Huang Jing, Dai Mengmeng, Huang Xinyu, Qi Wenqing, Jing Jing, He Jiayi, Lu Zhizhuo, Zhang Chaofang, Wang Guiling, Ma Yuanfang, Zhang Hailong, Cao Run
Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, 475004, People's Republic of China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
Sci Rep. 2025 May 30;15(1):19037. doi: 10.1038/s41598-025-03512-8.
Shikonin (SHK) is a plant-derived naphthoquinone known for its anti-inflammatory activity, though the mechanism remains largely unexplored. The NLRP3 inflammasome, one of the most studied inflammasomes, can cause uncontrolled inflammation and drive various diseases when dysregulated. Here, we confirmed that SHK specifically abolished NLRP3 inflammasome activation by suppressing caspase-1 maturation and the secretion of IL-1β and IL-18. Our data demonstrated that SHK disrupted NLRP3 inflammasome assembly, primarily by blocking NLRP3 and ASC binding, thereby preventing ASC oligomerization and ASC speck formation. Furthermore, SHK reduced reactive oxygen species (ROS) production, inhibiting the generation of oxidized mitochondrial DNA (ox-mtDNA), a known inducer of NLRP3 inflammasome activation. In vivo, we showed that SHK's anti-inflammatory effect in DSS-induced ulcerative colitis (UC) and LPS-induced systemic inflammation associated with the reduction of NLRP3 inflammasome activation, as confirmed by decreased IL-1β and IL-18 release. This paper reveals the mechanism through which SHK inhibits inflammation and provides a potentially effective pharmacological strategy for treating NLRP3-related diseases.
紫草素（SHK）是一种源自植物的萘醌，以其抗炎活性而闻名，但其作用机制在很大程度上仍未得到探索。NLRP3炎性小体是研究最多的炎性小体之一，当其失调时可导致不受控制的炎症并引发各种疾病。在此，我们证实SHK通过抑制半胱天冬酶-1成熟以及白细胞介素-1β和白细胞介素-18的分泌，特异性地消除了NLRP3炎性小体的激活。我们的数据表明，SHK主要通过阻断NLRP3与凋亡相关斑点样蛋白（ASC）的结合来破坏NLRP3炎性小体的组装，从而防止ASC寡聚化和ASC斑点形成。此外，SHK减少了活性氧（ROS）的产生，抑制了氧化线粒体DNA（ox-mtDNA）的生成，而氧化线粒体DNA是已知的NLRP3炎性小体激活诱导剂。在体内，我们表明SHK在葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎（UC）和脂多糖（LPS）诱导的全身炎症中的抗炎作用与NLRP3炎性小体激活的减少有关，白细胞介素-1β和白细胞介素-18释放的减少证实了这一点。本文揭示了SHK抑制炎症的机制，并为治疗NLRP3相关疾病提供了一种潜在有效的药理学策略。
