Metabolic Dysfunction-Associated Steatotic Liver Disease and Emerging Oligonucleotide Therapies

TL;DR

This paper reviews new oligonucleotide therapies for treating a common liver disease linked to metabolic dysfunction.

Contribution

It highlights the novel use of oligonucleotide drugs like ASO, siRNA, and miRNA for precise targeting in MASLD treatment.

Findings

Oligonucleotide therapies offer precise targeting of genes involved in MASLD pathogenesis.

Advanced delivery systems like GalNAc conjugation improve hepatocyte-specific targeting.

Current challenges and future directions in oligonucleotide drug development for MASLD are discussed.

Abstract

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.

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