FAP KO concomitantly inhibited the CaMKIIδ-Calcineurin A-NFATc2 signaling pathway, thereby suppressing cardiac hypertrophy, fibrosis, inflammation, oxidative stress, apoptosis, and energy metabolism dysfunction, ultimately alleviating T2DM-induced HFpEF. Here, NFATC2 is linked to type 2 diabetes mellitus.