An antisense oligonucleotide targeting STK25 as a long-acting therapeutic candidate for early MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disorder worldwide and a leading cause of liver-related morbidity and mortality. Insulin resistance and dysregulated hepatic lipid metabolism are key pathological mechanisms for simple hepatic steatosis, yet no specific drug is currently approved. Antisense oligonucleotides (ASOs) are single-stranded nucleotide drugs with high target specificity and long-lasting activity, representing a promising therapeutic approach for chronic metabolic diseases. Here, we report a novel ASO candidate targeting serine/threonine kinase 25 (STK25), a lipid droplet-associated kinase implicated in MASLD pathogenesis. The ASO (S-10c) potently suppressed STK25 expression in multiple human cell lines. Liver-specific delivery was achieved through N-acetylgalactosamine (GalNAc) conjugation, generating GS-10c. In a high-fat diet-induced early MASLD mouse model, GS-10c significantly improved insulin sensitivity, reduced hepatic lipid accumulation, and lowered body weight, exhibiting efficacy similar to resmetirom, the only FDA-approved treatment for metabolic steatohepatitis. A single injection achieved >50% hepatic Stk25 knockdown for over 35 days, demonstrating durable activity. Importantly, GS-10c was designed to avoid all known SNPs, ensuring consistent efficacy across genetically diverse populations. Notably, an alternative ASO differing by only 4 nt showed inconsistent silencing and safety, suggesting the unique therapeutic precision and translational robustness of GS-10c.