<p>Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac hypertrophy. SMURF2 (SMAD-specific E3 ubiquitin ligase 2) is an important member of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) family of HECT E3 ubiquitin ligases. In this study we investigated the regulatory role of SMURF2 in cardiac hypertrophy. Experiment models were established in mice by transverse aortic constriction (TAC) in vivo, as well as in neonatal rat cardiomyocytes (NRCMs) by treatment with angiotensin II (Ang II, 1 μM) in vitro. We showed that the expression levels of SMURF2 were significantly elevated in cardiac tissues from patients with cardiac hypertrophy and the two experiment models. In NRCMs, SMURF2 knockdown or treatment with a specific SMURF2 inhibitor heclin (8 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, evidenced by reduced mRNA levels of <i>Anp</i>, <i>Bnp</i> and <i>β-Mhc</i> as well as cell surface. Prophylactic or therapeutic administration of heclin (10 mg·kg^–1·d^–1, i.p., for 5 or 4 weeks) effectively suppressed TAC-induced cardiac hypertrophy, and rescued heart function. We demonstrated that SMURF2 interacted with AXIN1 and increased ubiquitination degradation of AXIN1 in myocardial tissues, activating the Wnt/β-catenin signaling pathway. Heclin inhibited the ubiquitination degradation of AXIN1 by SMURF2 to alleviate cardiac hypertrophy. In conclusion, upregulated SMURF2 leads to AXIN1 ubiquitination and degradation, thereby facilitating the progression of cardiac hypertrophy. SMURF2 inhibitor heclin may serve as a therapeutic strategy for the treatment of cardiac hypertrophy.</p>