Abstract: Objective To explore whether vericiguat inhibits myocardial fibrosis and improves cardiac structure and function through the cyclic guanosine monophosphate（cGMP）-phosphorylated Smad2（p-Smad2） pathway in mice with chronic heart failure. Methods In animal experiments, forty male C57BL/6 mice were randomly divived into 4 groups: control group, heart failure（HF） group, HF with vericiguat 3 mg/（kg·d） group（HF-Ver3 group） and HF with vericiguat 10 mg/（kg·d） group（HF-Ver10 group）, with 10 mice in each group. Heart failure model was established by intraperitoneal injection of doxorubicin（5 mg/kg, twice a week, for 6 consecutive weeks）. Vericiguat was given by gavage once a day for 8 weeks. Echocardiography was performed to evaluate the structure and function of heart. Picrosirius red staining was used to determine myocardial collagen deposition. Radioimmunoassay was used to detect the levels of cGMP. Enzyme linked immunosorbent assay（ELISA） was used to assay the levels of tansforming growth factor β₁（TGF-β₁）, collagenⅠand collagen Ⅲ. Western-blot was used to determine the levels of p-Smad2/T-Smad2. Cell experiments: cardiac fibroblasts（FBs） were cultured by tissue sticking method. The synthesises of collagenⅠand collagen Ⅲ in FBs were induced by TGF-β₁. The levels of p-Smad2/T-Smad2 in FBs were measured by Western-blot. The levels of collagenⅠ and collagen Ⅲ in FBs supernatant were determined by ELISA.Results Animal experiments: compared with control group, in the HF group, the interventricular septum thickness at end-diastole（IVSD）, left ventricular posterior wall thickness at end-diastole（LVPWD） increased, left ventricular ejection fraction（EF） decreased（P＜0.05）, the levels of cGMP in plasma and left ventricular myocardium decreased cGMP in plasma:（4.12±0.86） vs（6.24±1.35） nmol/L, P＜0.05; in myocardium:（62.01±9.13） vs（145.68±24.29） pmol/mg, P＜0.05, the levels of TGF-β₁, p-Smad2 and collagen volume fraction（CVF） in myocardium increased（P＜0.05）. Compared with HF group, in HF-Ver3 group and HF-Ver10 group, IVSD, LVPWD decreased, and EF increased（P＜0.05）, the levels of cGMP in plasma and left ventricular myocardium increased cGMP in plasma:（6.68±1.13）,（15.49±2.07） vs（4.12±0.86） nmol/L, P＜0.05; in myocardium:（139.25±21.54）,（162.74±30.92） vs（62.01±9.13） pmol/mg, P＜0.05, the levels of p-Smad2 and CVF in myocardium decreased（P＜0.05）. However, there was no significant difference for the level of TGF-β₁ in serum and myocardial tissue among HF group, HF-Ver3 group and HF-Ver10 group（P＞0.05）. Cell experiments: TGF-β₁（1-30 ng/mL） promoted the synthesis of collagen Ⅰ and collagen Ⅲ in FBs. Vericiguat(10^-6-10^-4 mol/L) inhibited the synthesis of collagen Ⅰ and collagen Ⅲ induced by TGF-β₁ （10 ng/mL） in FBs. Vericiguat(10^-5 mol/L) significantly decreased the synthesis of collagen Ⅰ and collagen Ⅲ induced by TGF-β₁ （10 ng/mL） in FBs（P＜0.01）. Vericiguat(10^-5mol/L) and Smad2-inhibitors(10^-4 mol/L) could significantly decrease the levels of p-Smad2, collagen Ⅰ and collagen Ⅲ in FBs treated with TGF-β₁（10 ng/mL）（P＜0.01）. The inhibitory effect of vericiguat(10^-5 mol/L) on p-Smad2, collagenⅠ and collagen Ⅲ in FBs treated with TGF-β₁（10 ng/mL） was significantly attenuated by cGMP-inhibitor(10^-4 mol/L)（P＜0.05）. Conclusion Vericiguat reduces myocardial fibrosis and improves cardiac structure and function in chronic heart failure mice by increasing cGMP and inhibiting p-Smad2 levels in myocardial tissue.