Zhao Yue, Zheng Zuguo, Jin Xuexiao, Liang Shaoshan, Zhang Changming, Zhang Mingchao, Lang Yue, Li Ping, Liu Zhihong
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
EBioMedicine. 2025 Feb;112:105553. doi: 10.1016/j.ebiom.2024.105553. Epub 2025 Jan 11.
Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical efficacy, we aimed to develop a single-agent therapy with comparable efficacy to MT, offering a simplified treatment regimen.
AZD1152, an Aurora kinase B (Aurkb) inhibitor, was identified through transcriptomic analyses and the L1000 CMap drug repurposing database. The therapeutic efficacy of AZD1152 was evaluated in MRL/lpr mice. Transcriptome sequencing and functional assays were performed to elucidate its mechanisms of action. Aurkb expression and its clinical relevance were assessed in lupus-prone mice and patients with LN.
AZD1152 significantly attenuated systemic immune activation and renal injury in MRL/lpr mice, demonstrating efficacy comparable to MT regimens in animal studies. AZD1152 treatment modulated immune-inflammatory pathways in the kidney. Aurkb expression was upregulated in T cells infiltrating the renal interstitium in LN. Additionally, Aurkb expression levels positively correlated with the activity index (AI) and serum creatinine (Scr) in patients with LN. Mechanistic studies revealed that AZD1152 exerts therapeutic effects primarily by inhibiting T-cell proliferation.
This study presents a drug development strategy that integrates clinically validated LN therapies with drug repurposing approaches. This strategy could accelerate drug development and clinical translation processes for LN.
A full list of funding sources can be found in the acknowledgements section.
狼疮性肾炎（LN）是系统性红斑狼疮（SLE）最常见且最严重的并发症之一。在狼疮性肾炎的治疗中，多靶点疗法（MT）相较于传统疗法，完全缓解（CR）率高出20%。受其出色临床疗效的启发，我们旨在开发一种疗效与多靶点疗法相当的单药疗法，提供一种简化的治疗方案。
通过转录组分析和L1000 CMap药物重新利用数据库，确定了Aurora激酶B（Aurkb）抑制剂AZD1152。在MRL/lpr小鼠中评估了AZD1152的治疗效果。进行了转录组测序和功能测定，以阐明其作用机制。评估了狼疮易感小鼠和狼疮性肾炎患者中Aurkb的表达及其临床相关性。
AZD1152显著减轻了MRL/lpr小鼠的全身免疫激活和肾损伤，在动物研究中显示出与多靶点疗法相当的疗效。AZD1152治疗调节了肾脏中的免疫炎症途径。在狼疮性肾炎患者肾间质浸润的T细胞中，Aurkb表达上调。此外，狼疮性肾炎患者的Aurkb表达水平与活动指数（AI）和血清肌酐（Scr）呈正相关。机制研究表明，AZD1152主要通过抑制T细胞增殖发挥治疗作用。
本研究提出了一种将经过临床验证的狼疮性肾炎疗法与药物重新利用方法相结合的药物开发策略。该策略可加速狼疮性肾炎的药物开发和临床转化进程。
完整的资金来源清单可在致谢部分找到。
