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 previous studies. In this study, the therapeutic effects of LGZGD that 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 and fractional shortening, decreased left ventricular internal dimension in end-systole and left ventricular internal dimension in end-diastole, and reduced mitochondrial damage. LGZGD also decreased creatine kinase and malondialdehyde activities, and increased the content of superoxide dismutase, 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-related protein 1, an increased optic atrophy 1, 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.