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.

中文翻译：

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针对法尼醇 X 受体、铁死亡和纤维化的联合纳米治疗方法治疗非酒精性脂肪性肝炎

奥贝胆酸 (OCA) 是一种法尼醇 X 受体 (FXR) 激动剂，对脂肪和葡萄糖代谢具有良好作用，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的有效性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，与 NASH 的进展有关。一氧化氮（NO）是一种多功能生物分子，可以降解细胞外基质。在这项研究中，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)，以及铁死亡抑制剂 liproxsatin-1 和 NO 供体亚硝基硫醇 (ONL@MSN)。利用生化分析、组织学、多重流式细胞术、大量组织 RNA 测序和粪便 16S 核糖体 RNA 测序来评估组合纳米颗粒 (ONL@MSN) 在小鼠 NASH 模型中的效果。与负载 OCA 的纳米颗粒 (O@MSN) 相比，ONL@MSN 不仅可以预防肝脂肪变性，还可以大大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。这些发现提出了一种有前途的协同纳米治疗策略，通过同时靶向 FXR、铁死亡和纤维化来治疗 NASH。