巨细胞是先天免疫防御对抗病原体感染的第一道防线，它处在通过感染或有毒刺激引起的多种形式的调控细胞死亡（RCD）之中，从而导致多器官受损。雷公藤中分离得到的一种活性化合物三七三酮具有多种药理学活性，包括抗肿瘤和抗炎作用，但其应用受到毒性不良效应的阻碍。目前还不清楚三七三酮是否以及如何在巨细胞中诱导不同形式的RCD。本研究中，我们展示了三七三酮在体外培养的巨细胞上表现出显著的细胞毒性，其与多种溶解性细胞死亡形式相关，这些形式无法完全被任何单一RCD形式的特异性抑制剂所抑制。一致的是，三七三酮引起了热凋亡、凋亡和坏疽特征的同时激活，伴随的是ASC斑点与RIPK3或半胱乳酸裂解酶-8的共定位以及它们之间的相互作用，表明了PANoptosome的形成以及PANoptosis的诱导。三七三酮诱导的PANoptosis与线粒体功能障碍和ROS产生有关。三七三酮在小鼠腹腔巨细胞中也能引起PANoptosis。此外，三七三酮引起了肾脏和肝脏损伤，这与体内系统性炎症反应和PANoptosis特征的激活相关。综上所述，我们的数据揭示了三七三酮在体外诱导巨细胞中的PANoptosis，并显示出与体内PANoptosis诱导相关联的肾毒性和肝毒性，这提示通过利用PANoptosis来减轻三七三酮的毒性是一条新的途径。© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.