Kim Seungyeon, Han Hyun-Ji, Rho Hyunjin, Kang Subin, Mukherjee Sulagna, Kim Jiwoo, Kim Doyoun, Ko Hyuk Wan, Lim Sang Min, Im Seung-Soon, Chung Joon-Yong, Song Jaewhan
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
Department of Physiology, Keimyung University School of Medicine, Daegu, 42601, Republic of Korea.
Cell Mol Life Sci. 2025 Jan 31;82(1):66. doi: 10.1007/s00018-024-05535-2.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition encompassing metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), which can progress to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). The heterogeneous and complex nature of MASLD complicates optimal drug development. Ebastine, an antihistamine, exhibits antitumor activity in various types of cancer. However, its effects on MASH remain unexplored. In the present study, we identified ebastine as a potential treatment for MASH. Our results indicated that ebastine acts as a novel MKRN1 inhibitor by promoting MKRN1 destabilization through self-ubiquitination, leading to AMP-activated protein kinase (AMPK) activation. Ebastine appeared to bind to the C-terminal domain of MKRN1, particularly at residues R298 and K360. Notably, Mkrn1 knockout (KO) mice demonstrated resistance to MASH, including obesity, steatosis, inflammation, and fibrosis under high-fat-high-fructose diet (HFHFD) conditions. Additionally, liver-specific Mkrn1 knockdown using AAV8 alleviated MASH symptoms in HFHFD-fed mice, implicating MKRN1 as a potential therapeutic target. Consistent with these findings, treatment with ebastine significantly reduced the risk of MASH in HFHFD-fed mice, with a decrease in MKRN1 expression and an increase in AMPK activity. Our study suggests that ebastine binds to MKRN1, promoting its destabilization and subsequent degradation by stimulating its ubiquitination. This enhances AMPK stability and activity, suppressing lipid accumulation, inflammation, and fibrosis. Moreover, the knockout of Mkrn1 mice decreased the risk of MASH, suggesting that ebastine could be a promising therapeutic agent for the treatment of MASH.
代谢功能障碍相关脂肪性肝病（MASLD）是一种慢性疾病，包括代谢功能障碍相关脂肪性肝病（MASL）和代谢功能障碍相关脂肪性肝炎（MASH），可进展为纤维化、肝硬化或肝细胞癌（HCC）。MASLD的异质性和复杂性使最佳药物开发变得复杂。依巴斯汀是一种抗组胺药，在各种类型的癌症中表现出抗肿瘤活性。然而，其对MASH的影响尚未得到探索。在本研究中，我们确定依巴斯汀是MASH的一种潜在治疗方法。我们的结果表明，依巴斯汀通过自泛素化促进MKRN1不稳定，从而作为一种新型MKRN1抑制剂，导致AMP激活的蛋白激酶（AMPK）激活。依巴斯汀似乎与MKRN1的C末端结构域结合，特别是在R298和K360残基处。值得注意的是，Mkrn1基因敲除（KO）小鼠在高脂高果糖饮食（HFHFD）条件下对MASH具有抗性，包括肥胖、脂肪变性、炎症和纤维化。此外，使用AAV8进行肝脏特异性Mkrn1基因敲低可减轻HFHFD喂养小鼠的MASH症状，这表明MKRN1是一个潜在的治疗靶点。与这些发现一致，依巴斯汀治疗显著降低了HFHFD喂养小鼠患MASH的风险，MKRN1表达降低，AMPK活性增加。我们的研究表明，依巴斯汀与MKRN1结合，通过刺激其泛素化促进其不稳定并随后降解。这增强了AMPK的稳定性和活性，抑制脂质积累、炎症和纤维化。此外，Mkrn1基因敲除小鼠患MASH的风险降低，这表明依巴斯汀可能是治疗MASH的一种有前景的治疗药物。
