Herein, although ANGPTL8 under physiological conditions had no influence on either baseline Akt/GSK3β activation or cardiac structure and function, in the Ang II- or TAC-induced pathological cardiac hypertrophy model, increased p-Akt levels in the heart were observed and further increased following ANGPTL8 knockout in mice, leading to the deterioration of pathological cardiac hypertrophy. This evidence concerns the gene ANGPTL8 and cardiac hypertrophy.