Hederagenin通过JAK2/STAT3信号通路抑制AIM2介导的PANoptosis抗肝损伤的机制研究
Mechanistic study of Hederagenin against liver injury by inhibiting AIM2-mediated PANoptosis via the JAK2/STAT3 signaling pathway.
摘要(中文译文)
急性肝损伤（ALI）是由多种因素诱发的严重肝脏疾病，包括肝炎病毒和药物毒性。严重且持续的急性肝损伤在缺乏有效干预的情况下最终可进展为多器官功能衰竭。目前，现有的肝损伤治疗方法无法提供有效且安全的长期管理方案。因此，迫切需要开发新的抗肝损伤药物。本研究旨在探究常春藤皂苷元（HD）是否能够减轻急性肝损伤，并阐明HD对肝损伤保护作用的潜在机制。采用HE染色、TUNEL染色、ROS检测、免疫荧光、ELISA和生化检测评估HD对急性肝损伤的干预效果。通过RNA-seq和蛋白质组学分析鉴定潜在的靶点通路。利用从GEO数据库获取的GSE14668和GSE38941数据集分析对照组与肝损伤患者之间的差异基因表达。进一步应用Western blot、qRT-PCR、分子对接和免疫荧光，结合药理学抑制剂和激动剂，在体外和体内进行验证。研究发现HD可显著减轻小鼠肝损伤，包括减轻病理损伤、改善肝功能指标和降低炎症水平。随后的RNA-seq和蛋白质组学分析结果表明，HD对肝损伤的保护作用与JAK/STAT信号通路和PANoptosis相关。在GSE14668和GSE38941数据集中，患者肝组织中AIM2表达上调。通过使用JAK2/STAT3抑制剂AG490和JAK2/STAT3激动剂α7nAChR-JAK2-STAT3 agonist 1，结果表明HD通过调控JAK2/STAT3信号通路改善肝损伤。随后，本研究发现AIM2是JAK2/STAT3通路的下游靶点。使用AIM2抑制剂ODN TTAGGG和AIM2过表达，验证了HD对肝损伤的保护作用与AIM2调控的PANoptosis相关。HD对急性肝损伤具有一定的改善作用。此外，HD通过JAK2/STAT3信号通路抑制AIM2介导的PANoptosis发挥肝损伤保护作用。
Abstract
Acute liver injury (ALI) is a severe liver disease induced by various factors, including hepatitis viruses and drug toxicity. Severe and persistent ALI can eventually progress to multiple organ failure in the absence of effective intervention. At present, existing treatments for liver injury fail to provide effective and safe long-term management. Therefore, it is urgent to develop new anti-liver injury drugs. This study aimed to investigate whether Hederagenin (HD) alleviates ALI and to elucidate the mechanism underlying the protective effect of HD against liver injury. The intervention efficacy of HD on ALI was assessed using HE staining, TUNEL staining, ROS detection, immunofluorescence, ELISA, and biochemical assays. RNA-seq and proteomic analysis were performed to identify the potential target pathways. Differential gene expression between controls and patients with liver injury was analyzed using the GSE14668 and GSE38941 datasets retrieved from the GEO database. Western blot, qRT-PCR, molecular docking, and immunofluorescence, together with pharmacological inhibitors and agonists, were further applied for verification both in vitro and in vivo. HD was found to significantly alleviate liver injury in mice, including attenuating pathological injury, improving liver function indices and reducing inflammation levels. Subsequent RNA-seq and proteomic analysis results indicated that the protective effect of HD against liver injury was related to the JAK/STAT signaling pathway and PANoptosis. In the GSE14668 and GSE38941 datasets, AIM2 expression was upregulated in liver tissues from patients. By employing the JAK2/STAT3 inhibitor AG490 and the JAK2/STAT3 agonist α7nAChR-JAK2-STAT3 agonist 1, the results demonstrated that HD ameliorated liver injury by regulating the JAK2/STAT3 signaling pathway. Following that, our study found that AIM2 was the downstream target of the JAK2/STAT3 pathway. Using the AIM2 inhibitor ODN TTAGGG and AIM2 overexpression, the protective effect of HD against liver injury was verified to be associated with AIM2-regulated PANoptosis. HD exerted a certain ameliorative effect on ALI. In addition, HD protected against liver injury by inhibiting AIM2-mediated PANoptosis through the JAK2/STAT3 signaling pathway.
如何引用
AMA
Qinqin Zhang, Haoyang Dai, Tianyi Cui, Suiqing Chen. Mechanistic study of Hederagenin against liver injury by inhibiting AIM2-mediated PANoptosis via the JAK2/STAT3 signaling pathway.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158354.
APA
Qinqin Zhang, Haoyang Dai, Tianyi Cui, Suiqing Chen (2026). Mechanistic study of Hederagenin against liver injury by inhibiting AIM2-mediated PANoptosis via the JAK2/STAT3 signaling pathway.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158354
GB/T 7714
Qinqin Zhang, Haoyang Dai, Tianyi Cui, Suiqing Chen. Mechanistic study of Hederagenin against liver injury by inhibiting AIM2-mediated PANoptosis via the JAK2/STAT3 signaling pathway.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158354.
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