Xanthoxylin alleviates dextran sulfate sodium (DSS)-induced colitis by targeting macrophage infiltration via the tumor necrosis factor (TNF) /nuclear factor-kappa B (NF-κB) signaling pathway

  • Phytomedicine. 2026 Apr:153:157971. doi: 10.1016/j.phymed.2026.157971.
Yuxin Chen  1 ,  Ziyan Chen  2 ,  Jiacheng Li  3 ,  Rui Zhao  4 ,  Qiwen Chen  1 ,  Chuyue Zhong  1 ,  Mengmeng Lu  1 ,  Yuzhe Shi  5 ,  Lushuang Wang  6 ,  Lishimeng Bao  7 ,  Zhigui Zuo  8 ,  Xinli Mao  9 ,  Fang Wu  10
Affiliations
  • 1. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3. Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Taizhou 317000, China.
  • 4. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
  • 5. Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 6. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 7. Qianxing Campus of Kunming Children's Hospital, Kunming, Yunnan 650000, China.
  • 8. Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 9. Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Taizhou 317000, China. Electronic address: [email protected].
  • 10. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
PMID: 41720014 DOI: 10.1016/j.phymed.2026.157971
Abstract

Background: Ulcerative colitis (UC) is a relapsing-remitting inflammatory bowel disease (IBD) hallmarked by mucosal ulceration and bloody diarrhea. Its rising prevalence worldwide has led to a significant healthcare burden. Edible and medicinal herbs (EMHs) represent promising alternative therapies. Xanthoxylin (XT; 2‑hydroxy‑4,6-dimethoxyacetophenone), both an acetophenone and a phenol compound that is isolated from several spp of Zanthoxylum genus, has shown anti-inflammatory effects in Other Diseases, but its potential in UC remains unexplored.

Purpose: We aimed to investigate the therapeutic effects and mechanisms of XT in dextran sulfate sodium (DSS)-induced colitis.

Methods: To establish DSS-induced model, mice were given 2.5% DSS for 5 days, followed by distilled water for 3 days. XT is injected intraperitoneally. We measured the colon length, disease activity index (DAI), and histopathological score to evaluate XT's impact on inflammation. Multiplex immunohistochemistry (mIHC), flow cytometry, bulk RNA-seq, enzyme-linked immunosorbent assay (ELISA), Western blot, and molecular docking were employed to delve into the mechanisms underlying XT. Indirect co-culture models involving RAW 264.7 with Caco-2 cells and THP-1 with NCM460 cells were applied to further illustrate the multi-target effect of XT in vitro.

Results: Our results confirmed that XT (5 and 10 mg kg⁻¹) proficiently restored the integrity of the intestinal mucosal barrier, reduced local and systemic pro-inflammatory cytokines in DSS-induced colitis. Mechanistically, XT suppressed colonic lamina propria (CLP) macrophage infiltration by mediating the tumor necrosis factor (TNF) /nuclear factor-kappa B (NF-κB) pathway, specifically affecting the F4/80loCD11b+ macrophage subset. In vitro, XT (20-40 µM) exerted protective effects through attenuation of TNF/NF-κB signaling in macrophages and directly stabilizing tight junctions.

Conclusion: Xanthoxylin (XT; 2‑hydroxy‑4,6-dimethoxyacetophenone), a phenolic acetophenone from Zanthoxylum spp., exhibits anti-inflammatory efficacy through regulating both F4/80loCD11b+ macrophage infiltration and the TNF/NF-κB pathway, positioning it as a promising agent for UC.

Keywords
Colonic lamina propria macrophage; Intestinal epithelial barrier; TNF/NF-κB pathway; Ulcerative colitis; Xanthoxylin.
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