Targeting the circ_0042819-PLA2G6 axis sensitizes multiple myeloma to proteasome inhibitors through ferroptosis induction

Multiple myeloma (MM) is a refractory plasma cell neoplasm characterized by frequent development of drug resistance, leading to poor clinical outcomes. Activation of ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a promising cancer therapeutic strategy. In this study, we show that the circular RNA circ_0042819 exhibits high expression in both bone marrow and plasma samples from MM patients, with its overexpression strongly associated with disease progression and unfavorable prognosis. Mechanistically, circ_0042819 directly interacts with Up-frameshift protein 1 (UPF1) in MM cells, and the circ_0042819-UPF1 complex upregulates the expression of phospholipase A2 group VI (PLA2G6) via interacting with, and thus stabilizing, its mRNA. Furthermore, the circ_0042819-PLA2G6 axis suppresses ferroptosis through phospholipid remodeling in MM cells. Importantly, depletion of circ_0042819 or PLA2G6 enhances MM sensitivity to proteasome inhibitors (bortezomib and carfilzomib) by promoting ferroptosis both in vitro and in vivo. Collectively, our findings demonstrate that circ_0042819 is a potential non-invasive biomarker for the diagnosis and prognosis of MM, and that inhibition of the circ_0042819-PLA2G6 axis can mitigate the resistance of MM to proteasome inhibitors through ferroptosis sensitization, thus suggesting a novel therapeutic approach.