Li Honglian, Chen Jiayun, Guo Huiyi, Yang Hao, Liu Jing, Yuan Haoxing, Zhang Junzhe, Wang Jigang, Liu Shuwen
Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory of Drug Metabolism Research and Evaluation, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
State Key Laboratory for Quality Ensuanse and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Biochem Biophys Res Commun. 2025 Jun 1;764:151821. doi: 10.1016/j.bbrc.2025.151821. Epub 2025 Apr 15.
Acute liver injury (ALI) is a prevalent inflammatory disease with no currently available effective targeted therapies that characterized by high mortality and morbidity. Dihydroartemisinin (DHA), a derivative of the renowned antimalarial compound artemisinin, has garnered attention for its anti-inflammatory property. However, the precise anti-inflammatory mechanisms underlying its efficacy in treating ALI remain unclear. Notably, the excessive inflammatory cytokines secreted by macrophages represents a critical factor of liver damage. In our comprehensive study, transcriptome and proteomic analysis of M1 macrophages after DHA treatment was performed to unearth the potential anti-inflammatory targets for ALI treatment. Transcriptomics analysis indicated that DHA significantly mitigated inflammation, primarily by downregulating the expressions of CCL1, CCL2, CCL7, CCL13, and CXCL13. Concurrently, proteomics analysis identified six proteins, such as CYBA and CYBB, that were consistently downregulated in the DHA intervention groups compared to the M1 group. Intriguingly, a protein-protein interaction network analysis highlighted the close association of CYBA and CYBB with the aforementioned chemokine genes. Through meticulous screening, DHA curtailed the production of reactive oxygen species (ROS) by targeting CYBA and CYBB, subsequently suppressing the secretion of several chemokines and dampening the inflammatory response in M1 macrophages. More importantly, DHA not only reduced ROS and chemokine levels but also restored liver function by downregulating CYBA and CYBB to inhibit NF-κB pathway in ALI mice, demonstrating strong anti-inflammatory effects. In conclusion, our findings throw novel light into the underlying anti-inflammatory mechanism of DHA in ALI management, offering valuable insights for future clinical research and therapeutic strategies for inflammatory diseases.
急性肝损伤（ALI）是一种常见的炎症性疾病，目前尚无有效的靶向治疗方法，其死亡率和发病率都很高。双氢青蒿素（DHA）是著名抗疟化合物青蒿素的衍生物，因其抗炎特性而受到关注。然而，其治疗ALI疗效的确切抗炎机制仍不清楚。值得注意的是，巨噬细胞分泌的过量炎性细胞因子是肝损伤的关键因素。在我们的综合研究中，对DHA处理后的M1巨噬细胞进行了转录组和蛋白质组分析，以挖掘治疗ALI的潜在抗炎靶点。转录组学分析表明，DHA主要通过下调CCL1、CCL2、CCL7、CCL13和CXCL13的表达来显著减轻炎症。同时，蛋白质组学分析鉴定出六种蛋白质，如CYBA和CYBB，与M1组相比，它们在DHA干预组中持续下调。有趣的是，蛋白质-蛋白质相互作用网络分析突出了CYBA和CYBB与上述趋化因子基因的密切关联。通过细致筛选，DHA通过靶向CYBA和CYBB减少活性氧（ROS）的产生，随后抑制几种趋化因子的分泌并减轻M1巨噬细胞中的炎症反应。更重要的是，DHA不仅降低了ROS和趋化因子水平，还通过下调CYBA和CYBB来抑制ALI小鼠的NF-κB通路，从而恢复肝功能，显示出强大的抗炎作用。总之，我们的研究结果为DHA在ALI治疗中的潜在抗炎机制提供了新的线索，为未来炎症性疾病的临床研究和治疗策略提供了有价值的见解。
