The dark proteome refers to proteins or sequence regions whose three-dimensional structures cannot be resolved experimentally or reliably predicted by homology modeling. These elements often originate from noncanonical open reading frames, including those embedded in lncRNAs, the untranslated regions of mRNAs, circular RNAs, and cryptic coding sequences generated by alternative splicing. With advances in proteomics, the critical roles of dark proteins in the immune system have increasingly come to light. Typically short, lacking known structural domains yet potentially possessing stable folding characteristics, dark proteins participate in signaling regulation, protein processing, and tissue-specific biological functions. Within immune processes, they are involved in antigen presentation, tumor immunity,inflammatory regulation, and viral immune evasion, making them an emerging focus in immune-related disease research. For example, microproteins derived from ncORFs can serve as important sources of MHC-I-presented antigens; viral dark proteins exploit intrinsically disordered regions to disrupt host antiviral pathways; and some microproteins modulate autoimmune and inflammatory responses. As their essential roles in cancer, neurodegenerative disorders, and infectious diseases continue to be uncovered, the dark proteome is increasingly recognized as a promising reservoir of novel biomarkers and therapeutic targets, offering new opportunities for precision medicine and drug development.
TUERDEBIEKE Wu-Kelai1
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FENG Jin-Yan1
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ZHANG Jun-Jia1
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3
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SHEN Shi-Xiong1
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CHU Ming1
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ZHANG Xin5
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LI Min4
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WANG Yue-Dan1
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. The Dark Proteome: Emerging Therapeutic Targets and Biomarkers in Immune-Related Diseases[J]. Progress in Physiological Sciences, 2026
, 57(3)
: 289
-298
.
DOI: 10.20059/j.cnki.pps.2026.02.1340
