Abstract
Doxorubicin (DOX) is a common clinical chemotherapeutic drug. However, DOX-induced cardiotoxicity (DIC) limits the wide and long-term clinical use to treat cancers. This study aims to dissect the mechanism in which DNA damage-triggered micronucleus (MN) formation activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-STAT1 pathway in cardiac fibroblasts during DIC. C57BL/6J mice were intravenously injected with 10 mg/kg of DOX to establish an acute DOX-induced cardiac injury mouse model. Meanwhile, C57BL/6J mice were intraperitoneally injected with STING inhibitor C-176 (10 mg/kg/week) or intravenously injected with STING siRNA (10 nM/week) prior to DOX (5 mg/kg/week) intravenous injection for 4 weeks to establish a chronic DIC mouse model. After 1 week of Dox injection, mice were harvested for further analysis. Measurements included echocardiography, immunohistochemical analyses, Masson and Sirius Red staining, and Western blots. Here, we showed that the cGAS-STING-STAT1 pathway was activated in cardiac fibroblasts during DIC. The STING inhibition by C-176 or the STING knockdown via siRNA in DOX-induced chronic cardiotoxicity mouse heart attenuated the DOX-induced cardiac dysfunction, cardiac fibrosis, and the inflammatory response. Mechanistically, we also demonstrated that the DOX-induced DNA damage-triggered MN formation impaired the nuclear stability, initiating the activation of the cGAS-STING-STAT1 pathway in cardiac fibroblasts during DIC. Our study illustrated that the activation of the cGAS-STING-STAT1 pathway initiated by DOX-induced DNA damage and MN formation stimulated proinflammatory responses in cardiac fibroblasts, thus promoting myocardial fibrosis during DIC.