AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells

Multiple myeloma (MM) is an incurable malignancy of plasma cells that is sensitive to T-5224, an AP-1 Inhibitor. Previous study indicated that T-5224 inhibits proliferation and induces Apoptosis in MM cells. However, the high mortality cannot be fully explained. To date, no studies have investigated Ferroptosis induced by T-5224 in MM. Therefore, we further investigated the mechanism by which T-5224 kills MM cells. We observed that T-5224 exhibits antimyeloma properties both in vitro and in vivo. T-5224-induced MM cell death was reversed by the ferroptosis-specific inhibitor ferropstatin-1 (Fer-1). The protein levels of the key Ferroptosis regulators GPX4 and SLC7A11 were decreased by T-5224 in MM cells. Furthermore, T-5224 reduced the phosphorylation of PI3K and Akt signaling pathway components, ultimately causing MM cell death. Using 740 Y-P, a PI3K Activator, and Fer-1, a Ferroptosis inhibitor, we discovered that T-5224 induces Ferroptosis through the PI3K/Akt pathway. Bortezomib (BTZ), an FDA-approved drug for MM treatment, can be administered in combination with Other agents. We evaluated the synergistic effect of BTZ combined with AP-1 inhibitors on MM in vivo. Our findings provide a better theoretical basis for the potential mechanism of T-5224 and a new perspective on MM treatment.

Bortezomib; Ferroptosis; Multiple myeloma; PI3K/AKT; T-5224.