Microprotein, macro-effect: DWORF as a therapeutic strategy in heart failure

Heart failure (HF) is a global health crisis and remains a leading cause of morbidity, mortality, and healthcare expenditure despite substantial advances in pharmacological and device-based therapy. Impaired sarcoplasmic reticulum (SR) Ca 2+ cycling, driven largely by reduced activity of the SR Ca 2+ -ATPase 2a (SERCA2a), is a hallmark molecular feature of the failing myocardium. The SERCA2a-phospholamban (PLN) regulatory axis has long attracted therapeutic interest, however, clinical translation of SERCA2a gene therapy has been inconsistent, and strategies targeting PLN raise safety concerns, as complete PLN loss is lethal in humans. Dwarf Open Reading Frame (DWORF; gene name STRIT1 ) is a 34–35 amino acid single-pass transmembrane microprotein and the only known endogenous positive regulator of SERCA2a within the SERCA-regulin family. In contrast to inhibitory regulins including PLN, sarcolipin (SLN), myoregulin (MLN), endoregulin (ELN), and another-regulin (ALN), DWORF enhances SERCA2a activity by increasing its catalytic turnover and displacing PLN from a shared regulatory binding site, thereby promoting Ca 2+ reuptake into the SR. Structurally, a proline at position 15 (Pro15) introduces a critical kink that separates DWORF’s N-terminal amphipathic helix from its C-terminal transmembrane domain, with disruption of this feature abolishing DWORF’s activating properties and converting DWORF into a PLN-like inhibitor. DWORF expression is restricted to ventricular myocardium and slow-twitch skeletal muscle, increases postnatally with cardiac maturation, and is consistently reduced in heart failure models. Across multiple preclinical models including dilated cardiomyopathy, Duchenne muscular dystrophy cardiomyopathy, pressure overload-induced heart failure, PLN-R14del cardiomyopathy, and ischemia-reperfusion injury, DWORF gene therapy improves Ca 2+ handling, reduces fibrosis, and restores mitochondrial energetics, even when administered after established disease. The compact coding sequence of DWORF is ideally suited for adeno-associated virus delivery, enabling efficient packaging and potential multiplexing strategies. Together, these features position DWORF as a mechanistically distinct and physiologically robust strategy for enhancing SERCA2a function. This review summarizes the molecular mechanisms underlying DWORF activity, evaluates preclinical therapeutic evidence, and discusses key translational considerations, including species differences, safety, and remaining knowledge gaps that must be addressed to advance DWORF-based therapy toward clinical application in heart failure.