Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate β-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.

非酒精性脂肪肝疾病（NAFLD）被认为是下一个主要的健康流行病，估计全世界的流行程度为25％。尚未批准任何药物，NAFLD仍然是主要的未满足需求。在这里，我们确定MCJ（甲基化控制的J蛋白）为非酒精性脂肪性肝炎（NASH）（NAFLD的晚期）的靶标。MCJ是呼吸链复合体I的内源性负调节剂，可抑制线粒体呼吸。我们显示，具有纳米颗粒和GalNAc配制的siRNA的肝靶向MCJ在多个NASH小鼠模型中有效降低了肝脂质蓄积和纤维化。降低MCJ表达可增强肝细胞介导脂肪酸β-氧化的能力，并最大程度地减少脂质积聚，从而减少肝细胞损伤和纤维化。此外，相对于健康受试者，NAFLD患者肝脏中的MCJ水平升高。因此，抑制MCJ成为治疗NAFLD的替代方法。