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

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.

Ac2-26 attenuates hepatic ischemia-reperfusion injury in mice via regulating IL-22/IL-22R1/STAT3 signaling

“…AML12 cells treated with or without Ac2-26 were stained in 0.4% trypan blue in phosphate buffered saline (PBS) for 3 min, washed two times with PBS, and then observed under a phase-contrast microscope (Leica Microsystems, Germany) ( Sun et al, 2022 ).…”

NcRNA Regulated Pyroptosis in Liver Diseases and Traditional Chinese Medicine Intervention: A Narrative Review

“… 118 Curcumol is an effective active ingredient extracted from the genuine medicinal herb Curcuma kwangsiensis S. G. Lee et C. F. Liang in Guangxi, China, which is known for its ability to invigorate blood circulation and remove blood stasis, protect the liver, and have anti-inflammatory, cholagogic and antioxidant effects. 119 , 120 Curcumol inhibits miR-125b/NLRP3 pathway to prevent liver fibrosis. Mechanistically, it can upregulate the expression of miR-125b, which decreases the downstream NLRP3 inflammasome and the expression of Caspase-1, GSDMD, IL-1β, and IL-18, reduces the onset of pyroptosis, and inhibits the activation of HSC to prevent liver fibrosis.…”

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

“…Fifth, it has been found that the effect of curcumin in the treatment of LF is to remove activated HSCs by inducing necrosis of HSCs. In terms of mechanism, curcumin induces endoplasmic reticulum stress-mediated necrotic prolapse of HSCs through the Sirt1/NICD pathway to attenuate LF [200] . Moreover, curcumin downregulates the Smad pathway and reduces HSC activation in experimental fibrosis [190] .…”