Long-acting STK25 antisense oligonucleotide as a therapeutic candidate for MASLD

ABSTRACT: Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and a leading cause of liver-related morbidity. Insulin resistance and hepatic lipid metabolism dysfunction are recognized as central pathological mechanisms, yet no therapy is currently approved specifically for MASLD. Antisense oligonucleotides (ASOs) are single-stranded nucleotide drugs with high target specificity and long-lasting activity, making them well suited for chronic metabolic diseases. Here, we describe a novel ASO candidate targeting serine/threonine kinase 25 (STK25), a lipid droplet–associated kinase implicated in MASLD pathogenesis. In three human cell lines, the ASO (S-10c) robustly reduced STK25 expression. For in vivo validation, we generated GS-10c by GalNAc conjugation to enable liver-specific delivery. In a high-fat diet-induced MASLD mouse model, GS-10c significantly improved insulin sensitivity, reduced hepatic lipid accumulation, and lowered body weight, with efficacy comparable to resmetirom, the only FDA-approved therapy for metabolic-associated steatohepatitis. A single injection sustained >50% hepatic Stk25 knockdown for 35 days, underscoring its long-acting therapeutic profile. Importantly, S-10c was designed to avoid all known single-nucleotide polymorphisms (SNPs), ensuring efficacy across genetically diverse populations. Together, these findings establish GS-10c as a durable, SNP-aware, and clinically translatable nucleic acid–based therapeutic candidate for MASLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE308862 | GEO | 2025/09/28

REPOSITORIES: GEO