Oroxylin A regulates cGAS DNA hypermethylation induced by methionine metabolism to promote HSC senescence

Relevant studies have recognized the important role of hepatic stellate cell (HSC) senescence in anti-liver fibrosis. Cellular senescence is believed to be regulated by the cGAS-STING signaling pathway. However, underlying exact mechanisms of cGAS-STING pathway in hepatic stellate cell senescence are still unclear. Here, we found that Oroxylin A could promote senescence in HSC by activating the cGAS-STING pathway. Moreover, activation of the cGAS-STING pathway was dependent on DNMT3A downregulation, which suppressed cGAS gene DNA methylation. Interestingly, the attenuation of DNMT activity relied on the reduction of methyl donor SAM level. Noteworthy, the downregulation of SAM levels implied the imbalance of methionine cycle metabolism, and MAT2A was considered to be an important regulatory enzyme in metabolic processes. In vivo experiments also indicated that Oroxylin A induced senescence of HSCs in mice with liver fibrosis, and DNMT3A overexpression partly offset this effect. In conclusion, we discovered that Oroxylin A prevented the methylation of the cGAS gene by preventing the production of methionine metabolites, which promoted the senescence of HSCs. This finding offers a fresh hypothesis for further research into the anti-liver fibrosis mechanism of natural medicines.

Automated summary

Relevant studies have shown that Oroxylin A promotes senescence in hepatic stellate cells (HSC) by activating the cGAS-STING pathway. The activation of this pathway is dependent on the downregulation of DNMT3A, which suppresses cGAS gene DNA methylation. Oroxylin A prevents the production of methionine metabolites, leading to a decrease in SAM levels and consequently a reduction in DNMT activity. In vivo experiments also confirmed the induction of HSC senescence by Oroxylin A, with partially offset by DNMT3A overexpression.