Micropeptides: challenges and opportunities in cardiovascular pharmacology

Micropeptides are small proteins that generally comprise fewer than 100 amino acids and are translated from short or noncanonical open reading frames. They were long overlooked, but their role is being actively explored as biologically active regulators with potential pharmacological relevance. Advances in ribosome profiling, proteogenomics, peptidomics, and computational modelling have enabled the identification and characterization of a substantially larger repertoire of micropeptides. Yet, it is important to focus on rigorous validation of endogenous translation, molecular targets, concentration-dependent activity, and peptide-specific effects. In particular, cardiovascular micropeptides can regulate myocardial calcium handling and contractility, exemplified by DWORF, which activates sarcoplasmic reticulum Ca2+-ATPase 2a and has shown therapeutic potential in multiple preclinical models of cardiomyopathy and heart failure. Other candidates, including mitoregulin, mitolamban, BRAWNIN, IAMP, SPAAR, and MFRLP, have been linked to distinct aspects of mitochondrial bioenergetics, inflammatory signalling, ischemia-reperfusion injury, angiogenesis, vascular smooth-muscle phenotypic switching, and arterial remodeling. Collectively, these findings suggest that micropeptides may provide novel therapeutic targets or pharmacological tools across several cardiovascular conditions, including heart failure, ischemia-reperfusion injury, and vascular remodeling. However, clinical translation will require advances in tissue-specific delivery, control of expression and stoichiometry, pharmacokinetic characterization, safety assessment, biomarker development, and demonstration of reproducible effectiveness in human-relevant and large-animal models before evaluation in clinical trials.