Linderane from Lindera aggregata attenuates ulcerative colitis by suppressing IL-6/STAT3-mediated Th17 differentiation and apoptosis resistance

  • J Ethnopharmacol. 2026 Feb 28:357:120965. doi: 10.1016/j.jep.2025.120965.
Huimin Lai  1 ,  Minhua Chen  2 ,  Weida Xuan  3 ,  Feng Xie  4 ,  Pansheng Xu  5 ,  Mincong Huang  6 ,  Hu Wang  7
Affiliations
  • 1. Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, Zhejiang, China; School of Medicine, Westlake University, Hangzhou, 310024, Zhejiang, China. Electronic address: [email protected].
  • 2. Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, 310053, China. Electronic address: [email protected].
  • 3. Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, 310053, China. Electronic address: [email protected].
  • 4. Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, 310053, China. Electronic address: [email protected].
  • 5. Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, 310053, China. Electronic address: [email protected].
  • 6. Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products, School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China. Electronic address: [email protected].
  • 7. Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, Zhejiang, China. Electronic address: [email protected].
PMID: 41308714 DOI: 10.1016/j.jep.2025.120965
Abstract

Ethnopharmacological relevance: Lindera aggregata, the dried tuberous root of the Lauraceae family, is a traditional Chinese medicinal herb that is extensively applied in clinical practice to treat gastrointestinal disorders. Linderane (LDR), a major bioactive and quality control ingredient from L. aggregata, has therapeutic potential in ulcerative colitis (UC); however, it remains underexplored.

Aim of the study: This study aimed to investigate the therapeutic effect of LDR on UC and explore its potential underlying mechanisms.

Methods: Dextran sulfate sodium-induced UC model mice were used to evaluate the in vivo anti-UC efficacy of LDR. Transcriptomics was employed to examine the anti-UC mechanism of LDR. Furthermore, the lipopolysaccharide (LPS)-induced RAW264.7 inflammatory cell model was utilized to investigate the in vitro anti-inflammatory activity of LDR. Moreover, flow cytometry and western blotting were applied to detect the phosphorylation levels of STAT3 and the Apoptosis resistance effect induced by interleukin (IL)-6 in lymphocytes. Naïve CD4+ T-cells were sorted and induced to differentiate into Th17 or regulatory T (Treg) cells in vitro. The frequencies of Th17/Treg subsets were quantified to assess the modulatory effects of LDR.

Results: LDR considerably reduced the disease activity index, ameliorated colon histopathological lesions, and demonstrated promising anti-UC pharmacological potential in vivo. Transcriptomic analysis of colon tissue revealed that LDR's effects involved the IL-6/JAK/STAT3-and IL-17-signaling pathways, as established using Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of downregulated differentially expressed genes, respectively. LDR not only suppressed IL-6 production in macrophages induced by LPS but also significantly inhibited STAT3 phosphorylation and weakened IL-6-induced Apoptosis resistance in lymphocytes. Moreover, LDR substantially inhibited IL-6-driven Th17 cell differentiation but did not alter transforming growth factor-β-induced Treg cell differentiation, suggesting selective modulation of the Th17/Treg imbalance via the IL-6/STAT3-signaling pathway.

Conclusion: The findings from this study indicate that LDR from L. aggregata is a novel therapeutic agent for UC that specifically targets the IL-6/STAT3-signaling pathway to suppress Th17 differentiation and induce Apoptosis resistance.

Keywords
Apoptosis resistance; IL-6/STAT3; Lindera aggregata; Linderane; Th17/treg balance; Ulcerative colitis.
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