LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis

Li, Changzhi; Dong, Xuan; Du, Wenjing; Shi, Xiaoxuan; Chen, Kangjie; Zhang, Wei; Gao, Minghui

doi:10.1038/s41392-020-00297-2

Cited by 130 publications

(70 citation statements)

References 5 publications

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“…Acetyl coenzyme A carboxylase ( ACACA ) is a biotin carboxylase that catalyzes the ATP-dependent condensation of acetyl coenzyme A and carbonates to form malonyl coenzyme and this reaction governs the rate of the first stage of fatty acid synthesis (Brownsey et al, 2006 ). When cells are stimulated by iron death, AMPK is activated, which in turn phosphorylates and inhibits the activity of the AMPK downstream substrate acetyl coenzyme A carboxylase 1, as well as inhibits fatty acid synthesis, thereby slowing the accumulation of lipid oxides and the onset of iron death (Li et al, 2020a ). ACACA was proved to be a poor prognostic biomarker in various cancers (Chajès et al, 2006 ; Fang et al, 2014 ), and we also found it high-expressed in the high-risk group.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The depletion of LKB1 also can sensitize mouse embryonic fibroblasts to lipid hydroperoxidation and ferroptosis. 28 Long-chain fatty acids are mainly obtained from the diet and are named PUFA when they include more than two double bonds. 29 …”

Section: Regulation Of Ferroptosismentioning

confidence: 99%

Ferroptosis: mechanisms and links with diseases

Yan

Zou

Tuo

et al. 2021

Sig Transduct Target Ther

761

477

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Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

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“…Additionally, AMPK activation causes the degradation of ferritin (Fer), accumulation of ROS, and activation of ferroptosis [ 20 , 21 ]. A study suggested that AMPK is an upstream regulator of ferroptosis, and AMPK depletion sensitizes cells to ferroptosis [ 22 ]; however, due to insufficient detection of ferroptosis-related biomarkers and lack of mitochondrial phenotype support, the specific regulatory effect of AMPK on ferroptosis remains obscure. Assuming that the intracellular iron content and mitochondrial phenotype display an opposing trend to ferroptosis following AMPK deletion, despite lipid peroxidation occurrence, would this cell death still be considered ferroptosis?…”

Section: The Characteristics Of Ferroptosismentioning

confidence: 99%

The Cross‐Link between Ferroptosis and Kidney Diseases

Wang

Liu

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Acute and chronic kidney injuries result from structural dysfunction and metabolic disorders of the kidney in various etiologies, which significantly affect human survival and social wealth. Nephropathies are often accompanied by various forms of cell death and complex microenvironments. In recent decades, the study of kidney diseases and the traditional forms of cell death have improved. Nontraditional forms of cell death, represented by ferroptosis and necroptosis, have been discovered in the field of kidney diseases, which have reshuffled the role of traditional cell death in nephropathies. Although interactions between ferroptosis and acute kidney injury (AKI) have been continuously explored, studies on ferroptosis and chronic kidney disease (CKD) remain limited. Here, we have reviewed the therapeutic significance of ferroptosis in AKI and anticipated the curative potential of ferroptosis for CKD in the hope of providing insights into ferroptosis and CKD.

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LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis

Cited by 130 publications

References 5 publications

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

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

Ferroptosis: mechanisms and links with diseases

The Cross‐Link between Ferroptosis and Kidney Diseases

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