Transcription factor NFYA inhibits ferroptosis in lung adenocarcinoma cells by regulating PEBP1.

Background: Ferroptosis is an iron-dependent programmed cell death mediated by lipid peroxidation. The purpose was to explore the molecular mechanism by which phosphatidylethanolamine-binding protein 1 (PEBP1) regulates ferroptosis in lung adenocarcinoma (LUAD), hoping to identify novel therapeutic targets for LUAD.

Methods: The expression, enrichment pathways and upstream transcription factors of PEBP1 were analyzed using bioinformatics tools. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) experiments were conducted to validate the interaction and binding relationship between PEBP1 and the upstream transcription factor nuclear transcription factor Y subunit α (NFYA). Quantitative reverse transcription PCR (qRT-PCR) was conducted to measure the expression levels of PEBP1 and NFYA mRNA in LUAD cells. Cell viability was detected by cell counting kit-8 assay. In addition, levels of malondialdehyde (MDA), Fe, and lipid reactive oxygen species (ROS) were assessed to evaluate ferroptosis levels in LUAD cells.

Results: PEBP1 was downregulated and significantly enriched in the ferroptosis signaling pathway in LUAD. Overexpression of PEBP1 suppressed cell viability remarkably, while levels of MDA, Fe, and lipid ROS were increased. Conversely, knockdown of PEBP1 produced the opposite effects. The upstream transcription factor NFYA, predicted to be involved in the regulation of PEBP1, was also upregulated in LUAD. Dual-luciferase reporter assay, ChIP, and molecular experiments revealed that NFYA transcriptionally suppressed the expression of PEBP1, and overexpression of NFYA could reverse the effects caused by PEBP1 overexpression.

Conclusion: PEBP1 regulated ferroptosis in LUAD, and the transcription factor NFYA inhibited ferroptosis in LUAD cells by transcriptionally downregulating PEBP1 expression.