Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of Institute of Health and Medicine (IHM), University of Science and Technology of China, Hefei, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of Institute of Health and Medicine (IHM), University of Science and Technology of China, Hefei, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Int Immunopharmacol. 2024 Apr 20;131:111915. doi: 10.1016/j.intimp.2024.111915. Epub 2024 Mar 23.
The aberrant activation of NLRP3 inflammasome contributes to pathogenesis of multiple inflammation-driven human diseases. However, the medications targeting NLRP3 inflammasome are not approved for clinic use to date. Here, we show that ascorbyl palmitate (AP), a lipophilic derivative of ascorbic acid (AA) and a safe food additive, is a potent inhibitor of NLRP3 inflammasome. Compared with AA, AP inhibited the activation of NLRP3 inflammasome with increased potency and specificity. Mechanistically, AP directly scavenged mitochondrial reactive oxygen species (mitoROS) by its antioxidant activity and blocked NLRP3-NEK7 interaction and NLRP3 inflammasome assembly. Moreover, AP showed more significant preventive effects than AA in LPS-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE). Thus, our results suggest that AP is a potential therapeutic combating NLRP3-driven diseases.
NLRP3 炎性小体的异常激活导致多种炎症驱动的人类疾病的发病机制。然而，迄今为止，尚无针对 NLRP3 炎性小体的药物被批准用于临床。在这里，我们表明抗坏血酸棕榈酸酯 (AP)，抗坏血酸 (AA) 的亲脂性衍生物和安全的食品添加剂，是 NLRP3 炎性小体的有效抑制剂。与 AA 相比，AP 通过其抗氧化活性更有效地抑制 NLRP3 炎性小体的激活，且具有更高的特异性。从机制上讲，AP 通过其抗氧化活性直接清除线粒体活性氧 (mitoROS)，并阻断 NLRP3-NEK7 相互作用和 NLRP3 炎性小体组装。此外，AP 在脂多糖诱导的全身炎症、葡聚糖硫酸钠 (DSS) 诱导的结肠炎和实验性自身免疫性脑脊髓炎 (EAE) 中比 AA 显示出更显著的预防作用。因此，我们的研究结果表明，AP 是一种有潜力的治疗 NLRP3 驱动疾病的药物。
