Targeting Toll-like Receptors 7, 8, and 9 Inhibition in Systemic Lupus Erythematosus: Therapeutic Advance and Future Directions

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, characterized by aberrant immune activation leading to widespread inflammation and organ damage. Accumulating studies underscore the pivotal roles of Toll-like receptors 7, 8, and 9 (TLR7/8/9) in SLE development through recognizing nucleic acid ligands and initiating downstream proinflammatory cascades related to the pathogenesis of SLE. In parallel, advances in medicinal chemistry have led to the discovery of monoclonal antibodies and selective small-molecule antagonists. This review uniquely summarizes significant progress in structural biology, structure-activity relationship (SAR) studies-driven antagonist optimization, and the clinical translation of TLR7/8/9 antagonists for SLE therapy, with a particular focus on chemical scaffolds, structure-based drug design, and clinical translation strategies, providing a valuable roadmap for the future design of novel antagonists for SLE.