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

  • J Med Chem. 2025 May 22;68(10):10425-10438. doi: 10.1021/acs.jmedchem.5c00609.
Jyoti Jaiswal  1 ,  Amit Kumar Srivastav  2 ,  Manish Kushwaha  1  3 ,  Anupam Teotia  1  4 ,  Rajeev Singh  4 ,  Anand Mohan  5 ,  Govind Makharia  6 ,  Anil Kumar  1
Affiliations
  • 1. Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India.
  • 2. Department of Forensic Science, UP State Institute of Forensic Sciences, Lucknow 226401, Uttar Pradesh, India.
  • 3. School of Life Science, Department of Biotechnology, Mahatma Gandhi Central University, Motihari 845401, Bihar, India.
  • 4. Department of Environmental Science, Jamia Millia Islamia (Central University), New Delhi 110025, India.
  • 5. School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India.
  • 6. Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi 110016, India.
PMID: 40347180 DOI: 10.1021/acs.jmedchem.5c00609
Abstract

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.

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