2. Academic Validation
  3. Mechanism of Qingjie Fuzheng Granules in inhibiting colitis associated colorectal cancer by regulating TLR4 and IL-4R mediated macrophage polarization

Mechanism of Qingjie Fuzheng Granules in inhibiting colitis associated colorectal cancer by regulating TLR4 and IL-4R mediated macrophage polarization

  • J Ethnopharmacol. 2025 Mar 26:344:119511. doi: 10.1016/j.jep.2025.119511.
Haiqin Liu 1,  Ruiming Yang 1,  Hangyan Zhong 2,  Youquan Zhang 3,  Shunyong Wang 4,  Kangyue Guo 4,  Zhishan Jiang 5,  Jiajun He 5,  Yunmei Huang 1,  Ying Lin 6,  Xuzheng Chen 7,  Jiumao Lin 8
Affiliations

Affiliations

  • 1 College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China.
  • 2 College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Department of Proctology, Shanghang Hospital of Traditional Chinese Medicine, Longyan, Fujian Province, 364200, China.
  • 3 The Second People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350001, China.
  • 4 College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China.
  • 5 College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China.
  • 6 Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, China; Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, 350001, China.
  • 7 College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China. Electronic address: 2003037@fjtcm.edu.cn.
  • 8 College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou, Fujian Province, 350122, China. Electronic address: linjiumao@fjtcm.edu.cn.
PMID: 39978444 DOI: 10.1016/j.jep.2025.119511
Abstract

Ethnopharmacological relevance: Qingjie Fuzheng Granules (QFG), a herbal formula, has been employed as an Adjuvant therapy for colitis-associated colorectal Cancer (CAC), yet the underlying mechanisms by which QFG operates remain unclear.

Aims of the study: The aim of this study is to investigate whether the potential mechanism of QFG against CAC is associated with macrophage polarization.

Materials and methods: Non-targeted metabolomics and molecular docking assessed potential compounds of QFG to interact with targets associated with macrophage polarization. A model of AOM/DSS-induced CAC mice was established to analyze the effects of QFG on macrophage polarization using flow cytometry and immunohistochemical staining. In vitro experiments involved models of Ana-1 macrophages, either induced by varying QFG concentrations or with MD2 knockdown, to analyze M1-like phenotype. Meanwhile, M2-like macrophages models induced by IL-4 or culture supernatant of CT26 cells were utilized to assess the effects of QFG on M2-like macrophages. Finally, the mRNA expression of M1-like phenotype related to TLR4 pathways and the protein expression in IL-4R-mediated pathways were analyzed using RT-qPCR and Western blot, respectively.

Results: Molecular docking confirmed the presence of binding sites between the ingredients of QFG and IL-4R or TLR4/MD2 receptor complex. QFG could induce a shift in macrophages towards an M1-like phenotype while inhibiting an M2-like phenotype in the colon with CAC mice and Ana-1 macrophages. QFG resulted in the upregulation of iNOS, IL-6, IL-1β, and TNF-α mRNA expression, which could be counteracted by TAK242, SR11302, INH14, PDTC, and LY294002, or by the knockdown of MD2. Meanwhile, QFG inhibited IL-4R-induced phosphorylation of STAT 6 and Akt.

Conclusion: Various monomer components within QFG can bind to MD2 or IL-4R, respectively, thereby inducing macrophages towards an M1-like phenotype through TLR4-mediated NF-κB, MAPK, and PI3K/Akt pathway activation, or inhibiting macrophages towards an M2-like phenotype via IL-4R-mediated JAKs pathway inhibition, ultimately exerting an inhibitory effect on the occurrence and development of CAC.

Keywords

Colitis associated colorectal cancer; IL-4R; Macrophage polarization; Qingjie Fuzheng Granules; TLR4.

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