Gene

NF-κB

Programmed cell death

Cell biology

Biology

GPX4

Apoptosis

Signal transduction

Cancer research

Biochemistry

Gene silencing

Glutathione peroxidase

Downregulation and upregulation

NFKB1

Glioma

Superoxide dismutase

Oxidative stress

Gene knockdown

Transcription factor

Chemistry

Oxidative Medicine and Cellular Longevity

Glioblastoma, the most aggressive form of malignant glioma, is very difficult to treat because of its aggressively invasive nature and high recurrence rates. RAS-selective lethal 3 (RSL3), a well-known inhibitor of glutathione peroxidase 4 (GPX4), could effectively induce oxidative cell death in glioblastoma cells through ferroptosis, and several signaling pathways are involved in this process. However, the role of the nuclear factor kappa-B (NF-κB) pathway in glioblastoma cell ferroptosis has not yet been investigated. Therefore, we aimed to clarify the underlying mechanism of the NF-κB pathway in RSL3-induced ferroptosis in glioblastoma cells. We found that RSL3 led to an increase in lipid ROS concentration and downregulation of ferroptosis-related proteins such as GPX4, ATF4, and SLC7A11 (xCT) in glioblastoma cells. Additionally, the NF-κB pathway was activated by RSL3, and its inhibition by BAY 11-7082 could alleviate ferroptosis. The murine xenograft tumor model indicated that NF-κB pathway inhibition could mitigate the antitumor effects of RSL3 in vivo. Furthermore, we found that GPX4 knockdown could not effectively induce ferroptosis. However, NF-κB pathway activation coupled with GPX4 silencing induced ferroptosis. Additionally, ATF4 and xCT expression might be regulated by the NF-κB pathway. Collectively, our results revealed that the NF-κB pathway plays a novel role in RSL3-induced ferroptosis in glioblastoma cells and provides a new therapeutic strategy for glioblastoma treatment.

RSL3 Drives Ferroptosis through NF‐<i>κ</i>B Pathway Activation and GPX4 Depletion in Glioblastoma

RSL3 Drives Ferroptosis through NF‐κB Pathway Activation and GPX4 Depletion in Glioblastoma