Tea seed-derived leucoside attenuates sepsis via inhibition of TLR4-MD2 complex formation.

Authors

Yan Zhang, Yingxue Liang, Wenjuan Li, Lulu Zang, Xi Chen, Xiaofan Xiong, Siyu Zhang, Yuhao Gu, Shuaijie Zhong, Yingnan Li, Jing Geng, Yanlong Xin

Published in

Biochemical pharmacology. Volume 243. Issue Pt 1. Pages 117464. Epub Oct 24, 2025.

Abstract

Sepsis, a life-threatening condition driven by dysregulated inflammation, remains a major clinical challenge due to high mortality rates and limited therapeutic options. This study investigates the anti-inflammatory properties of Leucoside, a natural flavonoid isolated from tea seed extract, and its potential as a therapeutic agent for sepsis. Using a bacterial infection-induced septic mouse model and lipopolysaccharide (LPS)-activated macrophages, we demonstrated that Leucoside significantly improves survival rates, reduces hypothermia, and attenuates organ damage by suppressing systemic inflammation. Mechanistically, network pharmacology and molecular docking identified Toll-like receptor 4 (TLR4) as a primary target of Leucoside. Biochemical and structural analyses revealed that Leucoside competitively binds to conserved positively charged residues in the B patch of TLR4, specifically Lys263 and Arg337, forming a spatial barrier that inhibits the formation of the myeloid differentiation protein 2 (MD2)-TLR4 complex and subsequent nuclear factor kappa-B (NF-κB) signaling. This inhibition was further validated through co-immunoprecipitation assays, which showed a reduced effect on the TLR4-MD2 complex dissociation when Lys263 and Arg337 were mutated. These findings highlight Leucoside as a novel TLR4 inhibitor with significant potential for treating sepsis and other TLR4-mediated inflammatory diseases. By elucidating its mechanism of action, this study provides a foundation for developing targeted therapies to address the unmet clinical needs in sepsis management.

PMID:
41489549
Bibliographic data and abstract were imported from PubMed on 06 Jan 2026.

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