Downregulation of MGST3 promotes colorectal cancer progression

Colorectal cancer (CRC), the third most common malignancy worldwide, presents significant treatment challenges due to an incomplete understanding of its molecular progression. Therefore, identifying the specific developmental mechanisms of CRC holds potential to improve diagnosis, treatment and prognosis. In the present study, RNA-sequencing analysis of samples from patients with an early-stage tumor, advanced carcinoma or adenoma was conducted with the aim of uncovering differentially expressed genes. At the same time, gene knockdown and tumor-related phenotype verification were conducted using a normal colon epithelial cell line. Subsequently, a group of genes related to the target gene was analyzed using The Cancer Genome Atlas (TCGA) database and the differences in colon tumor mutation burden, immune infiltration, epithelial-mesenchymal transition (EMT) and ferroptosis were observed between samples with high and low expression of the gene group. Microsomal glutathione S-transferase 3 (MGST3) was identified as a crucial tumor-suppressive gene in colon cancer pathogenesis. Functional studies demonstrated that MGST3 knockdown in normal human colonic epithelial cells activated glutathione metabolic pathways and induced tumorigenic transformation, characterized by accelerated proliferation and suppression of EMT. TCGA database analysis revealed distinct phenotypes associated with low MGST3 expression, including elevated tumor mutational burden, attenuated EMT processes, diminished immune cell infiltration and enhanced ferroptosis. These findings establish MGST3 as a potential novel regulator of colon carcinogenesis, with its downregulation creating a tumor microenvironment conducive to ferroptosis while simultaneously suppressing EMT and immune responses. The present study not only elucidates previously unrecognized mechanisms driving colon cancer progression but also identifies MGST3-related pathways as promising therapeutic targets for intervention.