Endoplasmic reticulum stress(ER stress)plays a key role in the development of cardiac hypertrophy and diabetic cardiomyopathy(DCM).Zonisamide(ZNS)was originally developed as an antiepileptic drug.Studies have shown that ZNS suppresses ER stress-induced neuronal cell damage in the experimental models of Parkinson's disease.Herein,we investigated whether ZNS improved DCM by attenuating ER stress-induced apoptosis.C57BL/6J mice were fed with high-fat diet(HFD)and intraperitoneally injected with low-dose streptozotocin(STZ)to induce type 2 diabetes mellitus(T2DM),and then treated with ZNS(40 mg·kg-1·d-1,i.g.)for 16 weeks.We showed that ZNS administration slightly ameliorated the blood glucose levels,but significantly alleviated diabetes-induced cardiac dysfunction and hypertrophy.Furthermore,ZNS administration significantly inhibited the Bax and caspase-3 activity,upregulated Bcl-2 activity,and decreased the proportion of TUNEL-positive cells in heart tissues.We analyzed the hallmarks of ER stress in heart tissues,and revealed that ZNS administration significantly decreased the protein levels of GRP78,XBP-1 s,ATF6,PERK,ATF4,and CHOP,and elevated Hrd1 protein.In high glucose(HG)-treated primary cardiomyocytes,application of ZNS(3 μM)significantly alleviated HG-induced cardiomyocyte hypertrophy and apoptosis.ZNS application also suppressed activated ER stress in HG-treated cardiomyocytes.Moreover,preapplication of the specific ER stress inducer tunicamycin(10ng/mL)eliminated the protective effects of ZNS against HG-induced cardiac hypertrophy and ER stress-mediated apoptosis.Our findings suggest that ZNS improves the cardiac diastolic function in diabetic mice and prevents T2DM-induced cardiac hypertrophy by attenuating ER stress-mediated apoptosis.