bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2026–05–17
ten papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Microproteins at the Frontiers of Biology and Medicine.
  2. Comprehensive annotation and analysis of human microproteins by human microprotein atlas platform.
  3. Micropeptides in Cancer and Immunity: Diagnostic, Therapeutic, and Synthetic Biology Frontiers.
  4. Micropeptide PEP1695 mitigates lung injury in COPD mice by inhibiting epithelial-mesenchymal transition of type II alveolar epithelial cells.
  5. High-resolution multi-omics enhances prediction and detection of smORF-encoded proteins in the human gut microbiome.
  6. A proteogenomic approach to discover novel lncRNA-derived microproteins and their potential clinical utility in hepatocellular carcinoma.
  7. Additional layers of systemic plant immunity: Apoplastic pH and uORF peptides.
  8. iMPI: An Integrative Database for MicroProteins Encoded by Intron Retention in Tumors.
  9. MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.
  10. MOTS-c is associated with oxidative stress and arterial stiffness in peritoneal dialysis patients: a pilot study.
  1. Annu Rev Cell Dev Biol. 2026 May 13.
    Microproteins at the Frontiers of Biology and Medicine.
    Andrea Rocha, Alan Saghatelian.
      Small proteins, known as microproteins, typically consisting of fewer than 150 amino acids, have recently emerged as a previously unrecognized class of functional genes in biology. Advances in ribosome profiling, proteogenomics, and genome-wide functional screens have revealed that thousands of small open reading frames are actively translated, producing microproteins, some of which regulate essential processes in metabolism, immunity, cancer, and neurodegeneration. These discoveries have challenged long-held assumptions that gene function is confined to large, conserved proteins and have underscored microproteins as critical modulators. Dysregulation or mutation of small open reading frame-encoding microproteins contributes to a diverse range of biology, and in some cases links the noncanonical proteome to pathophysiological biology. In this review, we summarize current knowledge of microprotein discovery and function, describe key examples connecting microproteins to human disease, and discuss the opportunities and challenges that define this rapidly evolving field.
    DOI:  https://doi.org/10.1146/annurev-cellbio-101323-122347
  2. Commun Chem. 2026 May 12.
    Comprehensive annotation and analysis of human microproteins by human microprotein atlas platform.
    Boming Kang, Rui Fan, Xiangwen Ji, Yuan Zhou, Qinghua Cui, Chunmei Cui.
      Small open reading frames (sORFs) and their encoded microproteins are increasingly recognized as a widespread but poorly characterized components of the human proteome. Here we show a Human Microprotein Atlas (HMPA) platform that integrates 617,462 human microproteins with sequence features, predicted three-dimensional structures, variant effect predictions, subcellular localization, essentiality, and bioactivity annotations. Structural analyses revealed substantial conformational diversity, and structure-based functional inference suggested roles in cellular regulation, signaling, and cell-cell communication. Deep learning-based analyses further prioritized microproteins with tissue-specific essentiality and enabled the prediction of diverse bioactivities across multiple functional categories. To support the exploration of these data, we also provide an interactive web server with sequence-, structure-, and function-oriented search and analysis utilities. This resource provides a systematic framework for studying microprotein biology and supports the discovery of functional and therapeutically relevant microproteins.
    DOI:  https://doi.org/10.1038/s42004-026-02054-y
  3. Gene. 2026 May 14. pii: S0378-1119(26)00227-1. [Epub ahead of print] 150217
    Micropeptides in Cancer and Immunity: Diagnostic, Therapeutic, and Synthetic Biology Frontiers.
    Rania El Majzoub, Racha Wehbe, Hassan El Said, Amal Fneish, Ali Nasrallah, Walid Rachidi, Hussein Fayyad-Kazan, Bassam Badran, Mohammad Fayyad-Kazan.
