantly, increasing ferroptotic cells were also revealed by INSA. Further, observed variations during ferroptosis first time. In brief, this work not only introduced INSA disclosure interplays but pioneered visualization organellar alternation specific disease model.

Язык: Английский

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