非酒精性脂肪性肝病（NAFLD）进展机制的复杂性仍然是开发有效疗法的重大挑战。 miRNA 作为生物过程的调节剂和复杂疾病的治疗靶点已显示出巨大的前景。在这里，我们研究了肝脏 miR-33（脂质代谢的重要调节因子）在 NAFLD 进展和肝细胞癌 (HCC) 发展过程中的作用。我们报告说，患有 NAFLD 的人和小鼠的肝脏中 miR-33 升高，并且肝细胞中的 miR-33 HKO 缺失可改善该疾病的多个方面，包括脂肪变性和炎症，从而限制非酒精性脂肪性肝炎的进展。 NASH）、纤维化和肝癌。从机制上讲，肝脏 miR-33 缺失会减少脂质合成并促进线粒体脂肪酸氧化，从而减轻脂质负担。此外，miR-33 的缺失会改变参与代谢的几个已知 miR-33 靶基因的表达，从而改善线粒体功能并减少氧化应激。脂质积累和肝损伤的减少导致 YAP/TAZ 通路激活减少，这可能与 HKO 肝脏中 HCC 进展的减缓有关。总之，这些结果表明抑制肝脏 miR-33 可能是减缓肥胖中 NAFLD、NASH 和 HCC 发展的有效治疗方法。

The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.