Therefore, our study demonstrated that CD38 deficiency‐mediated SIRT3 activation inhibits cardiac hypertrophy through inhibiting the MAPK/ERK and PI3K/Akt signalling pathways which was induced by the ROS decreasing as well as the direct inhibition from SIRT3–LKB1–AMPK signalling pathway. The gene discussed is CD38; the disease is cardiac hypertrophy.