Celastrol ameliorates fibrosis in Western diet/tetrachloromethane-induced nonalcoholic steatohepatitis by suppressing Notch/osteopontin signaling

Dingwu Li; Jianing Chen; Chenhui Ye; Bingru Lin; Tiantian Zhang; Qingxia Chen; Chaohui Yu; Xingyong Wan

doi:10.1016/j.phymed.2025.156369

Celastrol ameliorates fibrosis in Western diet/tetrachloromethane-induced nonalcoholic steatohepatitis by suppressing Notch/osteopontin signaling

Phytomedicine. 2025 Jan 6:137:156369. doi: 10.1016/j.phymed.2025.156369. Online ahead of print.

Authors

Dingwu Li¹, Jianing Chen², Chenhui Ye¹, Bingru Lin¹, Tiantian Zhang¹, Qingxia Chen¹, Chaohui Yu³, Xingyong Wan⁴

Affiliations

¹ Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
² State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
³ Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China. Electronic address: zyyyych@zju.edu.cn.
⁴ Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China. Electronic address: w-xy1207@zju.edu.cn.

PMID: 39798343
DOI: 10.1016/j.phymed.2025.156369

Abstract

Background: Celastrol was recently identified as a potential treatment for obesity and hepatic steatosis. However, whether Celastrol effectively suppresses the nonalcoholic fatty liver disease (NAFLD) stage remains unknown. This study aimed to evaluate the role of Celastrol in the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis.

Methods: C57BL/6 mice were fed a Western diet combined with a weekly low-dose injection of CCl₄ (WD/CCl₄) for 16 weeks to establish NASH models. The effects of Celastrol on NASH were further explored through histopathological assessments, immunoblotting, and in vitro analyses.

Results: Celastrol treatment effectively attenuated hepatic steatosis and fibrosis in WD/CCl₄-induced NASH models, in which Notch2 was downregulated by Celastrol in a posttranscriptional manner. In vitro experiments revealed that Notch2 suppression in Celastrol-treated hepatocytes further decreased osteopontin (OPN) levels, inhibiting hepatic stellate cells (HSCs) activation. Moreover, the protective effects of Celastrol on NASH progression were abolished in Notch2-overexpressing mice.

Conclusion: This study demonstrated the protective effects of Celastrol on NASH-related liver fibrosis by modulating Notch/OPN signaling, providing fresh insights into the potential application of Celastrol in NASH treatment.

Keywords: Celastrol; HSCs; Liver fibrosis; NASH; Notch.