Ling-Gui-Zhu-Gan decoction decreases doxorubicin-induced cardiotoxicity by regulating inflammation via the cGAS-STING pathway

Recent evidence has shown that the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway mediated by nuclear factor E2-related factor 2 (Nrf2) contributes to the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. Ling-Gui-Zhu-Gan decoction (LGZGD) ameliorated DOX-cardiotoxicity in cardiomyocytes in our previously studies. In this study, the therapeutic effects of LGZGD protect against DOX-induced cardiotoxicity in C57 male mice and HL-1 cells, and the underlying mechanisms were investigated. LGZGD-L (2.15 g/kg), LGZGD-M (4.29 g/kg) and LGZGD-H (8.58 g/kg) were administered daily in C57 male mice by gavage starting with the first intraperitoneal injection of DOX modeling for 4 weeks. LGZGD reduced the inflammatory cell infiltration, collagen of myocardial tissue, and collagen fiber deposition, increased ejection fraction (EF) and fractional shortening (FS), decreased left ventricular internal dimension in end-systole (LVIDs) and left ventricular internal dimension in end-diastole (LVIDd), and reduced mitochondrial damage. LGZGD also decreased creatine kinase (CK) and malondialdehyde (MDA) activities, and increased the content of superoxide dismutase (SOD), increased the Nrf2 expressions, and reduce expressions of cGAS, STING, nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (NLRP3), cysteine aspartate protease-1 (Caspase-1), gasdermin D (GSDMD) and GSDMD-N-terminal domain (GSDMD-N). In HL-1 cells, LGZGD suppressed DOX-induced oxidative stress injury and the mitochondrial membrane potential. LGZGD inhibited dynamin-relatedprotein 1 (DRP1), an increased optic atrophy 1 (OPA1) and Nrf2 expressions, as evidenced by decreased NLRP3, Caspase1, and GSDMD gene and protein expressions. In summary, we reveal a novel aspect of the cardiovascular protective effect of LGZGD, regulating the cGAS-STING pathway.