代谢功能障碍相关的脂肪肝病（MASLD）是一种复杂的多因素疾病，并成为肝脏相关发病率和死亡率的主要原因。 MASLD 从孤立性脂肪变性到代谢功能障碍相关脂肪性肝炎 (MASH)，后者可能进展为肝硬化和肝细胞癌 (HCC)。遗传、代谢和环境因素对 MASLD 的异质性有很大影响。生活方式干预和减肥是 MASLD 的可行治疗方法。此外，甲状腺激素β受体激动剂Resmetirom最近已被批准用于MASLD治疗。然而，大多数接受治疗的个体对这种治疗没有反应，这表明需要一种更有针对性的方法来治疗 MASLD。最近开发了基于寡核苷酸的疗法，即小干扰 RNA (siRNA) 和反义寡核苷酸 (ASO)，通过减少影响 MASH 进展的基因（例如 PNPLA3 和 HSD17B13）的表达来应对 MASLD。在这里，我们回顾了针对 MASH 遗传决定因素的基于寡核苷酸的药物的合成和开发的最新进展。

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.