Cell Mol Immunol| Cao Yingjiao's team reveals new targets for the treatment of systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by antinuclear antibodies, immune complex deposition, and chronic inflammation. Current mainstay drugs for SLE include glucocorticoids, immunosuppressants, and biological agents, which are associated with significant side effects, and approximately 30% of patients show poor response. The abnormal expansion of T follicular helper (Tfh) cells is a key pathogenic mechanism driving SLE. There is an urgent need to clarify the regulatory mechanisms and molecular targets of Tfh cells in SLE to develop effective new therapeutic strategies.
On June 25, the team of Associate Professor Cao Yingjiao from our college and their collaborators published a paper entitled "FXR inhibition functions as a checkpoint blockade of pathogenic Tfh cell response in lupus" in the journal Cellular & Molecular Immunology. This study is the first to reveal the critical role of farnesoid X receptor (FXR) in Tfh cells and its mechanism of influencing immune responses by regulating cholesterol metabolism, and proposes a 全新 non-hormonal, low-toxicity therapeutic strategy for SLE.
The study found that FXR is relatively upregulated in Tfh cells. Fxr deficiency significantly inhibits the expansion of Tfh cells under steady-state conditions and in pristane-induced lupus models, leading to germinal center dysfunction, reduced plasma cell numbers, and decreased autoantibodies. Ultimately, it effectively alleviates lupus pathological symptoms in the kidneys and liver of pristane-induced lupus models. Further research showed that FXR controls the proliferation of Tfh cells by endogenously regulating cholesterol homeostasis in Tfh cells. Finally, in preclinical therapy, treatment of MRL/LPR mice (a spontaneous lupus model) with the FDA-approved FXR antagonist ursodeoxycholic acid (UDCA) was found to alleviate lupus pathological symptoms by inhibiting Tfh cell expansion, germinal center (GC) response, and autoantibody production. These findings provide a basis for targeting FXR as a potential therapeutic target for SLE.
Dr. Wang Xiangyang, a postdoctoral fellow in Cao Yingjiao's research group, is the first author of the article. Associate Professor Cao Yingjiao, Professor Zhou Jie, Professor Ye Lilin, and Professor Fu Shunjun are the corresponding authors. The research was supported by the National Natural Science Foundation of China, the Key Research and Development Program of the Ministry of Science and Technology, and other projects. Animal experiments were conducted at the Laboratory Animal Center of Sun Yat-sen University, and Sun Yat-sen University is the first affiliated unit of the paper.
Original article link: https://www.nature.com/articles/s41423-025-01309-3
