EGR1 promotes ferroptosis in endometrial cancer cells by increasing NOX4 transcription

To investigate the role of early growth response 1 (EGR1) in the progression of endometrial cancer (EC) and to elucidate the molecular mechanism by which EGR1 regulates ferroptosis, with a focus on NADPH oxidase 4 (NOX4) as a downstream mediator.

An EC xenograft model was established in nude mice. EGR1 was overexpressed in HEC-1B cells, and cell proliferation and migration were assessed using CCK-8, colony formation, and Transwell assays. Ferroptosis-related indicators (Fe²⁺, MDA, GSH, and lipid ROS) and related proteins (GPX4, SLC7A11, and IREB2) were measured. The ferroptosis inhibitor Fer-1 was used for rescue experiments. Gene and protein expression were analyzed via RT-qPCR, western blotting, and immunohistochemistry. The transcriptional regulation of NOX4 by EGR1 was validated using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.

EGR1 expression was downregulated in EC. Overexpression of EGR1 inhibited the proliferation and migration of HEC-1B cells and suppressed tumor growth in vivo. EGR1 overexpression induced ferroptosis, as evidenced by increased levels of Fe²⁺, MDA, and lipid ROS; decreased GSH levels; downregulation of GPX4 and SLC7A11; and upregulation of IREB2. These effects were reversed by Fer-1. Mechanistically, EGR1 directly bound to the NOX4 promoter and increased its transcription, leading to increased ROS production and thereby facilitating ferroptosis.

EGR1 inhibits the progression of EC at least in part through transcriptionally activating NOX4, which promotes ROS accumulation and contributes to ferroptosis induction. This study provides a theoretical basis for targeting EGR1 as a potential therapeutic strategy for treating EC.