Lu Xueqin, Wang Shengjun, Du Yanchun, Xie Bixian, Chen Qingyan, Lin Jinzhen, Chen Bailing, Cui Kunyuan
Kylonova (Xiamen) biopharma Co., Ltd, Xiamen, China.
Hygieia pharmaceuticals Co., Ltd, Hangzhou, China.
PLoS One. 2025 Sep 15;20(9):e0331768. doi: 10.1371/journal.pone.0331768. eCollection 2025.
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.
代谢功能障碍相关脂肪性肝炎（MASH）是一种与肝脏相关并发症和死亡相关的进行性肝病。Kylo-0603是一种新型甲状腺激素受体β（THR-β）激动剂，它是通过将三种N-乙酰半乳糖胺（GalNAc）修饰的去唾液酸糖蛋白受体（ASPGR）配体的结构与三碘甲状腺原氨酸（T3）类似物融合而开发的。这种独特的设计既能激活THR-β，又能将其靶向递送至肝细胞，从而显著降低与全身甲状腺激素活性增加相关的不良反应风险。此外，在MASH小鼠模型中，它能有效降低血清胆固醇水平多达69.2%，降低低密度脂蛋白胆固醇（LDL-C）水平多达88.2%。同时，Kylo-0603在组织学参数方面有显著改善，脂肪变性降低多达1.3分（P<0.001），炎症降低1.8分（P<0.0001），气球样变降低0.8分（P<0.01）。非酒精性脂肪性肝炎（NASH）活动评分（NAS）显著降低多达3.7分（P<0.0001），而纤维化评分降低0.6分（P<0.05）。这些发现表明，Kylo-0603能有效改善肝脏MASH病理并减轻纤维化进展。总之，Kylo-0603是一种高度组织和靶点选择性、低毒性的THR-β激动剂，在治疗MASH方面具有巨大的治疗潜力，是受影响患者一种有前景的新型治疗选择。
