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Fibrosis is the process in which fibroblasts in damaged areas are transformed into fibrotic tissues composed of myofibroblasts and collagen-containing extracellular matrix after normal organs have been damaged beyond their ability to repair. Activated myofibroblasts are characterized by the expression of ACTA2. After severe damage to an organ or tissue, myofibroblasts will secrete excess extracellular matrix, and the body's own regeneration ability cannot completely repair the damage, resulting in the damaged part eventually being replaced by fibrotic tissue, and eventually the morphological and functional abnormalities of the damaged organ.
Fibrosis is a common disease, affecting 1 in 4 people worldwide. Fibrosis is mainly associated with myocardial infarction, heart failure, cirrhosis, hepatitis, nonalcoholic steatohepatitis, chronic kidney disease, idiopathic pulmonary fibrosis, diabetes, and scleroderma. As of 2024, there is no treatment for cardiac fibrosis. FDA-approved drugs for the treatment of idiopathic pulmonary fibrosis, pirfenidone and nintedanib, are not indicated for the treatment of patients with chronic heart disease due to their weak therapeutic effects or potential cardiotoxicity.
2024年10月15日，斯坦福大学Joseph Wu教授科研团队在张昊博士的带领下在Cell期刊发表了文章Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target。 研究者们开发了新的高通量多维度药物筛选技术，从约5000个小分子中找到了治疗心脏纤维化的破局新药，青蒿琥酯。
First, the research team established a drug discovery platform based on human pluripotent stem cells (iPSCs), tissue engineering, and animal models, and fabricated an ACTA2 reporter cell line using CRISPR gene editing technology. The researchers performed a high-throughput screening of 5,000 compounds, each testing seven different doses, followed by a back-screening of iPSC-derived cardiomyocytes and endothelial cells to rule out molecules with potential cardiovascular toxicity.
模式图（Credit: Cell）
The first seed was artesunate, with a semi-maximum effect concentration of 2.1 μM, and no significant damage to cardiomyocyte and endothelial cell viability at 50 μM. The researchers further verified that artesunate can effectively inhibit the activation of myofibroblasts and the secretion of collagen extracellular matrix in a variety of profibrotic factor cell models and 3D cardiac tissue models.
Next, the researchers constructed a mouse model of coarctation of the aorta and ischemia-reperfusion to mimic myocardial hypertrophy and cardiac fibrosis after myocardial infarction. Artesunate treatment significantly reduced fibrotic deposition and significantly improved cardiac dysfunction caused by heart failure. Through single-cell sequencing, the researchers found that artesunate not only inhibited fibroblast cells, but also reduced cardiomyocyte hypertrophy.
The researchers further explored the molecular mechanisms behind the therapeutic effects of artesunate. Using the molecular docking and dynamic simulation of computer simulation, the target of the drug was determined to be MD2, thereby inhibiting the MD2/TLR4 signaling pathway, inhibiting the expression of fibrosis genes and the transformation of myofibroblasts.
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https://www.cell.com/cell/fulltext/S0092-8674(24)01092-4
Editor-in-charge|Explore Jun
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