2. Academic Validation
  3. 6-Shogaol ameliorates experimental colitis and colitis-associated colorectal cancer in mice through the Nrf2-Keap1 signaling pathway

6-Shogaol ameliorates experimental colitis and colitis-associated colorectal cancer in mice through the Nrf2-Keap1 signaling pathway

  • Eur J Pharmacol. 2026 Apr 10:1020:178781. doi: 10.1016/j.ejphar.2026.178781.
Na Li 1,  Hehe Shi 1,  Wei Du 2,  Siqian Luo 3,  Xianyue Yang 3,  Xinyue Yang 1,  Bingyue Jiang 1,  Peng Xia 4,  Guangji Zhang 5,  Wanghui Jing 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China; Shaanxi Engineering Research Center of Cardiovascular Drugs Screening & Analysis, Xi'an, 710061, China.
  • 2 Shaanxi Institute for Food and Drug Control, Xi'an, 710065, China.
  • 3 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China; Shaanxi Engineering Research Center of Cardiovascular Drugs Screening & Analysis, Xi'an, 710061, China; Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 4 Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 5 Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 6 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China; Shaanxi Engineering Research Center of Cardiovascular Drugs Screening & Analysis, Xi'an, 710061, China. Electronic address: [email protected].
PMID: 41825712 DOI: 10.1016/j.ejphar.2026.178781
Abstract

The progression from ulcerative colitis to colitis-associated colorectal Cancer (CAC) represents a significant clinical challenge. 6-Shogaol, a bioactive phenolic compound of ginger, exhibits anti-inflammatory, antioxidant, and anti-tumor properties. This study aims to investigate the therapeutic efficacy of 6-shogaol against colitis and CAC, and explore the underlying mechanisms through network pharmacology and in vivo validation. Putative hub targets and pathways associated with 6-shogaol were identified through network pharmacology. Murine models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-induced CAC were established, and the mice were treated with 6-shogaol to assess the latter's therapeutic effects. The targets of 6-shogaol predicted through network pharmacology were mainly associated with oxidative stress and Reactive Oxygen Species (ROS) signaling pathways. In vivo, 6-shogaol relieved colitis symptoms and reduced CAC tumor burden. Furthermore, 6-shogaol alleviated intestinal inflammation by decreasing the colonic levels of TNF-α and MPO, and reduced oxidative stress in the colon tissues, as indicated by lower ROS production and malondialdehyde content. Moreover, 6-shogaol restored intestinal barrier function by upregulating claudin-4, occludin, and ZO-1, and decreasing intestinal permeability. Mechanistically, 6-shogaol promoted Nrf2 nuclear translocation by upregulating nuclear Nrf2 expression while downregulating cytoplasmic Keap1, thereby activating antioxidant response element driver genes, including Hmox1, Nqo1, and Gclc. Molecular docking confirmed strong binding affinity between 6-shogaol and Keap1 receptor, with a low binding energy of -6.89 kcal/mol. These findings collectively suggested that 6-shogaol alleviated colitis and CAC in murine models by inhibiting colonic inflammation, relieving oxidative stress, and enhancing intestinal barrier function through the activation of the Nrf2-Keap1 pathway.

Keywords

6-Shogaol; Colitis-associated colorectal cancer; Intestinal barrier; Nrf2-Keap1 signaling pathway; Ulcerative colitis.

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