2. Academic Validation
  3. CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway

CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway

  • Free Radic Biol Med. 2024 Aug 5:223:325-340. doi: 10.1016/j.freeradbiomed.2024.08.003.
Yingyi Wu 1,  Hsiang-I Tsai 2,  Huiming Zhu 3,  Yongqiang Zhang 4,  Shanshan Liu 3,  Panpan Guo 3,  Zining Zhang 2,  Zhengyang Zhang 2,  Xin Wen 3,  Dandan Wang 3,  Lingyun Sun 5
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China.
  • 2 Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China.
  • 3 Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 4 Huaihe Hospital, Henan University, Kaifeng, China.
  • 5 Department of Rheumatology and Immunology, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, China; Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; The Second Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: lingyunsun@nju.edu.cn.
PMID: 39111584 DOI: 10.1016/j.freeradbiomed.2024.08.003
Abstract

CX-5461, a first-in-class compound, is widely recognized as a selective inhibitor of RNA polymerase I. Recently, it has been reported to possess novel immunosuppressive properties with significant therapeutic effects in transplantation immune rejection. However, the potential use of CX-5461 for Systemic Lupus Erythematosus (SLE) treatment remains unknown. In this study, we elucidated the mechanism underlying the therapeutic efficacy of CX-5461 in lupus. Our findings demonstrated that CX-5461 selectively targets B cells and effectively reduces the proportions of B cells, germinal center B cells, and plasma cells in MRL/MPJ-Faslpr and Resiquimod (R848)-induced lupus mice. Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering Ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus.

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