Curcumol induces RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling in hepatic stellate cells

Abstract

It is generally recognized that hepatic fibrogenesis is an end result of increased extracellular matrix (ECM) production from the activation and proliferation of hepatic stellate cells (HSCs). An in-depth understanding of the mechanisms of HSC necroptosis might provide a new therapeutic strategy for prevention and treatment of hepatic fibrosis. In this study, we attempted to investigate the effect of curcumol on necroptosis in HSCs, and further to explore the molecular mechanisms. We found that curcumol ameliorated the carbon tetrachloride (CCl4)-induced mice liver fibrosis and suppressed HSC proliferation and activation, which was associated with regulating HSC necroptosis through increasing the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3). Moreover, curcumol promoted the migration of RIPK1 and RIPK3 into necrosome in HSCs. RIPK3 depletion impaired the anti-fibrotic effect of curcumol. Importantly, we showed that curcumol-induced RIPK3 up-regulation significantly increased mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization. ROS scavenger, N-acetyl-L-cysteine (NAC) impaired RIPK3-mediated necroptosis. In addition, our study also identified that the activation of c-Jun N-terminal kinase1/2 (JNK1/2) was regulated by RIPK3, which mediated curcumol-induced ROS production. Down-regulation of RIPK3 expression, using siRIPK3, markedly abrogated JNK1/2 expression. The use of specific JNK1/2 inhibitor (SP600125) resulted in the suppression of curcumol-induced ROS production and mitochondrial depolarization, which in turn, contributed to the inhibition of curcumol-triggered necroptosis. In summary, our study results reveal the molecular mechanism of curcumol-induced HSC necroptosis, and suggest a potential clinical use of curcumol-targeted RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling for the treatment of hepatic fibrosis.

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

“…Therefore, effective suppression of inflammation and improvement of inflammatory microenvironment are critical to control the progression of liver fibrosis. Currently, anti‐inflammatory drugs have been widely used to control liver inflammation in clinical, of which, remarkable achievements has been made using natural products to prevention and treatment of liver fibrosis in experimental and clinical research . Tripterygium wilfordii Hook F (TwHF), a Chinese medicinal plant, shows potent anti‐inflammatory effect, especially in rheumatoid arthritis (RA).…”

“…The active ingredients extracted from Traditional Chinese Medicine have become important choices for the treatment of several chronic diseases, including liver fibrosis . Celastrol is a pentacyclic triterpenoid compound (the chemical structure of celastrol is shown in Figure ), which is isolated from a common clinical used Traditional Chinese Medicine named Tripterygium wilfordii Hook F. Celastrol possesses multiple pharmacological effects and showed potent anti‐inflammatory effect against many disease models, and however, few reports can be seen regarding the anti‐inflammatory potential of celastrol in liver fibrosis.…”

Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis‐PROX1‐HIF‐1α in liver fibrosis

“…Recent studies also explained that different active components in natural medicinal plants could alleviate liver fibrosis by inhibiting pathological angiogenesis . We previously reported that curcumol mitigated liver pathological changes via promoting activated HSC necroptosis . However, the effects of curcumol on LSEC angiogenesis in liver fibrosis had not been investigated, and the underlying mechanism remained to be uncovered.…”

“…Sixty mice were randomly divided into six groups (n = 10), named separately control, CCl 4 , CCl 4 + vector, CCl 4 + Smo, CCl 4 + curcumol and CCl 4 + Smo+curcumol. The mice in the drug intervention groups were intraperitoneal injected with curcumol (Shanghai Institute of Material Medical) suspension (dissolved in oil at 5 mg/mL) at 30 mg/kg . All animals got 24 hours fasting at the end of the experiment and then executed to take blood and liver.…”

“…These studies suggested that curcumol is possible to participate in cell proliferation and migration correlated with angiogenesis closely. Moreover, a recent study demonstrated that curcumol is capable of alleviating liver fibrosis via triggering HSC necroptosis . Given the anti‐fibrotic effect of curcumol, we have investigated whether curcumol can inhibit hepatic fibrosis via regulating LSEC angiogenesis and elucidated the underlying mechanisms.…”