Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy

Zheng, Xiaogang; Jin, Xiaodong; Ye, Fei; Liu, Xiongxiong; Yu, Bang-Ying; Zheng, Liwei; Zhao, Ting; Chen, Weiqiang; Liu, Xinguo; Chen, Di; Li, Qiang

doi:10.1186/s40164-023-00427-w

Cited by 31 publications

(8 citation statements)

References 205 publications

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“…Ferroptosis, a novel form of cell death characterized by GSH depletion and lipid peroxidation [ 45 – 47 ], has gained attention due to its close association with various cancers [ 48 ]. Our RNA-seq analysis revealed that the combination therapy enriched pathways related to oxidative stress, GSH metabolism, and p53.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling

Tan,

Kong,

Tao

et al. 2024

Biomark Res

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Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking effective targeted therapies, necessitating innovative treatment approaches. While targeting ROS proto-oncogene 1 (ROS1) with crizotinib has shown promise, resistance remains a limitation. Recent evidence links focal adhesion kinase (FAK) to drug resistance, prompting our study to assess the combined impact of FAK inhibitor IN10018 and crizotinib in TNBC and elucidate the underlying mechanisms. Methods We employed the Timer database to analyze FAK and ROS1 mRNA levels in TNBC and adjacent normal tissues. Furthermore, we investigated the correlation between FAK, ROS1, and TNBC clinical prognosis using the GSE database. We conducted various in vitro assays, including cell viability, colony formation, flow cytometry, EdU assays, and western blotting. Additionally, TNBC xenograft and human TNBC organoid models were established to assess the combined therapy’s efficacy. To comprehensively understand the synergistic anti-tumor mechanisms, we utilized multiple techniques, such as RNA sequencing, immunofluorescence, cell flow cytometry, C11-BODIPY staining, MDA assay, and GSH assay. Results The Timer database revealed higher levels of FAK and ROS1 in TNBC tissues compared to normal tissues. Analysis of GEO databases indicated that patients with high FAK and ROS1 expression had the poorest prognosis. Western blotting confirmed increased p-FAK expression in crizotinib-resistant TNBC cells. In vitro experiments showed that the combination therapy down-regulated cyclin B1, p-Cdc2, and Bcl2 while up-regulating BAX, cleaved-Caspase-3, cleaved-Caspase-9, and cleaved PARP. In TNBC xenograft models, the tumor volume in the combination therapy group was 73% smaller compared to the control group (p < 0.0001). Additionally, the combination therapy resulted in a 70% reduction in cell viability in human TNBC organoid models (p < 0.0001). RNA sequencing analysis of TNBC cells and xenograft tumor tissues highlighted enrichment in oxidative stress, glutathione metabolism, and p53 pathways. The combined group displayed a fivefold rise in the reactive oxygen species level, a 69% decrease in the GSH/GSSG ratio, and a sixfold increase in the lipid peroxidation in comparison to the control group. Western blotting demonstrated p53 upregulation and SCL7A11 and GPX4 downregulation in the combination group. The addition of a p53 inhibitor reversed these effects. Conclusion Our study demonstrates that the combination of IN10018 and crizotinib shows synergistic antitumor effects in TNBC. Mechanistically, this combination inhibits cell proliferation, enhances apoptosis, and induces ferroptosis, which is associated with increased p53 levels.

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Section: Discussionmentioning

confidence: 99%

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling

Tan,

Kong,

Tao

et al. 2024

Biomark Res

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“…In mice and humans, distinct GPX4 isoforms with different subcellular localization are known to be produced through alternative splicing and transcription initiation; cytoplasmic GPX4, mitochondrial GPX4 (mGPX4), and nuclear GPX4 (nGPX4) [30]. The cytoplasmic GPX4 is the isoform essential for cell survival and prevention of lipid peroxidation and ferroptosis cell death [31,32]. Together, our data suggests that virulent IOE infection not only interferes with the nuclear translocation and activation of NRF2, but also with the stability of cytoplasmic NRF2, which is associated with significant downregulation of cytoplasmic GPX4 and antioxidant response.…”

