Ghrelin reduced the profibrotic effect of IHC-Exo in liver fibrosis by regulating lncMALAT1/GPX4 pathway mediated HSCs ferroptosis. Triggering HSCs ferroptosis via GHR-IHC-Exo may become a novel strategy to alleviate the progression of liver fibrosis. Liver fibrosis is the end stage of the continuous progression of a variety of chronic liver diseases. With the continuous action of various pathogenic factors, hepatic stellate cells in the liver are activated and produce a large amount of collagen fibers that are deposited in the liver, resulting in obvious damage to liver tissue and leading to cirrhosis and even liver cancer, which seriously affects human health. However, there are still clear and effective drugs approved for the treatment of liver fibrosis, so it is important to explore the possible mechanisms of liver fibrosis treatment. In previous studies, researchers found that exosomes secreted by injured hepatocytes promote the progression of liver fibrosis. In our study, we found that the role of exosomes in promoting liver fibrosis progression was attenuated after pretreatment with Ghrelin. This provides an important theoretical basis for the use of Ghrelin in the treatment of liver fibrosis.
Ghrelin is a gastric peptide that modulates various biological functions, including potential anti‐inflammatory and antifibrotic properties. Increasingly evidence have demonstrated that exosomes derived from injured hepatocytes (IHC‐Exo) can accelerate the activation of hepatic stellate cells (HSCs) and liver fibrosis. Ferroptosis, a type of novel programmed cell death, regulates diverse pathological processes, including liver fibrosis. However, it remains unclear whether ghrelin exerts its antifibrotic effect through mechanisms involving exosomes and ferroptosis. To explore the mechanism, IHC‐Exo were isolated from supernatant of injured mouse primary hepatocytes (HCs) treated with palmitic acid (PA). Mouse primary HSCs and a bile duct ligation (BDL)‐induced liver fibrosis murine model were then treated with IHC‐Exo or exosomes derived from ghrelin‐pretreated injured hepatocytes (GHR‐IHC‐Exo). The expression of α‐SMA, Collagen I and long noncoding (lnc) RNA MALAT1 in HSCs were then detected. The ferroptosis of HSCs was evaluated by assessing the level of CCK8, MDA, GSH, and GPX4 expression. Mouse serum and liver biopsy samples were used to determine whether ferroptosis is involved in the progression of liver fibrosis. Nanoparticle tracking analysis and electron microscopy characterized the features of IHC‐Exo. As the results suggested, compared with IHC‐Exo, GHR‐IHC‐Exo treatment significantly promoted ferroptosis of HSCs, inhibited their activation, and consequently alleviated liver fibrosis progression in BDL mice. The inhibitory effect of GHR‐IHC‐Exo on activation of HSCs was partially reversed by treatment with the ferroptosis inhibitor Ferrostatin‐1. The expression of lncMALAT1 was significantly down‐regulated in GHR‐IHC‐Exo as compared to IHC‐Exo. Serum exosome levels of MALAT1 were significantly higher in patients with severe liver fibrosis compared to those with mild liver fibrosis. Additionally, the expression of ferroptosis suppressor protein GPX4 was elevated as liver fibrosis progression, indicating decreased ferroptosis of HSCs in patients with severe liver fibrosis. In conclusion, Ghrelin reduced the pro‐fibrotic effect of IHC‐Exo in liver fibrosis by regulating lncMALAT1/GPX4 pathway mediated HSCs ferroptosis. Triggering HSCs ferroptosis via GHR‐IHC‐Exo may become a novel strategy to alleviate the progression of liver fibrosis.
Keywords: exosomes; ferroptosis; ghrelin; liver fibrosis; lncMALAT1.
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