Xin-Ji-Er-Kang alleviates chronic heart failure by suppressing mtDNA/cGAS-STING signaling through NR3C1-mediated MFN2...

cGAS/STING signaling activation driven by mitochondrial DNA (mtDNA) release contributes to chronic heart failure (CHF) pathogenesis. Although the traditional Chinese medicine Xin-Ji-Er-Kang (XJEK) shows cardioprotective potential, its regulation of mtDNA dynamics remains unclear.

To elucidate how XJEK inhibits mtDNA/cGAS/STING-driven inflammation and improves CHF.

Murine myocardial ischemia-reperfusion (MIR) injury models and cardiomyocyte hypoxia/reoxygenation (H/R) models were used to evaluate the cardioprotective effects of XJEK in vivo and in vitro. High-throughput sequencing identified potential therapeutic targets of XJEK. Network pharmacology and bioinformatic analyses were then applied for target prediction and pathway enrichment. Integrated experimental approaches including RT-qPCR, immunofluorescence, immunoblotting, dual-luciferase reporter assays, and ChIP-qPCR were implemented to elucidate XJEK-mediated regulatory mechanisms governing cGAS/STING signaling in both models.

XJEK treatment significantly ameliorated myocardial fibrosis and attenuated ventricular remodeling in mice with MIR-induced heart failure. High-throughput sequencing identified mitofusin 2 (MFN2) as a key regulator mediating XJEK's cardioprotective effects. XJEK rescued MIR- and H/R-induced downregulation of MFN2, thereby suppressing mtDNA release and the consequent excessive activation of the cGAS/STING signaling and downstream inflammatory responses. Furthermore, integrated network pharmacology and bioinformatic analyses revealed nuclear receptor subfamily 3 group C member 1 (NR3C1) as the transcription factor promoting MFN2 expression. Mechanistically, XJEK facilitated the nuclear translocation of NR3C1, enabling this process.

XJEK attenuates CHF progression by facilitating NR3C1 nuclear translocation, enhancing its binding to the MFN2 promoter to upregulate transcription and expression, thereby suppressing mtDNA/cGAS/STING signaling activation and inflammatory responses.