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<p>Aquaporins (AQPs) are membrane channels that facilitate the transport of water and small solutes. They are increasingly recognized for their role in cancer development, particularly colorectal cancer (CRC), where they regulate tumor microenvironment remodeling, cell migration, and proliferation. This study investigates metabolites derived from Lactiplantibacillus plantarum K25 (L. plantarum K25) as potential modulators of AQP8, a mitochondrial aquaporin implicated in CRC through its role in oxidative stress and metabolic regulation. Using GC-MS analysis, we identified (Z)-18-Octadec-9-enolide as a prominent bacterial metabolite with structural properties indicative of membrane interaction. Molecular docking revealed strong binding affinity (-6.2&#xa0;kcal/mol) between this compound and the AQP8 pore region, with key interactions involving residues His182 and Asn194 near the channel’s selectivity filter. ADMET profiling indicated good membrane permeability (LogP 5.56) but also highlighted potential hepatotoxicity and hERG inhibition risks, necessitating further optimization for safety. Molecular dynamics simulations confirmed stable complex formation, with low RMSD fluctuations (&lt; 2.0 Å) supporting binding stability. These in silico findings provide a computational hypothesis, that evolutionarily optimized microbiome-derived metabolites can modulate cancer-relevant aquaporins like AQP8, opening new avenues for CRC therapeutics. However, these computational insights require experimental validation in vitro and in vivo to assess biological activity, therapeutic efficacy, and safety. By leveraging host–microbe molecular crosstalk, this study proposes a novel microbiome-inspired strategy for anticancer drug discovery.</p>

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Revealing Lactiplantibacillus Plantarum K25 Derived (Z)-18-Octadec-9-Enolide in Modulating Aquaporin-8 in Colorectal Cancer by Bridging the Gut Microbiome and Membrane Biology

  • 期刊论文

  • 发表日期：

    2025年7月31日

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  • Tariq Aziz,
  • Muhammad Aqib Shabbir,
  • Abid Sarwar,
  • Zhennai Yang,
  • Lin Lin,
  • Wafa Abdullah I. Al-Megrin,
  • Ashwag Shami,
  • Maher S. Alwethaynani,
  • Areej A Alhhazmi,
  • Fahad Al-Asmari,
  • Fakhria A. Al-Joufi,
  • Deema Fallatah

摘要

Aquaporins (AQPs) are membrane channels that facilitate the transport of water and small solutes. They are increasingly recognized for their role in cancer development, particularly colorectal cancer (CRC), where they regulate tumor microenvironment remodeling, cell migration, and proliferation. This study investigates metabolites derived from Lactiplantibacillus plantarum K25 (L. plantarum K25) as potential modulators of AQP8, a mitochondrial aquaporin implicated in CRC through its role in oxidative stress and metabolic regulation. Using GC-MS analysis, we identified (Z)-18-Octadec-9-enolide as a prominent bacterial metabolite with structural properties indicative of membrane interaction. Molecular docking revealed strong binding affinity (-6.2 kcal/mol) between this compound and the AQP8 pore region, with key interactions involving residues His182 and Asn194 near the channel’s selectivity filter. ADMET profiling indicated good membrane permeability (LogP 5.56) but also highlighted potential hepatotoxicity and hERG inhibition risks, necessitating further optimization for safety. Molecular dynamics simulations confirmed stable complex formation, with low RMSD fluctuations (< 2.0 Å) supporting binding stability. These in silico findings provide a computational hypothesis, that evolutionarily optimized microbiome-derived metabolites can modulate cancer-relevant aquaporins like AQP8, opening new avenues for CRC therapeutics. However, these computational insights require experimental validation in vitro and in vivo to assess biological activity, therapeutic efficacy, and safety. By leveraging host–microbe molecular crosstalk, this study proposes a novel microbiome-inspired strategy for anticancer drug discovery.