LncRNA FEZF1-AS1 promotes the tumorigenesis and suppresses ferroptosis in non-small cell lung cancer through the TNF-α/NF-κB pathway

Objective: The purpose of this research was to examine the impact of FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) on Ferroptosis regulation in non-small cell lung Cancer (NSCLC) cells and to understand its molecular mechanism.

Methods: The effects of FEZF1-AS1 silencing on NSCLC cell proliferation, invasion, migration, and Apoptosis were evaluated through functional assays, utilizing the Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, and Transwell assays. The levels of cellular Reactive Oxygen Species, malondialdehyde, glutathione, and Fe²⁺ were measured using commercial assay kits. Proteins related to Ferroptosis and the tumor necrosis factor-alpha (TNF-α)/nuclear factor-κB (NF-κB) axis were analyzed using Western blot. Finally, rescue experiments were carried out by treating the cells with TNF-α.

Results: FEZF1-AS1 expression was significantly upregulated in NSCLC cells. Moreover, FEZF1-AS1 silencing suppressed proliferation, migration, and invasion, while enhancing Ferroptosis sensitivity in NSCLC cell lines. This knockdown also inhibited the TNF-α/NF-κB pathway. TNF-α attenuated both pro-ferroptotic and anti-tumor effects of FEZF1-AS1 silencing in NSCLC cells. Mechanistically, knockdown of FEZF1-AS1 modulates Ferroptosis and malignant behaviors in NSCLC cells through suppression of the TNF-α/NF-κB axis.

Conclusion: Our study uncovers a previously unrecognized mechanistic axis in which FEZF1-AS1 promotes NSCLC progression through suppressing Ferroptosis by activating the TNF-α/NF-κB axis.

FEZF1-AS1; Ferroptosis; NF-κB; Non-small cell lung cancer; TNF-α.