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  • In this study we intended


    In this study, we intended to explore the efficacy of artesunate on liver fibrosis and further clarify its potential molecular mechanism. Artemisinin, a sesquiterpene lactone obtained from a Chinese plant Artemisia annua [27]. Artesunate, as a stable derivative of artemisinin, is an effective drug for curing malaria, improving inflammation, protecting nerves, and treating tumor [[28], [29], [30], [31]]. Noubiap JJ et al. showed that artesunate was the first-line treatment of severe malaria in children and adults [28]. Furthermore, Zhao D et al. demonstrated that artesunate protected LPS (lipopolysaccharides)-induced acute lung injury by suppressing TLR4 (toll like receptor 4) activity and inducing Nrf2 (nuclear factor erythroid 2-related factor 2) activation [29]. In addition, Gugliandolo E et al. reported that artesunate protected neuronal survival through the modulation of neurotrophic factors including BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), NT-3 (neurotrophin 3) [30]. Besides, Wen L et al. found that artesunate inhibited cell proliferation and promoted G2/M arrest in MCF7 CEP 1347 sale through activating ATM (telangiectasia ataxia mutant protein) [31]. However, the research of artesunate on liver fibrosis treatment is lacking. Ferroptosis, as a form of regulated cell death, is characterized by accumulation of iron-based lipid reactive oxygen species (ROS) [32]. Ferroptosis plays a significant role in multiple kinds of organic diseases, such as brain, heart, kidney, and liver diseases [[33], [34], [35], [36]]. Thus, triggering or inhibiting ferroptosis might provide novel therapeutic strategy for treating these diseases. At present, some mechanisms are involving in regulating ferroptosis containing blockade of cystine/glutamate system Xc−-mediated cystine import, depletion of glutathione (GSH) and inhibition of glutathione peroxidase 4 (GPX4) [32,[34], [35], [36]]. Interestingly, numerous literature have identified that autophagy activation is associated with ferroptosis induction [37,38]. Autophagy is physiological process that maintaining cellular homeostasis during the periods of stress, starvation or hypoxia [[37], [38], [39]]. Divertingly, recent studies suggest that an autophagic cargo receptor nuclear receptor co-activator 4 (NCOA4) specifically targets ferritin to autophagosome, then formed mature autophagosome merges with the lysosome for ferritin degradation [40]. The latter process is termed ferritinophagy and mainly responsible for iron releasing and recycling [[40], [41], [42], [43], [44]]. More delightedly, occurrence of ferroptosis has been shown to activate ferritinophagy in a process whereby ferritin catabolism increases the labile iron pool (LIP) which promotes ROS accumulation that triggers ferroptosis [41,41,42,43,44]. Masaldan S et al. found that iron accumulation in senescent cells was coupled with impaired ferritinophagy and blackage of ferroptosis [41]. Moreover, Latunde-Dada GO et al. showed that induction of ferroptosis due to cysteine depletion lead to ferritin degradation (i.e. ferritinophagy), which released iron via the NCOA4-mediated autophagy pathway [42]. Furthermore, Gao M et al. reported that blockage of ferritinophagy by inhibition of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and lipid ROS [43]. In addition, Zhang Z et al. suggested that activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis [44]. Despite these compelling findings in vitro, however, whether ferritinophagy activation contributes to HSC ferroptosis and then attenuates liver fibrosis have not been studied.
    Materials and methods
    Discussion Currently, 45% of disease deaths in the developed world are closely related to chronic fibroproliferative diseases [[5], [6], [7]]. Among these, fibrotic liver diseases are more susceptible and usually silent without visible clinical symptoms until development of cirrhosis with portal hypertension and complications like ascites, bleeding varices, or even hepatocellular carcinoma [8,[11], [12], [13]]. Liver, as a main metabolic organ of the body, has multiple functions such as glycogen storage, red blood cells decomposition, plasma protein synthesis, urea production, and detoxification [1,2,8]. Although the liver has a powerful regenerative capacity regenerative capacity, continued and chronic pathological stimulation leads to the onset of liver fibrosis [[11], [12], [13]]. During the process of hepatic fibrosis, different types of CEP 1347 sale cells in the liver undergo impaired changes, including hepatocyte apoptosis and necrosis, liver sinusoids endothelial cell (LSECs) remodeling, inflammatory cells recruitment and HSC activation [[1], [2], [3]]. Therefore, depressing or retarding these pathological phenomena is an effective therapeutic strategy for anti-fibrotic therapy. Noteworthily, inhibition of hepatic stellate cell activation has been recognized as a kernel method for the prevention and treatment of liver fibrosis [[1], [2], [3]]. Previous studies have showed that retricting HSC contraction [57], inhibiting HSC glycolysis [58], inducing HSC appotosis [59], senescence [60], and autophagy [61] are effectual on inhibiting HSC activation. Xu W et al. revealed that dihydroartemisinin attenuated hepatic fibrosis by limiting HSC contaction via a FXR activation-dependent mechanism [57]. Du K et al. clarified that Hedgehog and YAP inhibitors reduced aerobic glycolysis and suppressed myofibroblastic activities in HSCs [58]. Yang H et al. confirmed that HO-1 (heme oxygenase 1) protected liver from fibrosis by enhancing HSC apoptosis, which was associated with the regulation of NF-κB (nuclear transcription factor kappa B) pathway [59]. Huang YH et al. reported that IL10 (interleukin 10) promoted the senescence of activated primary HSCs by up-regulating p53 and p21 expression [60]. Zhang Z et al. demonstrated that the molecular mechanism of DHA-induced anti-inflammatory effects was linked to ROS-JNK1/2-dependent activation of autophagy [61].