Section: Plos Pathogensmentioning

confidence: 99%

Evasion of host antioxidative response via disruption of NRF2 signaling in fatal Ehrlichia-induced liver injury

Sharma,

El Andaloussi,

Ismail

2023

PLoS Pathog

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Ehrlichia are Gram negative obligate intracellular bacterium that cause human monocytotropic ehrlichiosis (HME). HME is characterized by acute liver damage and inflammation that may progress to fatal toxic shock. We previously showed that fatal ehrlichiosis is due to deleterious activation of inflammasome pathways, which causes excessive inflammation and liver injury. Mammalian cells have developed mechanisms to control oxidative stress via regulation of nuclear factor erythroid 2 related 2 (NRF2) signaling. However, the contribution of NRF2 signaling to Ehrlichia-induced inflammasome activation and liver damage remains elusive. In this study, we investigated the contribution of NRF2 signaling in hepatocytes (HCs) to the pathogenesis of Ehrlichia-induced liver injury following infection with virulent Ixodes ovatus Ehrlichia (IOE, AKA E. japonica). Employing murine model of fatal ehrlichiosis, we found that virulent IOE inhibited NRF2 signaling in liver tissue of infected mice and in HCs as evidenced by downregulation of NRF2 expression, and downstream target GPX4, as well as decreased NRF2 nuclear translocation, a key step in NRF2 activation. This was associated with activation of non-canonical inflammasomes pathway marked by activation of caspase 11, accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Mechanistically, treatment of IOE-infected HCs with the antioxidant 3H-1,2-Dithiole-3-Thione (D3T), that induce NRF2 activation attenuated oxidative stress and caspase 11 activation, and restored cell viability. Importantly, treatment of IOE-infected mice with D3T resulted in attenuated liver pathology and inflammation, enhanced bacterial clearance, prolonged survival, and resistance to fatal ehrlichiosis. Our study reveals, for the first time, that targeting anti-oxidative signaling pathway is a key approach in the treatment of severe and potential Ehrlichia-induced acute liver injury and sepsis.

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“…Ferroptosis is unique in its capacity to target metabolic pathways other than those addressed by immunotherapy. This could provide an alternate or complementary option to current treatments, particularly when immunotherapy fails [ 26 , 27 ]. In addition, leukemia cells are more likely to express transferrin and contain more iron than other tumor cells, which makes it easier for ROS to accumulate in leukemia cells and trigger ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

Targeting ferroptosis for leukemia therapy: exploring novel strategies from its mechanisms and role in leukemia based on nanotechnology

Ashoub,

Razavi,

Heydaryan

et al. 2024

Eur J Med Res

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The latest findings in iron metabolism and the newly uncovered process of ferroptosis have paved the way for new potential strategies in anti-leukemia treatments. In the current project, we reviewed and summarized the current role of nanomedicine in the treatment and diagnosis of leukemia through a comparison made between traditional approaches applied in the treatment and diagnosis of leukemia via the existing investigations about the ferroptosis molecular mechanisms involved in various anti-tumor treatments. The application of nanotechnology and other novel technologies may provide a new direction in ferroptosis-driven leukemia therapies. The article explores the potential of targeting ferroptosis, a new form of regulated cell death, as a new therapeutic strategy for leukemia. It discusses the mechanisms of ferroptosis and its role in leukemia and how nanotechnology can enhance the delivery and efficacy of ferroptosis-inducing agents. The article not only highlights the promise of ferroptosis-targeted therapies and nanotechnology in revolutionizing leukemia treatment, but also calls for further research to overcome challenges and fully realize the clinical potential of this innovative approach. Finally, it discusses the challenges and opportunities in clinical applications of ferroptosis.

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Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy

Cited by 31 publications

References 205 publications

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling

Evasion of host antioxidative response via disruption of NRF2 signaling in fatal Ehrlichia-induced liver injury

Targeting ferroptosis for leukemia therapy: exploring novel strategies from its mechanisms and role in leukemia based on nanotechnology

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