Advances in molecular agents targeting toll-like receptor 4 signaling pathways for potential treatment of sepsis

• Published in: European journal of medicinal chemistry 2024-03, Vol.268, p.116300-116300, Article 116300
• Main Authors: Zheng, Yunyun, Gao, Yingying, Zhu, Weiru, Bai, Xian-guang, Qi, Jinxu
• Format: Article
• Language: English
• Subjects: Humans; Inflammatory response; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Liver - metabolism; Lung - metabolism; Sepsis; Sepsis - etiology; Signal Transduction; Signaling; Toll-like receptor 4; Toll-Like Receptor 4 - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116300

Sepsis is a systemic inflammatory response syndrome caused by an infection. Toll-like receptor 4 (TLR4) is activated by endogenous molecules released by injured or necrotic tissues. Additionally, TLR4 is remarkably sensitive to infection of various bacteria and can rapidly stimulate host defense responses. The TLR4 signaling pathway plays an important role in sepsis by activating the inflammatory response. Accordingly, as part of efforts to improve the inflammatory response and survival rate of patients with sepsis, several drugs have been developed to regulate the inflammatory signaling pathways mediated by TLR4. Inhibition of TLR4 signal transduction can be directed toward either TLR4 directly or other proteins in the TLR4 signaling pathway. Here, we review the advances in the development of small-molecule agents and peptides targeting regulation of the TLR4 signaling pathway, which are characterized according to their structural characteristics as polyphenols, terpenoids, steroids, antibiotics, anthraquinones, inorganic compounds, and others. Therefore, regulating the expression of the TLR4 signaling pathway and modulating its effects has broad prospects as a target for the treatment of lung, liver, kidneys, and other important organs injury in sepsis. [Display omitted] •TLR4 signaling pathway activates the inflammatory response, contributing to sepsis.•Advances on the impacts of small-molecule drugs and peptides on TLR4 signaling are reviewed.•Targeting intracellular LPS and its receptors in TLR4 interactions can attenuate sepsis.•Drugs targeting multiple TLR4 signaling components will likely have the best therapeutic effects.