The Metabolic Underpinnings of Ferroptosis

Zheng, Jiashuo; Conrad, Marcus

doi:10.1016/j.cmet.2020.10.011

Cited by 760 publications

(626 citation statements)

References 275 publications

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“…To validate these RNA-seq data, we perform a custom siRNA screen targeting 29 lipid metabolism genes. We found that 10 genes, including PLA2G4C , LPCAT3 , LPCAT1 , ACSL3 and glutathione peroxidase 4 ( GPX4 ), which counteracts ferroptosis by catalyzing the reduction of peroxided PL (Liu et al, 2018; Viswanathan et al, 2017; Yang et al, 2014, 2016; Zheng and Conrad, 2020), are selectively required for the viability of KM but not of KRAS-WT LC cells (Fig. 5H and 5I).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, in the presence of reactive oxygen species (ROS), polyunsaturated FA (PUFA), long-chain FA with multiple double bonds, undergo lipid peroxidation causing ferroptosis, a form of nonapoptotic ROS-dependent programmed cell death (Yang et al, 2016). Ferroptosis plays an important role in the regulation of cell survival in several physiologic as well as pathologic processes, including cancer (Zheng and Conrad, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Bartolacci

Andreani

et al. 2021

Preprint

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Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Bartolacci

Andreani

et al. 2021

Preprint

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“…Before further comparison, the “scale” function in the “limma” R package (version 4.0.3) was applied to normalize data among databases. We gathered 62 ferroptosis-related genes from prior studies and were presented in Supplementary table 1 (Dixon et al, 2012 ; Stockwell et al, 2017 ; Zheng and Conrad, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

A Novel Defined Risk Signature of the Ferroptosis-Related Genes for Predicting the Prognosis of Ovarian Cancer

Yang

Dai

et al. 2021

Front. Mol. Biosci.

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Ferroptosis is an iron-dependent, regulated form of cell death, and the process is complex, consisting of a variety of metabolites and biological molecules. Ovarian cancer (OC) is a highly malignant gynecologic tumor with a poor survival rate. However, the predictive role of ferroptosis-related genes in ovarian cancer prognosis remains unknown. In this study, we demonstrated that the 57 ferroptosis-related genes were expressed differently between ovarian cancer and normal ovarian tissue, and based on these genes, all OC cases can be well divided into 2 subgroups by applying consensus clustering. We utilized the least absolute shrinkage and selection operator (LASSO) cox regression model to develop a multigene risk signature from the TCGA cohort and then validated it in an OC cohort from the GEO database. A 5-gene signature was built and reveals a favorable predictive efficacy in both TCGA and GEO cohort (P < 0.001 and P = 0.03). The GO and KEGG analysis revealed that the differentially expressed genes (DEGs) between the low- and high-risk subgroup divided by our risk model were associated with tumor immunity, and lower immune status in the high-risk group was discovered. In conclusion, ferroptosis-related genes are vital factors predicting the prognosis of OC and could be a novel potential treatment target.

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“…Lipid peroxides yield aldehydes that react with intracellular and membrane proteins, compromising their function. To achieve lipid peroxidation, ferroptosis requires changes in a plethora of pathways, such as iron, glutaminolysis, and cholesterol and mevalonate pathways 53 . Furthermore, ferroptosis does not imply modifications in the morphology of the cell, except for the mitochondria 54 .…”

Section: Role Of Pufas and Etherpes With Pufas: Potential Hallmark Ofmentioning

confidence: 99%

“…Ferroptosis, a term for a non-apoptotic cell death introduced in 2012, is characterized by the intracellular accumulation of lipid hydroperoxides 50,53 . Lipid peroxides yield aldehydes that react with intracellular and membrane proteins, compromising their function.…”

Section: Role Of Pufas and Etherpes With Pufas: Potential Hallmark Ofmentioning

confidence: 99%

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

Balgoma

Kullenberg

Calitz

et al. 2021

Preprint

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Metabolic and personalized interventions in cancer treatment require a better under-standing of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes of the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethano-lamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggests supplementa-tion with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depend-ing on the type of tumor and the individual. Finally, we discuss the changes in the lipidome in re-lation to the endoplasmic reticulum stress and the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

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The Metabolic Underpinnings of Ferroptosis

Cited by 760 publications

References 275 publications

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Targetingde novolipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

A Novel Defined Risk Signature of the Ferroptosis-Related Genes for Predicting the Prognosis of Ovarian Cancer

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

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