中国科学院合肥物质科学研究院刘青松等研究人员合作发现，来自民族药用真菌的Hypocrellin A通过抑制炎症小体激活保护小鼠免受NLRP3驱动的痛风。2024年12月16日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

研究人员建立了一个由尼戈霉素诱导的炎症小体激活细胞模型，通过测量细胞上清液中的IL-1β分泌来筛选天然产物库。在测试的432种化合物中，研究人员发现来自中国西北云南的传统民族药用真菌Hypocrella bambusea中的主要活性成分——Hypocrellin A（HA），对IL-1β的生成具有最强的抑制作用（IC50=0.103 μM）。

在PMA诱导的THP-1细胞或骨髓来源巨噬细胞（BMDM）中，HA剂量依赖性地抑制了NLRP3炎症小体的激活，减少了随后的炎症因子和乳酸脱氢酶（LDH）的释放。此外，HA对炎症小体激活的抑制是特异性地作用于NLRP3，而非AIM2或NLRC4。在LPS诱导的BMDM中，HA抑制了ASC寡聚化和斑点形成，并在炎症小体组装过程中阻断了NLRP3与NEK7的相互作用，而不影响启动阶段。

此外，研究人员证明HA直接与NLRP3的NACHT结构域结合，Arg578和Glu629是HA与NLRP3结合的关键残基。在MSU诱导的腹膜炎和急性痛风性关节炎小鼠模型中，HA（10 mg/kg，腹腔注射，每日一次或两次）的给药有效抑制了由NLRP3炎症小体介导的炎症反应。

研究人员总结认为，HA是一种广谱且特异性的NLRP3抑制剂，是开发新型NLRP3驱动疾病治疗抑制剂的宝贵领先化合物。该研究还阐明了HA的抗炎机制及分子靶点，HA作为药用真菌Hypocrella bambusea中的主要活性成分，长期以来被中国少数民族群体使用。

据悉，NLRP3炎症小体的异常激活是痛风进展的主要原因，目前尚无批准用于临床的NLRP3小分子抑制剂。

附：英文原文

Title: Hypocrellin A from an ethnic medicinal fungus protects against NLRP3-driven gout in mice by suppressing inflammasome activation

Author: Yan, Le-jin, Qi, Shuang, Wu, Chao, Jin, Rui, Hu, Chen, Wang, Ao-li, Wang, Bei-lei, Yu, Hong-wei, Wang, Li, Liu, Jing, Qi, Zi-ping, Wang, Wen-chao, Liu, Qing-song

Issue&Volume: 2024-12-16

Abstract: Abnormal activation of NLRP3 inflammasome causes the progression of gout, and no small-molecule inhibitor of NLRP3 has been approved yet for clinical use. In this study we established a nigericin-induced inflammasome activation cell model for screening of a natural product library by measuring IL-1β secretion in cell supernatants. Among 432 compounds tested, we found that hypocrellin A (HA), one of the major active components of a traditional ethnic medicinal fungus Hypocrella bambusea in the Northwest Yunnan of China, exhibited the highest inhibition on IL-1β production (IC50=0.103μM). In PMA-primed THP-1 cells or bone marrow derived macrophages (BMDMs) treated with multiple stimuli (nigericin, ATP or MSU), HA dose-dependently suppressed the activation of NLRP3 inflammasome, reducing the subsequent release of inflammatory cytokines and LDH. Furthermore, the suppression of inflammasome activation by HA was specific to NLRP3, but not to AIM2 or NLRC4. In LPS-primed BMDMs treated with nigericin, HA inhibited ASC oligomerization and speckle formation, and blocked the NLRP3-NEK7 interaction during inflammasome assembly without influencing the priming stage. Moreover, we demonstrated that HA directly bound to the NACHT domain of NLRP3, and that Arg578 and Glu629 were the critical residues for HA binding to NLRP3. In MSU-induced peritonitis and acute gouty arthritis mouse models, administration of HA (10mg/kg, i.p., once or twice daily) effectively suppressed the inflammatory responses mediated by NLRP3 inflammasome. We conclude that HA is a broad-spectrum and specific NLRP3 inhibitor, and a valuable lead compound to develop novel therapeutic inhibitors against NLRP3-driven diseases. This study also elucidates the anti-inflammation mechanisms and molecular targets of HA, a major active component in medicinal fungus Hypocrella bambusea that has been long used by Chinese ethnic groups.

DOI: 10.1038/s41401-024-01434-1

Source: https://www.nature.com/articles/s41401-024-01434-1