We propose a novel pathophysiological model of HFpEF in which suppression of the Xbp1s arm of the UPR blunts STUB1 expression, leading to the stabilization and overactivation of FoxO1 in cardiomyocytes with consequent cardiomyocyte steatosis and associated detrimental sequelae (Fig. 6). This evidence concerns the gene STUB1 and steatosis.