Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting caspase-1 and interleukin 1β (IL-1β) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1β maturation and caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial reactive oxygen species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1β and tumor necrosis factor (TNF-α) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI.

异质性药物诱发的肝损伤（IDILI）是一种罕见但潜在的致命疾病，无法预测且与药物剂量无关。越来越多的证据表明，大多数IDILI病例是免疫介导的，炎性体的异常激活在进展中起着至关重要的作用。补骨脂补骨脂（PF）能够引起IDILI，但尚无确切的肝毒性机制。在这项研究中，研究了八种与PF诱导的炎性体活化有关的生物活性化合物。结果表明，补骨脂素激活炎性体，然后以剂量依赖的方式分泌caspase-1和白介素1β（IL-1β）。有趣的是，MCC950是一种含有NOD样受体家族的含吡喃域的3（NLRP3）炎性小体的有效抑制剂，不能完全抑制补骨脂素诱导的炎性体激活。此外，补骨脂素在NLRP3敲除的骨髓巨噬细胞（BMDM）中显着诱导IL-1β成熟和caspase-1活化，表明补骨脂素不仅激活NLRP3炎症小体，而且激活其他类型的炎症小体。结果还表明，补骨脂素通过促进C端半胱天冬酶募集结构域（ASC）寡聚化来激活炎性体，而线粒体活性氧（mtROS）的产生是补骨脂素诱导的炎性体激活的决定性因素。重要的是，体内数据显示，补骨脂素可诱发肝脏炎症，在脂多糖（LPS）介导的IDILI易感小鼠模型中，增加了氨基转移酶活性并增加了IL-1β和肿瘤坏死因子（TNF-α）的产生。总之，这些结果证实了补骨脂素通过诱导炎性体激活而引起IDILI。该研究表明，补骨脂素是可能的危险因素，并与PF诱导的IDILI有关。