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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 (c337) robustly reduced STK25 expression. For in vivo validation, we generated Gc337 by GalNAc conjugation to enable liver-specific delivery. In a high-fat diet-induced MASLD mouse model, Gc337 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 without hepatotoxicity, underscoring its long-acting therapeutic profile. Importantly, c337 was designed to avoid all known single-nucleotide polymorphisms (SNPs), ensuring efficacy across genetically diverse populations. Together, these findings establish Gc337 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

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Project description:Non-alcoholic fatty liver disease (NAFLD), defined as fatty infiltration in >5% of hepatocytes (steatosis) in the absence of excessive alcohol consumption, is emerging as a leading cause of liver disease worldwide (1). Subjects with NAFLD have an increased risk of progressing into non-alcoholic steatohepatitis (NASH) as well as developing type 2 diabetes, cardiovascular disease, and liver cancer (2-4). Thus, understanding the pathobiology of NAFLD is of high medical relevance for the efficient prevention and treatment of a range of complex metabolic diseases. In NAFLD, excess lipids accumulate within intrahepatocellular lipid droplets (LDs), which are composed of a neutral lipid core of mainly triacylglycerol (TAG) and cholesterol esters surrounded by a phospholipid monolayer that harbors specific proteins. Once thought to be only inert energy storage depots, hepatic LDs are increasingly recognized as organelles that orchestrate liver lipid partitioning but also play a critical role in protein quality control and storage, cell signaling, and viral replication (5). Notably, LDs are shown to dynamically interact with a variety of cellular organelles including the endoplasmic reticulum (ER), mitochondria, peroxisomes, and endosomes (6). Liver LD surface-associated proteins regulate the functional properties of LDs, and dietary fat content as well as liver metabolic status have been shown to dynamically influence the composition of hepatic LD proteins (7, 8). Consequently, exploring how LD-associated proteins affect hepatic metabolism is important for understanding the molecular pathophysiology of NAFLD. In the search for novel targets that regulate ectopic lipid accumulation in the context of nutritional stress and obesity, we identified serine/threonine protein kinase (STK)25, a member of the Ste20 kinase superfamily (9), as a hepatic LD-associated protein, which critically controls the development and progression of NAFLD (10-15). We found that STK25 knockdown attenuates lipid deposition in human hepatocytes and mouse liver by repressing lipid synthesis and enhancing β-oxidation and very-low-density lipoprotein (VLDL)-TAG secretion, with the reciprocal phenotype seen when STK25 protein is overexpressed (10-15). Notably, administration of hepatocyte-targeting GalNAc-conjugated Stk25 antisense oligonucleotide (ASO) in obese mice effectively ameliorates diet-induced hepatic steatosis as well as NASH features (i.e., liver inflammation, hepatocellular ballooning, and fibrosis), providing in vivo nonclinical proof-of-principle for the metabolic benefit of pharmacological STK25 inhibitors (15). Furthermore, we observed that STK25 levels in human liver biopsies correlate with the severity of NASH, and several common non-linked single nucleotide polymorphisms (SNPs) in the human STK25 gene are associated with altered liver fat content (12-14). Although these studies suggest a key role for STK25 in the control of liver LD dynamics, the mechanism-of-action of STK25 in regulation of hepatic lipid partitioning has remained elusive. To provide novel insights into biological function of STK25 in the liver under steatotic conditions, we here characterized the hepatic LD-associated phosphoproteome in Stk25 knockout mice and their wild-type littermates following high-fat diet feeding using non-biased approach by isobaric tagging for relative quantification. Of the 4,515 proteins and 982 phosphoproteins identified with a 1% false discovery rate, we report a total of 131 proteins and 69 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, antioxidant defense, and ubiquitination-mediated proteolysis were coordinately regulated in the livers from high-fat-fed Stk25-/- mice compared with wild-type controls.

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

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