Ji Eun Kim, Yun Kim, Jiwon Bae, Eileen Laurel Yoon, Hyun Sung Kim, Sung Ryol Lee, Tae Hyun Yoon, Dae Won Jun
{"title":"A novel 11β-HSD1 inhibitor ameliorates liver fibrosis by inhibiting the notch signaling pathway and increasing NK cell population.","authors":"Ji Eun Kim, Yun Kim, Jiwon Bae, Eileen Laurel Yoon, Hyun Sung Kim, Sung Ryol Lee, Tae Hyun Yoon, Dae Won Jun","doi":"10.1007/s12272-025-01534-4","DOIUrl":null,"url":null,"abstract":"<p><p>11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates hepatic glucose output and is implicated in liver fibrosis. We aimed to investigate the anti-fibrotic effect of a novel 11β-HSD1 inhibitor in a thioacetamide (TAA)-induced liver fibrosis mouse model. Mice were administered TAA for 19 weeks and treated with 11β-HSD1 inhibitor for the last 9 weeks. Treatment with 11β-HSD1 inhibitor significantly reduced fibrosis area, alanine aminotransferase, and aspartate aminotransferase levels compared to the TAA-only group. Inhibition of 11β-HSD1 led to a decrease in intracellular cortisol levels, which suppressed the activation of hepatic stellate cells. RNA sequencing revealed significant downregulation of the Notch signaling pathway, including reduced expression of Notch ligands and receptors, as well as downstream genes. Furthermore, 11β-HSD1 inhibition enhanced NK cell-mediated immune responses, as indicated by the upregulation of NK cell-related genes and increased NK cell populations confirmed by mass cytometry. This increase in NK cell activity contributed to the clearance of activated HSCs and the attenuation of fibrosis. These findings suggest that 11β-HSD1 inhibition alleviates liver fibrosis through Notch pathway suppression and enhancement of NK cell-mediated immune responses. Our results support the therapeutic potential of a novel 11β-HSD1 inhibitor for treating liver fibrosis.</p>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":" ","pages":""},"PeriodicalIF":6.9000,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Pharmacal Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12272-025-01534-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates hepatic glucose output and is implicated in liver fibrosis. We aimed to investigate the anti-fibrotic effect of a novel 11β-HSD1 inhibitor in a thioacetamide (TAA)-induced liver fibrosis mouse model. Mice were administered TAA for 19 weeks and treated with 11β-HSD1 inhibitor for the last 9 weeks. Treatment with 11β-HSD1 inhibitor significantly reduced fibrosis area, alanine aminotransferase, and aspartate aminotransferase levels compared to the TAA-only group. Inhibition of 11β-HSD1 led to a decrease in intracellular cortisol levels, which suppressed the activation of hepatic stellate cells. RNA sequencing revealed significant downregulation of the Notch signaling pathway, including reduced expression of Notch ligands and receptors, as well as downstream genes. Furthermore, 11β-HSD1 inhibition enhanced NK cell-mediated immune responses, as indicated by the upregulation of NK cell-related genes and increased NK cell populations confirmed by mass cytometry. This increase in NK cell activity contributed to the clearance of activated HSCs and the attenuation of fibrosis. These findings suggest that 11β-HSD1 inhibition alleviates liver fibrosis through Notch pathway suppression and enhancement of NK cell-mediated immune responses. Our results support the therapeutic potential of a novel 11β-HSD1 inhibitor for treating liver fibrosis.
期刊介绍:
Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.