Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway

PeerJ. 2022 May 12:10:e13376. doi: 10.7717/peerj.13376. eCollection 2022.

Abstract

Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.

Keywords: Curcumol; ER stress; Liver fibrosis; NICD; Necroptosis; Sirt1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endoplasmic Reticulum Stress
  • Hepatic Stellate Cells*
  • Liver Cirrhosis / chemically induced
  • Mice
  • Mice, Inbred ICR
  • Necroptosis
  • Sirtuin 1* / genetics

Substances

  • curcumol
  • Sirtuin 1
  • Sirt1 protein, mouse

Grants and funding

The work was supported by the National Natural Science Foundation of China (82073914, 82000572, 81870423), the Natural Science Foundation of Jiangsu Province (BK20200840), the Major Project of the Natural Science Research of Jiangsu Higher Education Institutions (19KJA310005), the General Projects of the Natural Science Research of Jiangsu Higher Education Institutions (20KJB310003), the Joint Project of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and Yangtze River Pharmaceutical (JKLPSE202005), the Natural Science Foundation of Nanjing University of Chinese Medicine (NZY82000572), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_1732, KYCX21_1637 and SJCX20_0569), and the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine (2020YLXK022 and 2020YLXK023). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.