The instrumental role of lipids in governing the sensitivity of multiple myeloma to ferroptosis

Abstract

Multiple myeloma (MM) is a malignancy characterised by the uncontrolled proliferation of clonal plasma cells, primarily within the bone marrow, and is still considered incurable. A significant proportion of patients relapse with drug-refractory disease, necessitating the development of novel therapeutic approaches. Ferroptosis is a recently-characterised form of non-apoptotic programmed cell death, linked to phospholipid peroxidation, that represents a promising approach for the treatment of MM and other cancers, that are refractory to more conventional apoptosis-inducing regimens. A better understanding of the relationship between cellular lipid composition and ferroptosis sensitivity is key to harnessing this form of programmed cell death as a therapeutic approach. In addition to the cellular proportions of phospholipids containing poly- and monounsaturated fatty acids, studies to date indicate that cholesterol levels impact not only the onset and progression of haematological malignancies but also the sensitivity of a variety of different cancers to ferroptosis. Therefore, manipulating the uptake and metabolism of lipids, including glycerophospholipids and cholesterol, may be an effective means of sensitising MM cells to ferroptosis. Findings from the limited number of studies concerning ferroptosis in MM and compelling evidence from other malignancies, provide a strong rationale for further investigation of ferroptosis as a novel therapeutic approach for MM.

Keywords: Cancer; Cholesterol; Fatty acids; Ferroptosis; Haematology; Lipids; Multiple myeloma; Phospholipids; Saturated; Unsaturated.

Fig. 1

Ferroptosis, driven by lipid peroxidation, is inhibited by system X_c^- and GPX4.

Fig. 2

Biochemical pathways of the mevalonate pathway in the inhibition of ferroptosis.