In the present study, FAP knockout (KO) attenuated the calmodulin-dependent protein kinase δ-Calcineurin A-NFATc2 signaling pathway and attenuated cardiac hypertrophy, fibrosis, inflammation, oxidative stress, apoptosis, and energy metabolism dysfunction, ultimately attenuating T2DM-induced HFpEF. Here, FAP is linked to cardiac hypertrophy.