Metabolic vulnerabilities in multiple myeloma: targeting iron and amino acid metabolism to induce ferroptosis.

Could ferroptosis, a novel cell death pathway, offer a potential therapeutic strategy for multiple myeloma (MM)? Our previous research showed that ferroptosis is suppressed in MM patients, with varying sensitivities among MM cells. In this study, metabolomic analysis highlighted the pivotal role of amino acid metabolism, rather than lipid metabolism, in determining MM cells' sensitivity to ferroptosis. We further analyzed iron metabolism, another key factor influencing ferroptosis sensitivity, by collecting peripheral blood samples from 120 MM patients. Our analysis revealed a significant reduction in the levels of transferrin (TF), an essential iron-transporting protein. Moreover, low TF levels were associated with significantly worse progression-free survival and overall survival. Erastin treatment together with TF supplementation markedly enhanced ferroptosis in MM cells in vitro and in xenograft models. MM cells suppressed TF secretion by monocytes in the bone marrow microenvironment, contributing to the decreased TF levels in MM patients. The transcription factor CEBPB, found in MM cell-derived extracellular vesicles, plays a key role in this process. In conclusion, Our findings identify amino acid metabolism and iron metabolism as distinct metabolic features associated with ferroptosis sensitivity in MM. Ferroptosis, induced by erastin and TF, holds promise as a potential therapeutic strategy for MM and provides new insights for developing more effective therapies.