Abstract

This study aimed to elucidate the role of ROS-related genes in esophageal squamous cell carcinoma (ESCC) prognosis and the cellular mechanisms involving FOXM1 and SESN2. A prognostic model incorporating six genes (FOXM1, SESN2, APOD, GATM, HEBP2, STAT1) was developed using three ESCC gene expression datasets via univariate Cox regression, LASSO-Cox algorithm, and multivariate validation. Functional assays revealed that FOXM1 knockdown elevated intracellular ROS and malondialdehyde (MDA) levels while reducing total glutathione and antioxidant capacity, impairing proliferation, migration, and cell cycle progression. RNA-seq and luciferase assays confirmed SESN2 as a transcriptional target of FOXM1. Dual knockdown of FOXM1 and SESN2 exacerbated oxidative stress, decreased mitochondrial membrane potential, and increased cell death, accompanied by mitochondrial morphological changes (reduced shrinkage, increased membrane density). Western blotting showed decreased BCL2 and GPX4 expression but increased LC3-II and p -mTOR levels. These findings demonstrate that the FOXM1-SESN2 axis shields ESCC cells from oxidative stress, offering a rationale for future mechanistic investigations.