TLR4 (Toll-like receptor 4) is a transmembrane pattern recognition receptor that initiates innate immune responses by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) 1. The receptor primarily recognizes bacterial lipopolysaccharide (LPS) at the plasma membrane in cooperation with LY96, triggering two distinct signaling cascades 12. Initially, TLR4 activates the MyD88/TIRAP pathway at the cell surface, leading to NF-κB activation and pro-inflammatory cytokine secretion 2. Subsequently, CD14-mediated endocytosis of TLR4 initiates a secondary TRIF/TRAM-dependent pathway in early endosomes, resulting in type I interferon production 1. TLR4 expression is regulated by m6A methylation through METTL3, which increases TLR4 mRNA translation and protein stability, enhancing neutrophil activation during endotoxemia 3. The receptor's clinical significance spans multiple diseases: it promotes hepatocellular carcinoma progression and metastasis through the HMGB1-KLF7-TLR4 feedback loop 4, associates with papillary thyroid carcinoma advancement 5, and modulates intestinal immune responses to breast milk components 6. Therapeutically, TLR4 can be targeted with specific inhibitors like TAK-242, which disrupts adaptor protein interactions 7, or with agonistic antibodies that require IgG3-mediated receptor clustering for tolerance induction 8.