PRDX6 knockdown sensitizes multiple myeloma cells to ferroptosis through inactivation of the PI3K/AKT pathway.

Background: This study probes into the impact and mechanisms of PRDX6 on ferroptosis multiple myeloma (MM).

Research design and methods: PRDX6 expression in MM cells were determined using Western blotting and qRT-PCR. MM cells were treated with pLKO-shPRDX6 vectors expressing PRDX6 shRNA alone or in combination with Erastin/ferrostatin-1 (ferroptosis activator/inhibitor) or 740Y-P (PI3K/AKT pathway activator). Cell viability, apoptosis, Fe²⁺ concentration, and ROS levels were examined using CCK-8, flow cytometric analysis, iron ion detection, and DCFH-DA assay, and ELISA. Malondialdehyde (MDA) and glutathione (GSH) levels were tested with ELISA, and SLC7A11 and GPX4 levels were measured with Western blotting.

Results: PRDX6 expression was sharply increased in MM cells (p < 0.01). Silencing of PRDX6 sensitized MM cells to ferroptosis, as indicated by elevated Fe²⁺, ROS, and MDA levels but decreased GSH, SLC7A11, and GPX4 levels (p < 0.05), and these trends were neutralized by 740Y-P treatment. Furthermore, PRDX6 knockdown lowered the levels of PI3K/AKT pathway-associated molecules (p < 0.05).

Conclusions: PRDX6 knockdown may exert pro-ferroptotic effects through inactivation of the PI3K/AKT pathway, underlying an appealing therapeutic target for MM.