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 2025-03-20T15:00:25Z 2025-03-20T15:00:25Z 2025-03-19 2025-01 1420-682X https://pubs.kist.re.kr/handle/201004/151930 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. English Springer Nature Ebastine-mediated destabilization of E3 ligase MKRN1 protects against metabolic dysfunction-associated steatohepatitis Article 10.1007/s00018-024-05535-2 1 Cellular and Molecular Life Sciences, v.82, no.1 Cellular and Molecular Life Sciences 82 1 Y scie scopus 001415313000003 2-s2.0-85217357180 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article AMPK ACTIVATION LIVER ANTIHISTAMINES STEATOSIS PRESSURE AMP-activated protein kinase (AMPK) MKRN1 Ebastine Metabolic dysfunction-associated steatohepatitis (MASH)