Abstract

Deciphering the role of ferroptosis as a therapeutic strategy in Acute Myeloid Leukemia

Ferroptosis refers to an iron-dependent form of regulated but non-apoptotic form of cell death, discovered by Scott Dixon in 2012. It involves the accumulation of lethal levels lipid peroxides within the cell, leading to their membrane degradation. A key component regulating this phenomenon is the Glutathione Peroxidase 4 (GPX4) enzyme, which catalyzes the conversion of these lethal lipid peroxides into lipid alcohols, thus acting as a ferroptosis inhibitor. GPX4 uses reduced Glutathione (GSH) as its cofactor.

However, GSH synthesis requires a steady source of Cysteine within the cell, which is predominantly regulated by a Cystine/Glutamate antiporter (xCT) that intakes a Cysteine molecule in exchange of a Glutamate molecule. Cells also use a GPX4 independent pathway to suppress ferroptosis called the Ferroptosis Suppressor Protein 1 (FSP1) pathway. FSP1 suppresses ferroptosis by reducing coenzyme Q10 which traps those lethal lipid peroxyl radicals.

Our study is focusses on understanding impact of ferroptosis induction as a method to combat Acute Myeloid Leukemia via inhibition of xCT and FSP1. The initial experimental outcomes show a significant reduction in the viability of AML cells post inhibition of xCT and FSP1, decreased GSH levels, increased cell membrane damage and a significantly reduced cell colonies in colony forming unit assay. Mice having a complete knock-out of the xCT encoding gene (SLC7A11) and FSP1 encoding gene (AIFM2) produce healthy offspring, lacking any adverse symptom and possess a healthy hematopoietic system raising a possibility of xCT and FSP1 inhibition as a prospective therapeutic strategy of AML. Thus, ferroptosis induction using xCT and FSP1 inhibition displays AML cell lethality in-vitro, and the lack of any hazardous phenotype in mice raises the possibility of the success of this anti-AML therapy in-vivo.