Li Kaili, Zhou Zixiang, Liu Feng, Huang Zuotian, Chen Xiaoying, Zhou Fachun
Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Yuzhong District, 3rd Floor, Building 7, 400016, Chongqing, China.
Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
Sci Rep. 2025 Apr 30;15(1):15207. doi: 10.1038/s41598-025-00028-z.
Although the drug therapeutic targets of acute respiratory distress syndrome (ARDS) are still unclear and no specific drugs for ARDS treatment have been found, some breakthroughs have been gradually made in the biological target pathways such as endothelial injury. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database suggests that Acetyl-11-keto-β-boswellic acid (AKBA), a processed product of boswellic acid, may be an effective intervention for ARDS. After preliminary in vitro and in vivo verification of the protective role of AKBA on ARDS, in order to explore the mechanism of AKBA in ARDS, we used transcriptomic and proteomic methods to explore its main targets, and used molecular docking and cell thermal shift assay (CETSA) to further reveal the potential value of bone marrow stromal cell antigen 2 (BST2) as a target. We subsequently examined the effect of AKBA targeting BST2 on tubule formation, cell proliferation (Colony formation and EdU assay), migration (transwell and scratch assays), apoptosis and autophagy levels both in vitro and in vivo, and protein changes (analyzed by Western blotting analysis). Our results show that the unphosphorylated signal transducers and transcription activation factors (U-STAT1) bins to the BST2 transcription promoter to encourage more AKBA anchoring the human pulmonary microvascular endothelial cells (HPMECs), thus inhibiting apoptosis and autophagy, promoting migration and tube formation, and restraining the cecal ligation and puncture (CLP) induced lung tissue damage in mice. In conclusion, AKBA treatment may be a potential strategy in the intervention of ARDS. Alternatively, BST2 may contribute to the anchoring of AKBA to HPMECs, and STAT1 as a transcription factor promoting BST2 expression may bind to its promoter.
尽管急性呼吸窘迫综合征（ARDS）的药物治疗靶点仍不明确，且尚未找到治疗ARDS的特效药物，但在内皮损伤等生物靶标途径方面已逐渐取得一些突破。中药系统药理学（TCMSP）数据库表明，乳香酸的加工产物乙酰-11-酮-β-乳香酸（AKBA）可能是治疗ARDS的有效干预药物。在对AKBA对ARDS的保护作用进行初步的体外和体内验证后，为了探究AKBA在ARDS中的作用机制，我们采用转录组学和蛋白质组学方法探索其主要靶点，并利用分子对接和细胞热位移分析（CETSA）进一步揭示骨髓基质细胞抗原2（BST2）作为靶点的潜在价值。随后，我们检测了靶向BST2的AKBA在体外和体内对小管形成、细胞增殖（集落形成和EdU检测）、迁移（transwell和划痕检测）、凋亡和自噬水平以及蛋白质变化（通过蛋白质印迹分析）的影响。我们的结果表明，未磷酸化的信号转导和转录激活因子（U-STAT1）与BST2转录启动子结合，促使更多AKBA锚定到人肺微血管内皮细胞（HPMECs）上，从而抑制凋亡和自噬，促进迁移和小管形成，并减轻盲肠结扎和穿刺（CLP）诱导的小鼠肺组织损伤。总之，AKBA治疗可能是干预ARDS的一种潜在策略。此外，BST2可能有助于AKBA锚定到HPMECs上，而作为促进BST2表达的转录因子STAT1可能与其启动子结合。
