Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. Kylo-0603 is a novel agonist for the thyroid hormone receptor β (THR-β) that has been developed by merging the structures of three acetylgalactosamine (GalNAc)-modified ASPGR ligands with a triiodothyronine (T3) analog. This unique design enables both THR-β activation and targeted delivery to hepatocytes, which significantly reduces the risk of adverse effects related to increased systemic thyroid hormone activity. Additionally, it effectively lowers serum cholesterol levels by as much as 69.2% and low-density lipoprotein cholesterol (LDL-C) levels by up to 88.2% in the MASH mouse model. Meanwhile, Kylo-0603 demonstrated a marked improvement in histological parameters, decreasing steatosis by up to 1.3 points (P < 0.001), inflammation by 1.8 points (P < 0.0001), and ballooning by 0.8 points (P < 0.01). The non-alcoholic steatohepatitis (NASH) activity score (NAS) demonstrated a significant reduction of up to 3.7 points (P < 0.0001), while the fibrosis score decreased by 0.6 points (P < 0.05). These findings indicate that Kylo-0603 effectively ameliorates hepatic MASH pathology and attenuates fibrosis progression. In summary, Kylo-0603-a highly tissue- and target-selective, low-toxicity THR-β agonist-exhibits substantial therapeutic potential for managing MASH and represents a promising novel treatment option for affected patients.