Lu, X.; Wang, S.; Du, Y.; Xie, B.; Chen, Q.; Lin, J.; Chen, B.; Cui, K.

Abstract: Metabolic dysfunction associated steatohepatitis (MASH) is a progressive liver disease associated with liver related complications and death. Kylo0603 is a novel agonist for the thyroid hormone receptor {beta} (THR-{beta}) that has been developed by merging the structures of three acetylgalactosamine (GalNAc)modified ASPGR ligands with a triiodothyronine (T3) analog. This unique design allows for both THR-{beta} activation and targeted delivery to hepato-cytes, significantly reducing the risk of adversed effects related to increased systemic thyroid hormone-like effects. Additionally, it effectively lowers serum cholesterol 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, Kylo0603 was shown to reduce 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) decreased by up to 3.7 points (P < 0.0001), and the fibrosis score dropped by 0.6 points (P < 0.05). These findings suggest that Kylo0603 is effective in enhancing liver tissue NASH status and inhibiting fibrosis progression. In summary, Kylo0603, as a highly both tissue and target selective and low toxicity THR-{beta} agonist, shows significant promise for treating MASH and is likely to emerge as a new ther-apeutic option for patients with this condition.