Niu Xia, Meng Yanan, Cui Jinjin, Li Rui, Ding Xiao, Niu Bingyu, Chang Ge, Xu Ning, Li Guiling, Wang Yucheng, Wang Lulu
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
ACS Nano. 2023 Dec 12;17(23):23608-23625. doi: 10.1021/acsnano.3c06626. Epub 2023 Nov 23.
Liver fibrosis is a major contributor to the morbidity and mortality associated with liver diseases, yet effective treatment options remain limited. Hepatic stellate cells (HSCs) are a promising target for hepatic fibrogenesis due to their pivotal role in disease progression. Our previous research has demonstrated the potential of Dihydrotanshinone I (DHI), a lipophilic component derived from the natural herb Bunge, in treating liver fibrosis by inhibiting the YAP/TEAD2 interaction in HSCs. However, the clinical application of DHI faces challenges due to its poor aqueous solubility and lack of specificity for HSCs. Additionally, recent studies have implicated the impact of liver microbiota, distinct from gut microbiota, on the pathogenesis of liver diseases. In this study, we have developed an HSC- and microbiome-specific delivery system for DHI by conjugating prebiotic-like cyclodextrin (CD) with vitamin A, utilizing PEG2000 as a linker (VP@CD). Our results demonstrate that VP@CD markedly enhances the cellular uptake in human HSC line LX-2 and enhances the deposition of DHI in the fibrotic liver . Subsequently, intervention with DHI-VP@CD has shown a notable reduction in bile duct-like structure proliferation, collagen accumulation, and the expression of fibrogenesis-associated genes in rats subjected to bile duct ligation. These effects may be attributed to the regulation of the YAP/TEAD2 interaction. Importantly, the DHI-VP@CD intervention has also restored microbial homeostasis in the liver, promoting the amelioration of liver inflammation. Overall, our findings indicate that DHI-VP@CD represents a promising therapeutic approach for liver fibrosis by specifically targeting HSCs and restoring the liver microbial balance.
肝纤维化是导致肝脏疾病发病和死亡的主要因素，然而有效的治疗选择仍然有限。肝星状细胞（HSCs）在疾病进展中起关键作用，是肝纤维化形成的一个有前景的治疗靶点。我们之前的研究表明，二氢丹参酮I（DHI）是一种从天然草药丹参中提取的亲脂性成分，可通过抑制肝星状细胞中的YAP/TEAD2相互作用来治疗肝纤维化。然而，由于其水溶性差且对肝星状细胞缺乏特异性，DHI的临床应用面临挑战。此外，最近的研究表明，与肠道微生物群不同的肝脏微生物群对肝脏疾病的发病机制有影响。在本研究中，我们通过将益生元样环糊精（CD）与维生素A结合，并利用聚乙二醇2000作为连接体（VP@CD），开发了一种针对肝星状细胞和微生物群的DHI递送系统。我们的结果表明，VP@CD显著增强了人肝星状细胞系LX-2中的细胞摄取，并增强了DHI在纤维化肝脏中的沉积。随后，对胆管结扎大鼠进行DHI-VP@CD干预后，胆管样结构增殖、胶原积累以及纤维化相关基因的表达均显著降低。这些作用可能归因于对YAP/TEAD2相互作用的调节。重要的是，DHI-VP@CD干预还恢复了肝脏中的微生物稳态，促进了肝脏炎症的改善。总体而言，我们的研究结果表明，DHI-VP@CD通过特异性靶向肝星状细胞并恢复肝脏微生物平衡，代表了一种有前景的肝纤维化治疗方法。
