美国斯坦福大学医学院吴庆明研究组，通过心脏纤维化的多尺度药物筛选确定MD2作为治疗靶点。相关论文于2024年10月15日发表在《细胞》杂志上。

研究人员使用由人诱导多能干细胞（iPSC）分化而来的心脏成纤维细胞（CFs），进行抗纤维化化合物的高通量筛选。通过使用由iPSC分化得到的心肌细胞和内皮细胞，对初步候选化合物进行反向筛选，排除了具有心脏毒性的化合物。

这一筛选过程确定了青蒿素作为领先化合物。在促纤维化刺激后，青蒿素抑制了人类原代心脏成纤维细胞的增殖、迁移和收缩，减少了胶原沉积，并改善了三维工程化心脏组织的收缩功能。青蒿素还减轻了心力衰竭小鼠模型中的心脏纤维化，并改善了心脏功能。

在机制上，青蒿素靶向髓样分化因子2（MD2），并抑制了MD2/ Toll样受体4（TLR4）信号通路，从而减轻了心脏成纤维细胞中的纤维化基因表达。他们的研究利用多尺度药物筛选，整合了人类iPSC平台、组织工程、动物模型、计算机模拟和多组学，以确定MD2作为心脏纤维化的治疗靶点。

附：英文原文

Title: Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target

Author: Hao Zhang, Phung N. Thai, Rabindra V. Shivnaraine, Lu Ren, Xuekun Wu, Dirk H. Siepe, Yu Liu, Chengyi Tu, Hye Sook Shin, Arianne Caudal, Souhrid Mukherjee, Jeremy Leitz, Wilson Tan Lek Wen, Wenqiang Liu, Wenjuan Zhu, Nipavan Chiamvimonvat, Joseph C. Wu

Issue&Volume: 2024-10-15

Abstract: Cardiac fibrosis impairs cardiac function, but no effective clinical therapies exist. To address this unmet need, we employed a high-throughput screening for antifibrotic compounds using human induced pluripotent stem cell (iPSC)-derived cardiac fibroblasts (CFs). Counter-screening of the initial candidates using iPSC-derived cardiomyocytes and iPSC-derived endothelial cells excluded hits with cardiotoxicity. This screening process identified artesunate as the lead compound. Following profibrotic stimuli, artesunate inhibited proliferation, migration, and contraction in human primary CFs, reduced collagen deposition, and improved contractile function in 3D-engineered heart tissues. Artesunate also attenuated cardiac fibrosis and improved cardiac function in heart failure mouse models. Mechanistically, artesunate targeted myeloid differentiation factor 2 (MD2) and inhibited MD2/Toll-like receptor 4 (TLR4) signaling pathway, alleviating fibrotic gene expression in CFs. Our study leverages multiscale drug screening that integrates a human iPSC platform, tissue engineering, animal models, in silico simulations, and multiomics to identify MD2 as a therapeutic target for cardiac fibrosis.

DOI: 10.1016/j.cell.2024.09.034

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01092-4