TKF, a mexicanolide-type limonoid derivative, suppressed hepatic stellate cells activation and liver fibrosis through inhibition of the YAP/Notch3 pathway

• Published in: Phytomedicine (Stuttgart) Vol. 107; p. 154466
• Main Authors: Yang, Ting, Wu, Enyi, Zhu, Xiaoyun, Leng, Yingrong, Ye, Shengtao, Dong, Ruirui, Liu, Jiaman, Zhong, Jiawen, Zheng, Ying, Xu, Wenjun, Luo, Jun, Kong, Lingyi, Zhang, Hao
• Format: Journal Article
• Language: English
• Published: Elsevier GmbH 01.12.2022
• Subjects: bile ducts; collagen; drugs; fibrosis; gene expression; Hepatic stellate cells; histopathology; humans; limonoids; liver cirrhosis; Liver fibrosis; liver neoplasms; mice; Notch3; therapeutics; TKF; Yap; AST; H&E; Yap; ALT; Liver fibrosis; BDL; TKF; COL1A1; Notch3; CCl4; αSMA; Hepatic stellate cells; TGF-β1; HSCs; NICD3
• ISSN: 0944-7113; 1618-095X; 1618-095X
• DOI: 10.1016/j.phymed.2022.154466

Liver fibrosis is a common scarring response and may ultimately lead to liver cancer, unfortunately, there is currently no effective antifibrotic drug approved for human use. Limonoids exhibit a broad spectrum of biological activities; however, the potential role of limonoids against fibrosis is largely unknown. This study investigates the antifibrotic activities and potential mechanisms of TKF (3-tigloyl-khasenegasin F), a natural mexicanolide-type limonoid derivative. Two well-established mouse models (CCl4 challenge and bile duct ligation) were used to assess anti-fibrotic effects of TKF in vivo. Human hepatic stellate cell (HSC) line LX-2 and mouse primary hepatic stellate cells (pHSCs) also served as in vitro liver fibrosis models. TKF administration significantly attenuated hepatic histopathological injury and collagen accumulation and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, and Timp1. In LX-2 cells and mouse pHSCs, TKF dose-dependently suppressed HSC activation and the expression levels of fibrogenic markers. Mechanistic studies showed that TKF inhibited Notch3-Hes1 and YAP signalings in vivo and in vitro. Furthermore, YAP inhibition or knockdown downregulated the Notch3 expression; however, Notch3 inhibition or knockdown did not affect the level of YAP in activated HSC. We revealed that TKF inhibited Notch3-Hes1 activation and downregulated hepatic fibrogenic gene expression via inhibiting YAP. The therapeutic benefit of TKF against liver fibrosis results from inhibition of YAP and Notch3-Hes1 pathways, indicating that TKF may be a novel therapeutic candidate for liver fibrosis. [Display omitted]