Abstract

Ferroptosis is a form of regulated necrotic cell death characterized by an iron-dependent lipid peroxidation. Although mounting evidence has demonstrated that diverse cellular metabolic processes contribute to ferroptosis, the detail mechanism by which cellular metabolism regulates ferroptosis is largely unknown. Here, we demonstrated that AMP-activated protein kinase (AMPK), a highly conversed master regulator of cellular energy homostasis is a crucial negative regulator of ferroptosis. Activation of AMPK by glucose starvation or a pharmaceutical activator suppresses ferroptotic cell death, and genetic knocking out of AMPK sensitizes cells to ferroptosis. Mechanistically, ferroptosis inducers activate AMPK which in turn phosphorylates acetyl-CoA carboxylase 1 (ACC1), leading to inhibition of fatty acid synthesis, lipid peroxide accumulation and ferroptosis. Importantly, loss of function of tumor suppressor liver kinase B1 (LKB1) sensitizes mouse embryonic fibroblasts (MEFs) and human non-small cell lung carcinoma cell lines to ferroptosis. Collectively, our results demonstrate the vital role of LKB1-AMPK-ACC1-FAS axis in dictating ferroptotic cell death, and suggest that malignant mutations in LKB1-AMPK signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies.

Highlights

  • Dear Editor, Ferroptosis has emerged as a new programmed cell death modality highly relevant to disease.[1]

  • Since both glucose starvation and inhibiting the activity of TCA cycle and electron transport chain (ETC) decrease cellular ATP level and lead to the activation of AMPK,[3] we investigated the involvement of AMPK in ferroptosis

  • Double knockout (DKO) of AMPK α1 and α2 subunits significantly enhanced the sensitivity of mouse embryonic fibroblasts (MEFs) to ferroptosis and accumulation of lipid hydroperoxides induced by erastin or RSL3 compared to wild-type MEFs (Fig. 1b, c, Supplementary Fig. 1d–h)

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Summary

Introduction

Dear Editor, Ferroptosis has emerged as a new programmed cell death modality highly relevant to disease.[1]. Double knockout (DKO) of AMPK α1 and α2 subunits significantly enhanced the sensitivity of MEFs to ferroptosis and accumulation of lipid hydroperoxides induced by erastin or RSL3 compared to wild-type MEFs (Fig. 1b, c, Supplementary Fig. 1d–h). Previous studies suggested that inhibition of AMPKα by compound C diminishes erastin-induced ferroptosis in cancer cells.[4] we found compound C inhibited ferroptosis in wild-type MEFs and in AMPK DKO MEFs, suggesting the inhibitory effect of compound C on ferroptosis is independent on AMPK (Supplementary Fig. 1o).

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