人们已经开发出多种生物制剂来靶向肿瘤坏死因子α（TNF-α）及其受体TNFR1来治疗类风湿性关节炎（RA），而与生物制剂相比，调节此类细胞因子受体的小分子却很少报道。在这里，通过揭示二萜类天然产物维尼醇的作用机制，我们发现小分子抑制蛋白质二硫键异构酶（PDI，PDIA1）会激活A解整合素和金属蛋白酶17（ADAM17），然后导致TNFR1脱落小鼠和人类细胞膜。这种小分子诱导的受体脱落不仅能有效阻断细胞内TNF-α引起的炎症反应，还能降低胶原诱导关节炎小鼠模型的关节炎评分和关节损伤。我们的研究表明，通过化学方法靶向 PDI-ADAM17 信号模块来调节细胞因子受体的脱落是缓解 RA 的一种有前景的策略。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

Various biological agents have been developed to target tumor necrosis factor alpha (TNF-α) and its receptor TNFR1 for the rheumatoid arthritis (RA) treatment, whereas small molecules modulating such cytokine receptors are rarely reported in comparison to the biologicals. Here, by revealing the mechanism of action of vinigrol, a diterpenoid natural product, we show that inhibition of the protein disulfide isomerase (PDI, PDIA1) by small molecules activates A disintegrin and metalloprotease 17 (ADAM17) and then leads to the TNFR1 shedding on mouse and human cell membranes. This small-molecule-induced receptor shedding not only effectively blocks the inflammatory response caused by TNF-α in cells, but also reduces the arthritic score and joint damage in the collagen-induced arthritis mouse model. Our study indicates that targeting the PDI-ADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a promising strategy for alleviating RA.Copyright © 2023 Elsevier Ltd. All rights reserved.