<p>Intracellular calcium (Ca²⁺) homeostasis is a central determinant of cardiometabolic physiology, integrating excitation–contraction coupling, metabolic signaling, and stress adaptation across multiple organs. The sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), regulated by the micropeptides phospholamban (PLN) and dwarf open reading frame (DWORF), governs ER/SR Ca²⁺ reuptake and thereby shapes Ca²⁺-dependent signaling dynamics. Dysregulation of the SERCA–PLN–DWORF axis is increasingly recognized as a shared pathogenic mechanism in type 2 diabetes–related complications, including diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF), where reduced SERCA2a activity prolongs diastolic Ca²⁺ clearance and promotes calcineurin–NFAT activation and mitochondrial Ca²⁺ overload. In the liver, loss of SERCA2b activity promotes chronic ER stress, Ca²⁺–phosphoinositide complex formation, insulin resistance, and fibrotic activation, thereby linking Ca²⁺ dysregulation to progressive metabolic liver injury in metabolic dysfunction–associated fatty liver disease (MAFLD) and steatohepatitis (MASH). These observations position Ca²⁺ dysregulation as a unifying mechanism across the cardiometabolic disease continuum, spanning myocardial dysfunction, systemic insulin resistance, and progressive fatty liver disease. Therapeutic strategies targeting the SERCA–PLN–DWORF axis, including SERCA activators, PLN-directed antisense oligonucleotides, DWORF gene therapy, and CRISPR-based modulation, have demonstrated efficacy in preclinical models by improving Ca²⁺ handling and alleviating metabolic or contractile stress. Further studies are required to determine the translational feasibility, long-term safety, and optimal patient subsets for SERCA-targeted interventions in cardiometabolic disease.</p>