Wang Yi, He Qian-Qian, Zhu Yan-Ting, Zhang Yang, Yan Jun, Liang Li-Fang, Zhan Xiao-Xia, Cao Song-Ling, Huang Jie-Ye, Peng Yan, Zhang Qiao-Xuan, He Min, Li Guo-Hua, Kang Chun-Min, Huang Xian-Zhang, Zhou Hua, Ke Pei-Feng
Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
Phytomedicine. 2025 Jun 20;145:156996. doi: 10.1016/j.phymed.2025.156996.
Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), lacks effective therapies because of its complex pathogenesis. PANoptosis, an integrated cell death pathway that combines apoptosis, pyroptosis, and necroptosis, has been implicated in inflammatory diseases; however, its role in LN and potential as a therapeutic target remain unexplored. Total glucosides of paeony (TGP), a traditional Chinese medicine derived from Paeonia lactiflora Pall, has shown promise in LN treatment due to its immunomodulatory and anti-inflammatory properties. Nevertheless, the mechanisms underlying its renoprotective effects, particularly its potential regulation of PANoptosis, are poorly understood.
This study investigated the role of PANoptosis in LN pathogenesis and elucidated the therapeutic mechanisms of TGP, focusing on ZBP1-mediated podocytes PANoptosis.
Four mRNA microarray datasets of renal tissues from patients with LN and LN mouse models were obtained from the GEO database, and were performed with gene set enrichment analysis (GSEA) to identify PANoptosis-related pathways. Renal pathology was assessed using HE staining and proteinuria detection. Cell death was evaluated in vivo using TUNEL staining and in vitro through flow cytometry and LDH release assay. The protein levels of ZBP1 and PANoptosis markers were detected by immunoblotting and immunohistochemistry (IHC).
PANoptosis-related pathways were significantly enriched in LN kidneys. TGP treatment suppressed podocytes PANoptosis and alleviated renal injury in MRL/lpr mice. Mechanistically, TGP inhibited PANoptosis by regulating the STAT2-ZBP1 axis, with ZBP1 identified as a pivotal regulator. ZBP1 overexpression attenuated the therapeutic effects of TGP, confirming its central role in LN pathogenesis.
This study reveals ZBP1-mediated podocytes PANoptosis as a key mechanism in LN and establishes TGP as a promising therapeutic agent targeting this pathway. These findings provide a novel, clinically translatable strategy for LN treatment.
狼疮性肾炎（LN）是系统性红斑狼疮（SLE）的一种严重并发症，由于其发病机制复杂，缺乏有效的治疗方法。PANoptosis是一种整合了凋亡、焦亡和坏死性凋亡的细胞死亡途径，与炎症性疾病有关；然而，其在LN中的作用以及作为治疗靶点的潜力仍未得到探索。白芍总苷（TGP）是一种源自芍药的传统中药，因其免疫调节和抗炎特性，在LN治疗中显示出前景。然而，其肾脏保护作用的机制，特别是其对PANoptosis的潜在调节作用，尚不清楚。
本研究探讨PANoptosis在LN发病机制中的作用，并阐明TGP的治疗机制，重点关注ZBP1介导的足细胞PANoptosis。
从GEO数据库中获得4个LN患者和LN小鼠模型肾组织的mRNA微阵列数据集，并进行基因集富集分析（GSEA）以鉴定与PANoptosis相关的途径。使用HE染色和蛋白尿检测评估肾脏病理。在体内使用TUNEL染色评估细胞死亡，在体外通过流式细胞术和LDH释放试验评估细胞死亡。通过免疫印迹和免疫组织化学（IHC）检测ZBP1和PANoptosis标志物的蛋白水平。
与PANoptosis相关的途径在LN肾脏中显著富集。TGP治疗抑制了MRL/lpr小鼠足细胞的PANoptosis并减轻了肾损伤。机制上，TGP通过调节STAT2-ZBP1轴抑制PANoptosis，其中ZBP1被确定为关键调节因子。ZBP1过表达减弱了TGP的治疗效果，证实了其在LN发病机制中的核心作用。
本研究揭示ZBP1介导的足细胞PANoptosis是LN的关键机制，并确定TGP是靶向该途径的有前景的治疗药物。这些发现为LN治疗提供了一种新的、可临床转化的策略。
