Yang Lanzexin, Zhuo Shixuan, Zhu Xinyu, Zhang Xinhui, Wang Zinan, Chen Yan
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
School of Clinical Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
Front Endocrinol (Lausanne). 2025 Jun 5;16:1480453. doi: 10.3389/fendo.2025.1480453. eCollection 2025.
Nonalcoholic steatohepatitis (NASH), characterized by progressive liver injury, inflammation, and fibrosis, is a leading chronic liver disease worldwide. Pharmacotherapy for NASH is thus urgently needed. Through a strategy of lineage tracing, it was recently discovered that deletion of a protein methyltransferase SMYD2 has a protective role in hepatic steatosis. In this study, we evaluated the potential therapeutic effect of two SMYD2 inhibitors AZ505 and LLY-507 in a mouse NASH model.
The mouse NASH model was induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks. SMYD2 inhibitors AZ505 and LLY-507 were administered in the last 4 weeks at a dose of 10 mg/kg by intraperitoneal injection three times per week. A series of biochemical and histological analyses were conducted to determine the therapeutic potential of SMYD2 inhibitors.
The inhibitory effect of AZ505 and LLY-507 on histone methylation was confirmed with liver samples. CDAHFD was able to induce marked liver fibrosis and inflammation in the mice. However, treatment of the mice with AZ505 and LLY-507 failed to show any improvement in NASH scores, liver damage, liver fibrosis, macrophage infiltration, or hepatic inflammation in mice.
In conclusion, our findings suggest that SMYD2 inhibition is not an effective strategy to alleviate NASH at least in mice.
非酒精性脂肪性肝炎（NASH）以进行性肝损伤、炎症和纤维化为特征，是全球主要的慢性肝病。因此，迫切需要针对NASH的药物治疗。最近通过谱系追踪策略发现，蛋白质甲基转移酶SMYD2的缺失在肝脂肪变性中具有保护作用。在本研究中，我们评估了两种SMYD2抑制剂AZ505和LLY-507在小鼠NASH模型中的潜在治疗效果。
通过胆碱缺乏、L-氨基酸限定的高脂饮食（CDAHFD）诱导小鼠NASH模型12周。在最后4周，以10mg/kg的剂量每周腹腔注射3次给予SMYD2抑制剂AZ505和LLY-507。进行了一系列生化和组织学分析以确定SMYD2抑制剂的治疗潜力。
用肝脏样本证实了AZ505和LLY-507对组蛋白甲基化的抑制作用。CDAHFD能够在小鼠中诱导明显的肝纤维化和炎症。然而，用AZ505和LLY-507治疗小鼠未能显示出NASH评分、肝损伤、肝纤维化、巨噬细胞浸润或肝脏炎症有任何改善。
总之，我们的研究结果表明，至少在小鼠中，抑制SMYD2不是缓解NASH的有效策略。
