BACKGROUND Cardiac hypertrophy usually results in heart failure and is an important cause of mortality worldwide. Wnt/ß-catenin signaling pathway hyper-activation is involved in the pathogenesis and progression of cardiac hypertrophy. Wnt-C59 is a small molecular compound, which strongly and specifically targets at Porcupine to pharmacologically inhibit Wnt palmitoylation, secretion, and other biological activities. However, the role of Wnt-C59 in cardiac hypertrophy remains unknown. MATERIAL AND METHODS We performed transverse aortic constriction (TAC) in adult male mice to induce pressure overload and establish an in vivo model of cardiac hypertrophy. Angiotensin II (Ang-II) was utilized to culture cardiomyocyte to establish a model of in vitro cardiomyocyte hypertrophy. Daily administration of Porcupine inhibitor Wnt-C59 was performed for 4 weeks after TAC surgery. RESULTS Wnt-C59 significantly improved cardiac function and enhanced survival of mice subjected to TAC surgery. Histologically, Wnt-C59 attenuated TAC-induced increase in heart mass, cross-section area of cardiomyocyte, cardiac fibrosis, cardiomyocyte apoptosis, and expression of the hypertrophic biomarkers ß-MHC, ANP, and BNP. TAC-induced oxidative stress was also ameliorated by Wnt-C59. Wnt-C59 attenuated Ang-II-induced in vitro cardiomyocyte hypertrophy, as indicated by decreased cell size and lower expression of ANP, BNP, and ß-MHC. Moreover, Wnt/ß-catenin activation was blocked by Wnt-C59 in cardiac hypertrophy, as indicated by decreased protein expression of Wnt3a and ß-catenin and the Wnt target genes cyclin D1 and c-Myc. CONCLUSIONS Collectively, Porcupine inhibitor Wnt-C59 attenuates pressure overload-induced cardiac hypertrophic via interruption of the Wnt/ß-catenin signaling pathway, and it might be a promising drug for patients with cardiac hypertrophy.