TLR8 is an endosomal pattern recognition receptor that plays a central role in innate immunity by recognizing viral RNA degradation products 12. Specifically, TLR8 detects guanosine- and uridine-rich single-stranded RNA derived from pathogens including HIV-1, SARS-CoV-2, and SARS-CoV-1 34. Upon RNA binding, TLR8 undergoes ligand-induced dimerization, recruiting the adapter protein MYD88 to form the myddosome signaling complex containing IRAK4, IRAK1, TRAF6, and TRAF3 56. This activation leads to phosphorylation and nuclear translocation of NF-κB and IRF7, inducing pro-inflammatory cytokines and interferons 78. Notably, endogenous RNA modifications such as pseudouridine suppress TLR8 activation by preventing both enzymatic processing to immunostimulatory ligands and direct receptor engagement 910. Gain-of-function TLR8 mutations cause immunodeficiency 98 with autoinflammation, characterized by neutropenia, lymphoproliferation, and impaired B-cell maturation 11. Additionally, dysregulated TLR8 signaling contributes to systemic lupus erythematosus pathogenesis through recognition of bacterial RNA from translocating gut pathobionts 1213.