Fu Jiangtao, Zhang Pingping, Sun Zhiguo, Lu Guodong, Cao Qi, Chen Yiting, Wu Wenbin, Zhang Jiabao, Zhuang Chunlin, Sheng Chunquan, Xu Jiajun, Lu Ying, Wang Pei
The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University, Shanghai 200433, China.
National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai 200433, China.
Acta Pharm Sin B. 2024 May;14(5):2228-2246. doi: 10.1016/j.apsb.2024.02.017. Epub 2024 Feb 26.
Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist with favorable effects on fatty and glucose metabolism, has been considered the leading candidate drug for nonalcoholic steatohepatitis (NASH) treatment. However, its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback. Ferroptosis, a newly recognized form of cell death characterized by uncontrolled lipid peroxidation, is involved in the progression of NASH. Nitric oxide (NO) is a versatile biological molecule that can degrade extracellular matrix. In this study, we developed a PEGylated thiolated hollow mesoporous silica nanoparticles (MSN) loaded with OCA, as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor -nitrosothiol (ONL@MSN). Biochemical analyses, histology, multiplexed flow cytometry, bulk-tissue RNA sequencing, and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle (ONL@MSN) in a mouse NASH model. Compared with the OCA-loaded nanoparticles (O@MSN), ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis. ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis, inhibition of immune response/lipid peroxidation, and correction of microbiota dysbiosis. These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR, ferroptosis, and fibrosis.
奥贝胆酸（OCA）是一种对脂肪和葡萄糖代谢有有益作用的法尼醇X受体（FXR）激动剂，被认为是治疗非酒精性脂肪性肝炎（NASH）的主要候选药物。然而，其在解决肝纤维化和脂毒性诱导的细胞死亡方面效果有限，仍然是一个主要缺点。铁死亡是一种新认识的细胞死亡形式，其特征是不受控制的脂质过氧化，参与NASH的进展。一氧化氮（NO）是一种多功能生物分子，可降解细胞外基质。在本研究中，我们开发了一种负载OCA的聚乙二醇化硫醇化中空介孔二氧化硅纳米颗粒（MSN），以及一种铁死亡抑制剂liproxsatin-1和一种NO供体亚硝基硫醇（ONL@MSN）。利用生化分析、组织学、多参数流式细胞术、组织RNA测序和粪便16S核糖体RNA测序来评估复合纳米颗粒（ONL@MSN）在小鼠NASH模型中的作用。与负载OCA的纳米颗粒（O@MSN）相比，ONL@MSN不仅能预防肝脂肪变性，还能显著改善纤维化和铁死亡。ONL@MSN在维持肝内巨噬细胞/单核细胞稳态、抑制免疫反应/脂质过氧化以及纠正微生物群失调方面也表现出增强的治疗作用。这些发现为通过同时靶向FXR、铁死亡和纤维化来治疗NASH提供了一种有前景的协同纳米治疗策略。
