Gut Microbial Metabolite 4-Ethylphenylsulfate Is Selectively Deleterious and Anticancer to Colon Cancer Cells

Gut microbiota-derived metabolites have emerged as promising candidates in cancer therapeutics. Among these metabolites, 4-ethylphenyl sulfate (4-EPS), produced through dietary metabolism, is linked to chronic diseases but remains unexplored as a therapeutic agent for colorectal cancer (CRC) treatment. This study investigates the selective anticancer activity of 4-EPS using HCT-116 human colorectal adenocarcinoma cells and CCD 841 normal colon epithelial cells. Treatment with 4-EPS significantly reduced cell proliferation, viability, ATP levels, and colony-forming ability while increased apoptosis rate. Morphological changes included cell shrinkage, intracellular vesicle formation, and loss of membrane integrity. Mechanistically, 4-EPS upregulated Bax, downregulated Bcl2, and induced G2/M phase cell cycle arrest. In silico investigations revealed strong interactions with HDAC isoforms, suggesting epigenetic modulation. Markedly, 4-EPS treatment showed no deleterious effect on CCD 841 normal colon epithelial cells, which proved its selective anticancer role for colon cancer cells. These findings highlight 4-EPS as a promising therapeutic agent for treating CRC.