ETV4 promotes colorectal cancer progression through SLC7A11-mediated ferroptosis inhibition

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally. Ferroptosis, a regulated form of cell death, has emerged as a promising frontier in CRC treatment. The transcriptional regulator ETV4 (ETS variant transcription factor 4) is implicated in CRC pathogenesis. However, its functional role has not been fully elucidated, and its potential to modulate ferroptosis in CRC is entirely unknown. This study aimed to investigate whether ETV4 modulates ferroptosis in CRC by regulating SLC7A11 and to explore the underlying mechanism involved.

Bioinformatic analysis was conducted to detect ETV4 expression and to identify pathways regulated by ETV4. Real‑time quantitative PCR (RT‑qPCR) and Western blot assays were used to measure gene expression at the mRNA and protein levels. The biological functions of ETV4 were assessed via CCK‑8, colony formation, wound‑healing, apoptosis analysis, transmission electron microscopy (TEM) and Transwell assays. Key ferroptosis markers-reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (JC‑1), and ferrous iron (FerroOrange) were examined to determine whether ETV4 knockdown promotes ferroptosis.

ETV4 is highly expressed in CRC tissues and cell lines, and its expression level is positively correlated with advanced TNM stages. Silencing ETV4 suppressed CRC cell proliferation, clonogenicity, and migration. Bioinformatic analysis confirmed that ETV4 may suppress the ferroptosis pathway. Functional assays revealed that ETV4 knockdown enhanced ferroptosis in CRC cells. Mechanistically, ETV4 depletion downregulated SLC7A11, whereas SLC7A11 overexpression reversed the ferroptosis phenotype induced by ETV4 knockdown.

ETV4 promotes CRC progression by inhibiting ferroptosis through the upregulation of SLC7A11. Therefore, the ETV4/SLC7A11 axis represents a potential therapeutic target for CRC treatment.