Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway

Background and Aims:Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease.The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.Methods:The relationship between the cGAS-stimulator of interferon genes(STING)pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database.Histopathology,immunohistochemistry,fluorescence staining,Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers.Molecular docking was performed to evaluate the relationship between naringenin and cGAS,and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.Results:Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease.Naringenin ameliorated liver injury and liver fibrosis,decreased collagen deposition and cGAS expression,and inhibited inflammation in carbon tetrachloride(CCl4)-treated mice.Molecular docking found that cGAS may be a direct target of naringenin.Consistent with the in vivo results,we verified the inhibitory effect of naringenin on activated hepatic stellate cells(HSCs).By using the cGAS-specific agonist double-stranded(ds)DNA,we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA.We verified that naringenin inhibited the cGAS-STING pathway,thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.Conclusions:Interrupting the cGAS-STING pathway helped reverse the fibrosis process.Naringenin has potential as an antihepatic fibrosis drug.

Methionine metabolism in chronic liver diseases:an update on molecular mechanism and therapeutic implication

As one of the bicyclic metabolic pathways of one-carbon metabolism,methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway.In addition to being a precursor for glutathione synthesis,and the principal methyl donor for nucleic acid,phospholipid,histone,biogenic amine,and protein methylation,methionine metabolites can participate in polyamine synthesis.Methionine metabolism disorder can aggravate the damage in the pathological state of a disease.In the occurrence and development of chronic liver diseases(CLDs),changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms.A methionine-deficient diet is commonly used for building CLD models.The conversion of key enzymes of methionine metabolism methionine adenosyltransferase(MAT)1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma.In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism,the liver injuries could be reduced.Recently,methionine supplementation has gradually attracted the attention of many clinical researchers.Most researchers agree that adequate methionine supplementation can help reduce liver damage.Retrospective analysis of recently conducted relevant studies is of profound significance.This paper reviews the latest achievements related to methionine metabolism and CLD,from molecular mechanisms to clinical research,and provides some insights into the future direction of basic and clinical research.

Methionine metabolism in chronic liver diseases:an update on molecular mechanism and therapeutic implication

As one of the bicyclic metabolic pathways of one-carbon metabolism,methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway.In addition to being a precursor for glutathione synthesis,and the principal methyl donor for nucleic acid,phospholipid,histone,biogenic amine,and protein methylation,methionine metabolites can participate in polyamine synthesis.Methionine metabolism disorder can aggravate the damage in the pathological state of a disease.In the occurrence and development of chronic liver diseases(CLDs),changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms.A methionine-deficient diet is commonly used for building CLD models.The conversion of key enzymes of methionine metabolism methionine adenosyltransferase(MAT)1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma.In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism,the liver injuries could be reduced.Recently,methionine supplementation has gradually attracted the attention of many clinical researchers.Most researchers agree that adequate methionine supplementation can help reduce liver damage.Retrospective analysis of recently conducted relevant studies is of profound significance.This paper reviews the latest achievements related to methionine metabolism and CLD,from molecular mechanisms to clinical research,and provides some insights into the future direction of basic and clinical research.