Emerging regulators of human physiology and disease; sORF-encoded microproteins
Ayman M Mustafa1,2, Rebaz M Ali3,4, Sami S Omar1,5
1Kscien Organization for Scientific Research (Middle East Office), Sulaymaniyah, Iraq.
Epigenomics
|August 11, 2026
Summary
Short open reading frame-encoded microproteins (sORFs) are crucial regulators in human health and disease. This review covers their discovery, regulation, and therapeutic potential in precision medicine.
Area of Science:
- Genomics
- Proteomics
- Epigenetics
Background:
- Hundreds of thousands of short open reading frames (sORFs) exist in the human genome.
- Their translational products, sORF-encoded microproteins (micropeptides), have been historically overlooked in genome annotation.
- Emerging evidence highlights critical regulatory roles of microproteins in human physiology and disease.
Purpose of the Study:
- To summarize current knowledge on sORF-encoded microproteins.
- To review their classification, discovery, and translational regulation.
- To discuss their biological significance and therapeutic potential.
Main Methods:
- Narrative review of existing literature.
- Analysis of epigenetic and epitranscriptomic regulatory mechanisms.
- Examination of key microproteins and their roles in disease.
Main Results:
- sORF-encoded microproteins are tightly controlled by epigenetic mechanisms (DNA methylation, H3K27 trimethylation, bivalent histone modifications) and epitranscriptomic regulation (N6-methyladenosine).
- Specific microproteins (Humanin, MOTS-c, Myoregulin, etc.) are implicated in cardiometabolic disease, neurodegeneration, and cancer.
- The sORF-encoded microproteome is a significant regulatory layer of the human proteome.
Conclusions:
- sORF-encoded microproteins are functionally significant and epigenetically integrated.
- They offer potential for novel therapeutic strategies, including epigenome editing and peptide replacement.
- Understanding the microproteome has major implications for fundamental biology and precision medicine.
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