Key result
Micropeptides like DWORF regulate myocardial calcium handling and show preclinical therapeutic potential in heart failure.
Why the study?
Micropeptides were long overlooked, and although recent advances have identified a larger repertoire with potential cardiovascular relevance, rigorous validation of their endogenous translation, molecular targets, and peptide-specific effects is still needed for clinical translation.
This review highlights the emerging potential of micropeptides as novel therapeutic targets in cardiovascular conditions like heart failure and ischemia-reperfusion injury, while outlining the key translational hurdles required before clinical trial evaluation.
Answers are grounded in this paper and cite their sources.
Micropeptides merit targeted preclinical validation in HF; leaves open clinical translation pending delivery optimization and large-animal studies.
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 Ca 2+ -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.
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Biondi‐Zoccai et al. (2026) conducted a review in Cardiovascular conditions (including cardiomyopathy, heart failure, ischemia-reperfusion injury, and vascular remodeling). Cardiovascular micropeptides (e.g., DWORF, mitoregulin, mitolamban, BRAWNIN, IAMP, SPAAR, MFRLP) was evaluated. Micropeptides (<100 amino acids) such as DWORF regulate myocardial calcium handling and mitochondrial bioenergetics, offering preclinical therapeutic potential in heart failure and vascular remodeling.
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