The Effect of Methyl Donors in a Murine Model of MASLD in a Multidisciplinary Study.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277537 | GEO | 2025/09/23
REPOSITORIES: GEO
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Project description: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.
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Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 30% of the world population. Its prevalence in the pediatric population is increasing, suggesting that the early life environment plays a role in the programming of MASLD. We previously proposed that imprinted genes, defined by their expression from a single parental allele, are strong candidates for driving MASLD in response to early life environmental exposures because of their susceptibility to environmental stress and their roles in liver metabolism. In support of this hypothesis, we previously showed that early life exposure to the toxic metal cadmium (Cd) or maternal metabolic syndrome (MetS) induce MASLD in juvenile mice and activate a transcriptional network in the liver enriched for imprinted genes termed the Imprinted Gene Network (IGN). Furthermore, artificial activation of the IGN in cultured hepatocytes or in vivo leads to MASLD-related phenotypes. Here, using publicly available bulk liver RNA-seq datasets, we tested whether early life exposure to other types of environmental stress that program juvenile MASLD also activate the IGN. We demonstrate that diverse types of stressors, including toxic metals, diet, and endocrine disruptors, activate the IGN in the liver. We also developed an in vitro model of toxicant exposure and show that the IGN is activated upon exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a cell autonomous manner. Overall, our findings confirm the IGN as a conserved mechanism that could be targeted to mitigate the effects of multiple developmental stressors on liver disease.
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