All in all, our study identified HMGCS2 as a hub gene in DCM pathophysiology and further functional studies indicated that HMGCS2 may aggravate DCM progression by reducing cardiomyocyte viability, increasing cardiomyocyte apoptosis, and promoting inflammation and oxidative stress in cardiomyocytes. Here, HMGCS2 is linked to familial dilated cardiomyopathy.