Pathological cardiac fibrosis is a common feature in multiple cardiovascular diseases that contributes to the occurrence of heart failure and life-threatening arrhythmias.Our previous study demonstrated that matrine could attenuate doxorubicin-induced oxidative stress and cardiomyocyte apoptosis.In this study,we investigated the effect of matrine on cardiac fibrosis.Mice received aortic banding(AB)operation or continuous injection of isoprenaline(ISO)to generate pathological cardiac fibrosis and then were exposed to matrine lavage(200 mg·kg-1·d-1)or an equal volume of vehicle as the control.We found that matrine lavage significantly attenuated AB or ISO-induced fibrotic remodeling and cardiac dysfunction.We also showed that matrine(200 μmol/L)significantly inhibited the proliferation,migration,collagen production,and phenotypic transdifferentiation of cardiac fibroblasts.Mechanistically,matrine suppressed p38 activation in vivo and in vitro,and overexpression of constitutively active p38 completely abolished the protective effects of matrine.We also demonstrated that ribosomal protein S5(RPS5)upregulation was responsible for matrine-mediated inhibition on p38 and fibrogenesis.More importantly,matrine was capable of ameliorating preexisting cardiac fibrosis in mice.In conclusion,matrine treatment attenuates cardiac fibrosis by regulating RPS5/p38 signaling in mice,and it might be a promising therapeutic agent for treating pathological cardiac fibrosis.