Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Eupalinolide B alleviates ulcerative colitis by targeting HMGB1 through modulation of the HMGB1/TLR4/MyD88/NF-κB signaling pathway.
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Luo Wennan, Zhuang Yuan, Shen Shengnan, Wang Yaxu, Zhu Yongping, Liu Yanqing, Zhang Shujie, Zhang Junzhe, Li Sainan, Zhong Linying, Xia Fei, Pan Lu, Meng Yuqing, Gao Peng, Liu Qingbo, Wang Jigang, Gu Liwei
Аннотация
BACKGROUND: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease with limited therapeutic options. Eupalinolide B (EB), a guaianolide sesquiterpene lactone derived from Eupatorium lindleyanum DC., exhibits anti-inflammatory and immunomodulatory activities. This study investigated the therapeutic potential and mechanism of EB against UC.
METHODS: In vitro anti-inflammatory effects of EB were assessed in LPS-induced RAW264.7 and IEC-6 cells by measuring NO production and inflammatory cytokine mRNA levels (IL-6, IL-1β, TNF-α). In vivo, a DSS-induced UC mouse model was used to evaluate EB's efficacy through body weight, DAI score, immunohistochemistry, and inflammatory factor levels. Target identification employed activity-based protein profiling (ABPP) with an EB-based probe, followed by validation via pull-down, CETSA, SIP, and immunofluorescence assays. Binding affinity and site were characterized using isothermal titration calorimetry (ITC), LC-MS/MS, molecular docking, and mutagenesis. Molecular mechanism was explored by analyzing HMGB1/TLR4/MyD88/NF-κB pathway by WB, qPCR and co-precipitation.
RESULTS: EB exerted anti UC effects by alleviating inflammation and enhancing intestinal barrier integrity in vitro and in vivo. Using ABPP, high mobility group box-1 protein (HMGB1) was established as a high-confidence target of EB, characterized by the covalent binding of Cys106 residue. Mechanistically, EB suppressed the TLR4/MyD88/NF κB pathway and disrupted HMGB1 TLR4 interaction.
CONCLUSION: EB ameliorates UC and exerts anti-inflammatory effects by targeting HMGB1 at Cys106 residue. By downregulating HMGB1 protein expression and reducing the binding affinity between HMGB1 and TLR4, EB inhibits the TLR4/MyD88/NF-κB signaling pathway. This study provides theoretical support for the development of EB as a potential anti-UC candidate drug.
METHODS: In vitro anti-inflammatory effects of EB were assessed in LPS-induced RAW264.7 and IEC-6 cells by measuring NO production and inflammatory cytokine mRNA levels (IL-6, IL-1β, TNF-α). In vivo, a DSS-induced UC mouse model was used to evaluate EB's efficacy through body weight, DAI score, immunohistochemistry, and inflammatory factor levels. Target identification employed activity-based protein profiling (ABPP) with an EB-based probe, followed by validation via pull-down, CETSA, SIP, and immunofluorescence assays. Binding affinity and site were characterized using isothermal titration calorimetry (ITC), LC-MS/MS, molecular docking, and mutagenesis. Molecular mechanism was explored by analyzing HMGB1/TLR4/MyD88/NF-κB pathway by WB, qPCR and co-precipitation.
RESULTS: EB exerted anti UC effects by alleviating inflammation and enhancing intestinal barrier integrity in vitro and in vivo. Using ABPP, high mobility group box-1 protein (HMGB1) was established as a high-confidence target of EB, characterized by the covalent binding of Cys106 residue. Mechanistically, EB suppressed the TLR4/MyD88/NF κB pathway and disrupted HMGB1 TLR4 interaction.
CONCLUSION: EB ameliorates UC and exerts anti-inflammatory effects by targeting HMGB1 at Cys106 residue. By downregulating HMGB1 protein expression and reducing the binding affinity between HMGB1 and TLR4, EB inhibits the TLR4/MyD88/NF-κB signaling pathway. This study provides theoretical support for the development of EB as a potential anti-UC candidate drug.