Mechanisms of food-derived bioactive compounds inhibiting TLR4 activation and regulating TLR4-mediated inflammation: A comprehensive review and future directions

In cases where inflammation is excessively activated, it can lead to autoimmune diseases, causing significant damage to the body. Food-derived bioactive compounds (FBACs) have received widespread attention owing to their safety, efficacy, and minimal side effects in preventing inflammatory diseases and inhibiting toll-like receptor 4 (TLR4) activation. The research progress of FBACs in inhibiting the activation of TLR4 and modulating TLR4-mediated inflammatory responses was systematically reviewed from the perspectives of the binding modes, structure-activity relationships, and animal studies. The results indicate that hydrogen bonding and hydrophobic interactions are the two key forces in how FBACs interact with the TLR4/myeloid differential protein-2 (MD-2) complex. Additionally, FBACs primarily inhibit TLR4 activation predominantly by interfering with the formation of the TLR4/MD-2 complex, hindering the dimerization process of TLR4, and restricting the binding of LPS to the hydrophobic cavity of MD-2. Moreover, FBACs undergo a series of intricate metabolic processes in vivo and act through multiple pathways to regulate TLR4-mediated inflammatory responses, including inhibition of TLR4 activation, modulation of intestinal bacterial flora, maintenance of intestinal barrier function, upregulation of microRNA expression, and enhancement of antioxidant capacity. These findings not only have significant implications for the screening and design of TLR4 inhibitors based on bioactive compounds in foods, but also enhance our understanding of the mechanisms of the role of FBACs in anti-inflammation and immunomodulation. Meanwhile, the shortcomings of current studies were highlighted and new perspectives for future research were proposed, laying a theoretical foundation for the in-depth study and clinical application of FBACs.