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

Abstract

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 (CCl 4 )-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 fibro-sis. Conclusions: Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.

The cytosolic DNA‐sensing cGAS–STING pathway in neurodegenerative diseases

“…Methylpyrazole (G140) or 2‐aminopyridine (G150), reported by Lama, have the exact mechanism as described above and were able to show inhibition of cGAS in THP1 cells and human macrophages 108 . At the same time, Naringenin, which is often used as an antioxidant and free radical scavenger, was also able to bind to the active site of cGAS, reducing the mRNA levels of IL‐1β, IL‐6, NF‐κB, and IL‐8 in LX2 cells, and also dose‐dependently reducing the expression of IRF3 protein 109 …”

“…108 At the same time, Naringenin, which is often used as an antioxidant and free radical scavenger, was also able to bind to the active site of cGAS, reducing the mRNA levels of IL-1β, IL-6, NF-κB, and IL-8 in LX2 cells, and also dose-dependently reducing the expression of IRF3 protein. 109 Steinhagen first proposed the cGAS inhibitor A151, which is capable of blocking self-DNA and suppressive oligodeoxynucleotides containing repetitive TTAGGG motifs in mammalian telomeres, 110 is dependent on telomeric sequences and phosphorothioates and inhibits the production of type I IFN by human monocytes through competing with DNA to prevent cGAS activation. 111 Suramin was also able to replace DNA bound to cGAS and inhibit the activity of the cGAS enzyme, while the addition of suramin to THP1 cells was shown to reduce the levels of IFNβ mRNA and protein.…”

Naringenin alleviates liver fibrosis by triggering autophagy-dependent ferroptosis in hepatic stellate cells

“…Naringenin, with significant anti-inflammatory and antitumor properties [ [42] , [43] , [44] ], has been shown to reduce liver injury and ECM deposition in animal models of hepatotoxicity and CCl 4 -induced liver fibrosis [ 28 ]. Our findings revealed that naringenin reduced HSC viability in a concentration- and time-dependent manner without affecting hepatocytes.…”

“…Naringenin (4,5,7-trihydroxyflavone), a flavonoid compound abundant in plants, exhibits a spectrum of pharmacological activities, including anti-inflammatory, antitumor, and immunomodulatory effects [ [24] , [25] , [26] , [27] ]. Although naringenin has demonstrated efficacy in mitigating liver fibrosis induced by carbon tetrachloride, a comprehensive understanding of its underlying mechanisms is lacking [ 28 , 29 ]. In this study, a bile duct ligation (BDL) mouse model was used to investigate the in vivo therapeutic effects of naringenin.…”

Update on the STING Signaling Pathway in Developing Nonalcoholic Fatty Liver Disease

“…68 Naringenin was shown to reduce liver inflammation and HSC activation by inhibiting the cGAS-STING signaling pathway, improving liver fibrosis. 31 Sorafenib may attenuate the signal transduction of the STING pathway by inhibiting the dimerization of STING and the recruitment of TBK1 and IRF3, thereby alleviating liver inflammation and fat accumulation induced by palmitic acid. 69,70 Bifidobacterium triple live bacteria powder relieves HFD-induced NAFLD by inhibiting the expression of STING, thereby inhibiting the release of TNF-α, IL-1β, IL-6, IFN-β and p-NF-κB p65 induced by macrophages.…”