In the past ten years, several publications have highlighted the role of the regulator of G protein signalling (RGS) family in multiple diseases.As one of the multifunctional family members, RGS14 is involved in various biological processes, including synaptic plasticity, cell division and phagocytosis.However, the role of RGS14 in pathological cardiac remodelling remains unclear.in the present study, we used a genetic approach to examine the role of RGS14 in pathological cardiac hypertrophy both in vivo and in vitro.We observed that RGS14 was downregulated in human failing hearts, murine hypertrophic hearts and isolated hypertrophic cardiomyocytes.Moreover, the extent of aortic banding-induced cardiac hypertrophy, dysfunction and fibrosis were exacerbated in RGS14 knockout mice, whereas RGS14 transgenic mice exhibited a significantly alleviated response to pressure overload.Mechanism research revealed that the RGS14-dependent rescue of cardiac remodelling was associated with the abrogation of mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated protein kinase (ERK) 1/2 signalling.Furthermore, constitutive activation of MEK1 nullified the cardiac protection in RGS14 transgenic mice.Conversely, inhibition of MEK-ERK1/2 by U0126 reversed RGS14 deletion-related hypertrophic aggravation.These results demonstrate that RGS14 attenuates the development of cardiac remodelling through the MEK-ERK1/2 signalling and RGS14 may be a promising target for the treatment of pathological cardiac remodelling.