Metabolic Dysfunction-Associated Steatotic Liver Disease and Emerging Oligonucleotide Therapies

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent chronic liver condition characterized by pathological fat accumulation in hepatocytes, with a global prevalence of approximately 30% that continues to rise. Current treatment options are limited, highlighting an urgent need for novel therapeutic strategies. This review systematically examines the emerging promise of oligonucleotide-based drugs for MASLD treatment, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA) mimic or inhibitor, small activating RNA (saRNA) and splicing-switching oligonucleotide (SSO). We summarize the mechanisms of action of these therapeutics, which enable precise targeting of genes involved in MASLD pathogenesis. Furthermore, the review explores advanced delivery systems, particularly N-acetylgalactosamine (GalNAc) conjugation, which enhances hepatocyte-specific targeting. Finally, we discuss the current challenges facing oligonucleotide drug development and outline future directions for this rapidly advancing field, underscoring its potential to revolutionize MASLD management.