What this means
The human genome contains hundreds of thousands of short open reading frames (sORFs), yet their translational products, hereafter referred to as sORF-encoded microproteins (also historically termed micropeptides), have long remained overlooked in conventional genome annotation. Increasing evidence demonstrates that these molecules play critical regulatory roles in human physiology and disease.
A plain-English summary is on its way. Until then, this is the start of the authors' own summary.
- Who it was tested in
- People
- Kind of research
- A summary of earlier studies
The science
- Original title
- Emerging regulators of human physiology and disease; sORF-encoded microproteins.
- Authors
- Mustafa AM, Ali RM, Omar SS et al.
- Journal
- Epigenomics
- Published
- Aug 11, 2026
- Study type
- Review · in humans
- PMID
- 42576277 ↗
Abstract
The human genome contains hundreds of thousands of short open reading frames (sORFs), yet their translational products, hereafter referred to as sORF-encoded microproteins (also historically termed micropeptides), have long remained overlooked in conventional genome annotation. Increasing evidence demonstrates that these molecules play critical regulatory roles in human physiology and disease. This narrative review summarizes current knowledge regarding the classification, discovery, translational regulation, and biological significance of sORF-encoded microproteins. Their expression is tightly controlled by epigenetic mechanisms, including DNA methylation, Polycomb-mediated H3K27 trimethylation, and bivalent histone modifications, as well as epitranscriptomic regulation through N6-methyladenosine-mediated translation. Key microproteins such as Humanin, MOTS-c, Myoregulin, DWORF, HOXB-AS3-p, Mitoregulin, and CASIMO1 illustrate the diverse roles of sORF-derived peptides in cardiometabolic disease, neurodegeneration, and cancer. The review also highlights emerging therapeutic strategies, including epigenome editing, peptide replacement, and immunopeptidome-based neoantigen targeting. Collectively, the sORF-encoded microproteome represents an epigenetically integrated and functionally significant regulatory layer of the human proteome with major implications for fundamental biology and precision medicine.
Mustafa AM, Ali RM, Omar SS et al. Emerging regulators of human physiology and disease; sORF-encoded microproteins. Epigenomics. 2026. doi:10.1080/17501911.2026.2715309. PMID: 42576277. https://pubmed.ncbi.nlm.nih.gov/42576277/
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