Abstract
Intracellular calcium (Ca(2+)) homeostasis is a central determinant of cardiometabolic physiology, integrating excitation-contraction coupling, metabolic signaling, and stress adaptation across multiple organs. The sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA), regulated by the micropeptides phospholamban (PLN) and dwarf open reading frame (DWORF), governs ER/SR Ca(2+) reuptake and thereby shapes Ca(2+)-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 Ca(2+) clearance and promotes calcineurin-NFAT activation and mitochondrial Ca(2)⁺ overload. In the liver, loss of SERCA2b activity promotes chronic ER stress, Ca(2+)-phosphoinositide complex formation, insulin resistance, and fibrotic activation, thereby linking Ca(2+) dysregulation to progressive metabolic liver injury in metabolic dysfunction-associated fatty liver disease (MAFLD) and steatohepatitis (MASH). These observations position Ca(2+) 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 Ca(2)⁺ 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.