Targeting ferroptosis as a vulnerability in cancer

Lei, Guang; Li, Zhuang; Gan, Boyi

doi:10.1038/s41568-022-00459-0

Cited by 1,180 publications

(800 citation statements)

References 203 publications

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“…Ferroptosis recently emerged as an iron-dependent, non-apoptotic form of regulated cell death particularly relevant to cancer therapy with implications in response to chemotherapy, radiotherapy and immunotherapy [67][68][69] . However, no selective GPX4 inhibitor is currently available for patient care.…”

Section: Discussionmentioning

confidence: 99%

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Sabatier

Birsen

Tamburini

et al. 2022

Preprint

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While transcription factor C/AAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBPα-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application

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Section: Discussionmentioning

confidence: 99%

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Sabatier

Birsen

Tamburini

et al. 2022

Preprint

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“…However, SLC40A1, encoding ferroportin-1, was upregulated in our analysis ( Figure 1C ). Theoretically, when ferroptosis occurs in septic patients, SLC40A1-mediated iron export was inhibited ( 33 ). However, SLC40A1 should be increased from a clinical or homeostasis view.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Predictive Values of Ferroptosis-Related Genes in Child Sepsis

Zhang²,

Liu³

et al. 2022

Front. Immunol.

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BackgroundEarly diagnosis of sepsis in children was essential to reducing mortality. This study aimed to explore the value of ferroptosis-related genes in children with sepsis.MethodsWe screened the septic children microarray dataset from the GEO database and analyzed the ferroptosis-related differentially expressed genes (DEGs). A functional analysis of ferroptosis-related DEGs was performed. The protein–protein interaction network was used to identify hub genes. We explored the immune landscape of sepsis and controls. The value of hub genes in diagnosing sepsis was tested in the training (GSE26440) and validation sets (GSE13904), and ELISA was used to verify their diagnostic value in children with sepsis in our hospital.ResultsA total of 2,103 DEGs in GSE26440 were obtained, of which ferroptosis-related DEGs were 34. Enrichment analysis showed significant enrichment in the ferroptosis and hypoxia pathways (i.e., HIF-1 pathway). The top three genes (HMOX1, MAPK14, TLR4) were selected as hub genes. Immunological analysis suggested that 10 cell types (i.e., CD8/CD4 T cells) were lower in sepsis. Immune checkpoint-related genes CD274 (PD-L1), HAVCR2 (TIM3), and SIGLEC15 were overexpressed in sepsis. The AUROC for the diagnosis of sepsis for HMOX1 and TLR4 ranged from 0.77 to 0.81, while the AUROC of MAPK14 reached 0.935 and 0.941 in the training and validation sets. Serum ELISA results of HMOX1 and TLR4 showed no significant difference in differentiating sepsis. The AUROC of MAPK14 was 0.877. When the diagnostic threshold was 74.852 ng/ml, the sensitivity and specificity were 0.906 and 0.719, respectively.ConclusionFerroptosis-related gene MAPK14 is of considerable value in the early diagnosis of sepsis in children.

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“…So far the subcellular localization of the GCH1/BH4/DHFR axis is not fully-illustrated. 32 The cyst(e)ine/GSH/GPX4 axis is the first discovered and most extensively studied pathway in suppressing ferroptosis. 33 GPX4 is a selenoprotein that catalyzes the reduction and detoxification of lipid ROS production in mammalian cells.…”

Section: Lpo-mediated Cytotoxicitymentioning

confidence: 99%

Role of Ferroptosis in Fibrotic Diseases

Zhou¹,

Yuan²,

Wang³

et al. 2022

JIR

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Ferroptosis is a unique and pervasive form of regulated cell death driven by iron-dependent phospholipid peroxidation. It results from disturbed cellular metabolism and imbalanced redox homeostasis and is regulated by various cellular metabolic pathways. Recent preclinical studies have revealed that ferroptosis may be an attractive therapeutic target in fibrotic diseases, such as liver fibrosis, pulmonary fibrosis, kidney fibrosis, and myocardial fibrosis. This review summarizes the latest knowledge on the regulatory mechanism of ferroptosis and its roles in fibrotic diseases. These updates may provide a novel perspective for the treatment of fibrotic diseases as well as future research.

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Targeting ferroptosis as a vulnerability in cancer

Cited by 1,180 publications

References 203 publications

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

Diagnostic and Predictive Values of Ferroptosis-Related Genes in Child Sepsis

Role of Ferroptosis in Fibrotic Diseases

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