**Abstract:** A collaborative research effort led by Professor Hang Yin's team at the School of Pharmacy, Tsinghua University, has resulted in the development of a novel TLR7-specific small molecule inhibitor, TH-407b. This inhibitor was designed to target the toll-like receptor 7 (TLR7), a pattern recognition receptor (PRR) that plays a crucial role in the immune response by recognizing pathogen-associated molecular patterns (PAMPs). The improper activation and signaling of TLR7 have been implicated in the development and progression of various autoimmune diseases, including systemic lupus erythematosus (SLE), a complex, multi-system autoimmune disorder. The research, published as the cover article in the latest issue of *Acta Pharmaceutica Sinica B* on November 22, 2023, details the structure-activity relationship (SAR) studies that led to the identification of TH-407b, a quinoline derivative with high efficacy and minimal cytotoxicity. The team successfully determined the cryo-electron microscopy (cryo-EM) structure of the TLR7/TH-407b complex, which is visually described as resembling a lotus flower floating on water, with the water surface representing the endosomal membrane. This structural insight is critical because it elucidates how TH-407b specifically interacts with the extracellular domain of TLR7 to stabilize it in a resting dimeric state, thereby inhibiting its activation and downstream signaling pathways. In the study, TH-407b demonstrated significant therapeutic potential in both in vitro and in vivo models. In vitro, the inhibitor effectively reduced the secretion of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) from SLE patients, without causing any cytotoxic effects. In vivo, the efficacy of TH-407b was evaluated using female MRL/lpr mice, a well-established model for SLE. After a four-week treatment period, mice that received TH-407b showed a significantly higher survival rate, reduced skin lesions, smaller spleens and lymph nodes, and lower levels of autoantibodies compared to the placebo group. Histological analysis of the kidneys further confirmed that TH-407b treatment resulted in mild glomerulonephritis, in contrast to the severe condition observed in the placebo group. These findings not only highlight the importance of TLR7 in the pathogenesis of SLE but also suggest that TH-407b could be a promising therapeutic candidate for the treatment of this autoimmune disease. The researchers employed a multi-disciplinary approach, integrating structural biology, biochemistry, cell biology, and animal studies, to provide a comprehensive understanding of how locking TLR7 in its resting state could serve as a novel therapeutic strategy for SLE. This work represents a significant step forward in the field of autoimmune disease research and opens new avenues for the development of targeted therapies. The study was a collaborative effort involving researchers from Tsinghua University and the University of Tokyo, with significant contributions from Meng Wang of Beijing TopLeader Biotech Co., Ltd., and doctoral students He Kai Chen and Tuan Zhang from Tsinghua University. The research was supported by the National Natural Science Foundation of China, the Beijing Higher Education Outstanding Young Scientist Program, and the Beijing Natural Science Foundation. For more details, the full paper titled "Targeting toll-like receptor 7 as a therapeutic development strategy for systemic lupus erythematosus" can be accessed at the following link: [https://www.sciencedirect.com/science/article/pii/S2211383524003368](https://www.sciencedirect.com/science/article/pii/S2211383524003368). **Key Elements:** - **Key Event:** Development of a TLR7-specific small molecule inhibitor, TH-407b. - **People:** Professor Hang Yin (Tsinghua University), Professor Toshiyuki Shimizu (University of Tokyo), Meng Wang (Beijing TopLeader Biotech Co., Ltd.), He Kai Chen and Tuan Zhang (Tsinghua University). - **Location:** Tsinghua University, Beijing, China; University of Tokyo, Japan. - **Time:** Published on November 22, 2023. - **Impact:** Potential new therapeutic strategy for systemic lupus erythematosus (SLE) and other autoimmune diseases.