Preliminary Study Of LKB1-AMPK Signaling Pathway In Ferroptosis

Ferroptosis is an adjustable form of cell death characterized by iron-dependent lipid peroxidation.Although more and more evidences show that a variety of cellular metabolic processes promote ferroptosis,the detailed mechanism that regulates ferroptosis in cells is still unclear.AMP-dependent protein kinase(AMPK)is a very important metabolic and energy sensor in cells.Its upstream kinase LKB1 is a very important tumor suppressor protein.LKB1 activates AMPK activity by phosphorylating the Thr-172 site of AMPK,thereby regulating cell energy homeostasis.Clinical data shows that more than 20% of patients with non-small cell lung cancer carry the inactivating mutation of LKB1,and there is currently no effective treatment strategy for such patients.At the beginning of this study,it was found that the lack of glucose can inhibit cell death induced by ferroptosis inducers Erastin or RSL3,which indicates that glucose has a key regulatory effect on ferroptosis.When glucose is lacking,the level of intracellular ATP decreases,which in turn leads to the activation of AMPK.Therefore,this study focused on the LKB1-AMPK signaling pathway and explored its regulatory mechanism in ferroptosis.In our experiments,we found that activating AMPK with drugs can inhibit ferroptosis of cells,and gene knock down AMPK can increase the sensitivity of cells to ferroptosis.Mouse Embryonic Fibroblast(MEF)and human non-small cell lung cancer cells with loss of LKB1 function are also more sensitive to ferroptosis.We believe that after cells are stimulated by ferroptosis inducers,AMPK is activated by the upstream kinase LKB1,which controls lipid biosynthesis to protect cells from the accumulation of lipid peroxides and ferroptosis.In our research,we found that tumor cells carrying LKB1 mutations are extremely sensitive to iron death,which laid a theoretical foundation for us to develop specific drugs that target tumors carrying LKB1 mutations.