白芍总苷通过抑制zbp1介导的足细胞PANoptosis改善狼疮性肾炎

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-20 DOI:10.1016/j.phymed.2025.156996

Yi Wang , Qian-Qian He , Yan-Ting Zhu , Yang Zhang , Jun Yan , Li-Fang Liang , Xiao-Xia Zhan , Song-Ling Cao , Jie-Ye Huang , Yan Peng , Qiao-Xuan Zhang , Min He , Guo-Hua Li , Chun-Min Kang , Xian-Zhang Huang , Hua Zhou , Pei-Feng Ke

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引用次数: 0

摘要

狼疮肾炎（LN）是系统性红斑狼疮（SLE）的严重并发症，由于其复杂的发病机制，缺乏有效的治疗方法。PANoptosis是一种结合凋亡、焦亡和坏死的综合细胞死亡途径，与炎症性疾病有关；然而，它在LN中的作用和作为治疗靶点的潜力仍未被探索。芍药总苷（TGP）是一种从芍药中提取的中药，由于其免疫调节和抗炎作用，在LN治疗中显示出良好的前景。然而，其肾保护作用的机制，特别是其对泛眼衰的潜在调节机制，尚不清楚。目的探讨PANoptosis在LN发病中的作用，阐明TGP的治疗机制，重点研究zbp1介导的足细胞PANoptosis。方法从GEO数据库中获取LN患者和LN小鼠模型肾组织的4个mRNA微阵列数据集，并进行基因集富集分析（GSEA）以鉴定panoptosis相关通路。采用HE染色和蛋白尿检测评估肾脏病理。在体内用TUNEL染色评估细胞死亡，在体外用流式细胞术和LDH释放试验评估细胞死亡。采用免疫印迹和免疫组化（IHC）检测ZBP1和PANoptosis标志物的蛋白水平。结果LN肾脏中凋亡相关通路显著富集。TGP可抑制MRL/lpr小鼠足细胞PANoptosis，减轻肾损伤。在机制上，TGP通过调节STAT2-ZBP1轴抑制PANoptosis，其中ZBP1被认为是关键调节因子。ZBP1过表达减弱了TGP的治疗作用，证实了其在LN发病机制中的核心作用。结论本研究揭示zbp1介导的足细胞PANoptosis是LN的关键机制，并确定TGP是一种有前景的靶向该通路的治疗药物。这些发现为LN治疗提供了一种新颖的、临床可翻译的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Total glucosides of paeony ameliorates lupus nephritis by suppressing ZBP1-mediated PANoptosis in podocytes

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Total glucosides of paeony ameliorates lupus nephritis by suppressing ZBP1-mediated PANoptosis in podocytes

Background

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.

Purpose

This study investigated the role of PANoptosis in LN pathogenesis and elucidated the therapeutic mechanisms of TGP, focusing on ZBP1-mediated podocytes PANoptosis.

Methods

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).

Results

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.

Conclusion

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.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.