Lin Zhuomiao, Yang Meiqing, Yu Xihui, Tan Guozhu, Zhong Jiahong
Department of Clinical Pharmacy, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China.
Joint Shantou International Eye Center, Shantou University and The Chinese University of Hong Kong, Shantou, China.
Front Pharmacol. 2025 Jan 7;15:1505768. doi: 10.3389/fphar.2024.1505768. eCollection 2024.
Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with lipid accumulation, inflammation, and liver fibrosis. Ponatinib, a third-generation tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia, was found to improve metabolic disorders in mice. However, the role of ponatinib in liver inflammation and fibrosis remains to be elucidated. Here we aimed to determine the effect of ponatinib in non-alcoholic steatohepatitis.
We explored the function and mechanism of ponatinib using a mouse model of NASH induced by a methionine and choline deficient (MCD) diet and LO2 cells cultured in MCD mimic medium.
Here, we found that ponatinib reduced liver lipid deposition, fibrosis, and inflammation induced by MCD diet without affecting body weight and blood glucose. Meanwhile, we found that ponatinib attenuated steatohepatitis and inflammation in LO2 cells induced by MCD mimic medium. We further discovered that the expression levels of LC3II and lysosomal associated membrane protein 1 (LAMP1) were reduced and the expression level of p62 was upregulated in both mouse and cell models, suggesting that autophagy was inhibited, which was restored by ponatinib treatment. In addition, transcription factor EB (TFEB) is a major regulator of autophagy and lysosome biogenesis and the transcription and protein expression levels of TFEB were decreased in steatosis hepatocytes, which could be ameliorated by ponatinib treatment.
These results revealed that the beneficial effects of ponatinib on NASH via TFEB-mediated autophagy.
非酒精性脂肪性肝炎（NASH）是一种伴有脂质蓄积、炎症和肝纤维化的进行性肝病。普纳替尼是一种用于治疗慢性髓性白血病的第三代酪氨酸激酶抑制剂，已发现其可改善小鼠的代谢紊乱。然而，普纳替尼在肝脏炎症和纤维化中的作用仍有待阐明。在此，我们旨在确定普纳替尼在非酒精性脂肪性肝炎中的作用。
我们使用蛋氨酸和胆碱缺乏（MCD）饮食诱导的NASH小鼠模型以及在MCD模拟培养基中培养的LO2细胞，探究了普纳替尼的功能和机制。
在此，我们发现普纳替尼可减少MCD饮食诱导的肝脏脂质沉积、纤维化和炎症，且不影响体重和血糖。同时，我们发现普纳替尼可减轻MCD模拟培养基诱导的LO2细胞中的脂肪性肝炎和炎症。我们进一步发现，在小鼠和细胞模型中，微管相关蛋白1轻链3II（LC3II）和溶酶体相关膜蛋白1（LAMP1）的表达水平降低，而p62的表达水平上调，这表明自噬受到抑制，而普纳替尼治疗可恢复自噬。此外，转录因子EB（TFEB）是自噬和溶酶体生物发生的主要调节因子，在脂肪变性的肝细胞中，TFEB的转录和蛋白表达水平降低，而普纳替尼治疗可改善这种情况。
这些结果表明，普纳替尼通过TFEB介导的自噬对NASH具有有益作用。
