Isolinderalactone is the main sesquiterpene lactone isolated from Lindera aggregata, a traditional Chinese medicine widely used to treat pain and inflammation. Although isolinderalactone has been demonstrated to possess anti-cancer effect, its anti-inflammatory activity and underlying mechanism has not been well characterized. Herein, isolinderalactone was able to significantly inhibit the production of NO and PGE₂ by reducing the expressions of iNOS and COX2 in LPS-stimulated RAW264.7 macrophages and BMDMs, and decreased the mRNA levels of IL-1β, IL-6, and TNF-α in LPS-induced RAW264.7 cells. In vivo, isolinderalactone effectively alleviated LPS-induced acute lung injury (ALI), which manifested as reduction in pulmonary inflammatory infiltration, myeloperoxidase activity, and production of PGE₂, IL-1β, IL-6, TNF-α, and malondialdehyde. Furthermore, isolinderalactone inhibited phosphorylation of IKKα/β, phosphorylation and degradation of IκBα, and nuclear translocation of NF-κB p65, thereby blocking NF-κB pro-inflammatory pathway. Meanwhile, isolinderalactone reduced the intracellular ROS through promoting the activation of Nrf2-HMOX1 antioxidant axis. By using drug affinity responsive target stability assay and molecular docking, isolinderalactone was found to covalently interact with IKKα/β and Keap1, which may contribute to its anti-inflammatory action. Additionally, a thiol donor β-mercaptoethanol significantly abolished isolinderalactone-mediated anti-inflammatory action in vitro, indicating the crucial role of the unsaturated lactone of isolinderalactone on its anti-inflammatory effects. Taken together, isolinderalactone protected against LPS-induced ALI in mice, which may be associated with its inhibition of NF-κB pathway and activation of Nrf2 signaling in macrophages.

异木内酯是从乌药中分离出来的主要倍半萜内酯，乌药是一种广泛用于治疗疼痛和炎症的中药。尽管异林内酯已被证明具有抗癌作用，但其抗炎活性和潜在机制尚未得到很好的表征。在此，异火龙内酯能够通过降低LPS刺激的RAW264.7巨噬细胞和BMDM中iNOS和COX2的表达来显着抑制NO和PGE 2 的产生，并降低IL-1β、IL-6和TNF的mRNA_水平LPS 诱导的 RAW264.7 细胞中的 -α。在体内，异火龙内酯有效减轻LPS诱导的急性肺损伤（ALI），表现为肺部炎症浸润、髓过氧化物酶活性以及PGE 2 、IL-1β、_IL -6、TNF-α和丙二醛的产生减少。此外，异林内酯抑制 IKKα/β 的磷酸化、IκBα 的磷酸化和降解以及 NF-κB p65 的核转位，从而阻断 NF-κB 促炎通路。同时，异火龙内酯通过促进Nrf2-HMOX1抗氧化轴的激活来减少细胞内ROS。通过药物亲和响应靶稳定性测定和分子对接，发现异林内酯与 IKKα/β 和 Keap1 共价相互作用，这可能有助于其抗炎作用。此外，硫醇供体β-巯基乙醇在体外显着消除异林内酯介导的抗炎作用，表明异林内酯的不饱和内酯对其抗炎作用至关重要。综上所述，异火龙内酯可保护小鼠免受 LPS 诱导的 ALI，这可能与其抑制 NF-κB 通路和激活巨噬细胞中的 Nrf2 信号传导有关。