Caddeo Andrea, Romeo Stefano
Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy.
Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.
Clin Mol Hepatol. 2025 Feb;31(Suppl):S76-S93. doi: 10.3350/cmh.2024.0438. Epub 2024 Aug 5.
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.
代谢功能障碍相关脂肪性肝病（MASLD）是一种复杂的多因素疾病，正成为肝脏相关发病和死亡的主要原因。MASLD涵盖从单纯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。生活方式干预和体重减轻是MASLD的一种可行治疗方法。此外，甲状腺激素β受体激动剂Resmetirom最近已被批准用于治疗MASLD。然而，大多数接受治疗的个体对这种治疗无反应，这表明需要一种更具针对性的方法来治疗MASLD。基于寡核苷酸的疗法，即小干扰RNA（siRNA）和反义寡核苷酸（ASO），最近已被开发出来，通过降低影响MASH进展的基因（如PNPLA3和HSD17B13）的表达来治疗MASLD。在此，我们综述了靶向MASH遗传决定因素的基于寡核苷酸的药物合成与开发的最新进展。