      Micropeptides are emerging as a previously hidden layer of the human proteome, redefining the long-standing separation between coding and noncoding genomic regions. Once dismissed as translational noise, sORFs embedded within lncRNAs, circRNAs, pseudogenes, and UTRs are now recognized as a reservoir of functional peptides that regulate core cellular programs, including metabolism, mitochondrial function, immune signaling, and stress adaptation. In cancer, micropeptides exert dual and context-dependent roles: oncogenic micropeptides such as SMIM30, circPDHK1-241aa, and PDL1P41 promote proliferation, angiogenesis, immune escape, and therapeutic resistance, whereas tumor-suppressive peptides, including HOXB-AS3, CIP2A-BP, SPAR, and ASRPS, restore metabolic homeostasis, reactivate the PP2A axis, inhibit mTORC1, and block tumor vascularization. Their small size, modular structure, and tissue specificity make them ideal biomarkers for liquid biopsies and attractive substrates for peptide-based and mRNA-encoded therapeutics. Emerging frameworks integrating single-cell proteogenomics, Ribo-seq, mass spectrometry, and deep-learning-based structural inference are accelerating micropeptide discovery and annotation. Synthetic biology now enables the rational design of micropeptide-based therapeutic constructs, including tumor-specific mRNA-encoded peptides, CRISPR-activated peptide circuits, and targeted peptide chimeras. Collectively, micropeptides represent a transformative paradigm, bridging genomics and proteomics, and establishing the hidden proteome as a new frontier in precision oncology, immunotherapy development, and programmable cancer therapeutics.
    Keywords:  Micropeptides; circular RNAs (circRNAs); immunoregulation; long noncoding RNAs (lncRNAs); precision medicine; small open reading frames (sORFs)
    DOI:  https://doi.org/10.1016/j.gene.2026.150217
  4. Eur J Pharmacol. 2026 May 07. pii: S0014-2999(26)00434-6. [Epub ahead of print] 178952
    Micropeptide PEP1695 mitigates lung injury in COPD mice by inhibiting epithelial-mesenchymal transition of type II alveolar epithelial cells.
    Min Zhang, Xue Zhang, Yan Zhou, Yingying Zhang, Yuning Huang, Guogang Xie, Wuping Bao, Xue Tian.
      Micropeptides encoded by small open reading frames (smORFs) within long noncoding RNAs (lncRNAs) have emerged as important regulators of various biological processes. However, whether micropeptides mitigate lung tissue damage in chronic obstructive pulmonary disease (COPD) remains poorly understood. In COPD, the epithelial-mesenchymal transition (EMT) of type II alveolar epithelial (ATII) cells plays a crucial role in lung injury, contributing to fibrosis and airway remodeling. Modulating EMT could offer a promising therapeutic strategy for COPD. In this study, we identified a micropeptide, PEP1695, encoded by lncRNA-MSTRG.1695.1, as a key regulator of EMT in mouse ATII cells. Mechanistic investigations revealed that PEP1695 inhibits EMT in ATII cells by binding to p38-MAPK. Using a COPD mouse model, we observed a significant reduction in PEP1695 expression in ATII cells, administration of PEP1695 effectively improved lung function and reduced inflammation, highlighting its potential as a novel targeted biologic therapy for COPD. Moreover, preliminarily serum analysis from COPD patients revealed a positive correlation between PEP1695 homolog levels and lung function PEP1695 represents a promising therapeutic target for lung injury in COPD and has preliminarily shown potential as a serum marker for the evaluation of early fibrosis in COPD patients.
    Keywords:  Chronic obstructive pulmonary disease (COPD); PEP1695; epithelial-mesenchymal transition (EMT); micropeptides; p38
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178952
  5. Nat Commun. 2026 May 09.
    High-resolution multi-omics enhances prediction and detection of smORF-encoded proteins in the human gut microbiome.
    Megan E Davin, Júlia Ortís Sunyer, Luis F Delgado, Steven L Tavis, Tuesday Lowndes, Zainab Zafar, Jordan Caussin, Rashi Halder, Oskar Hickl, Cédric C Laczny, Etienne Hanslian, Daniela A Koppold, Anika Rajput-Khokhar, Nico Steckhan, Sebastian Schade, Jochen Schneider, Brit Mollenhauer, Andreas Michalsen, Patrick May, Robert L Hettich, Paul Wilmes.
      Small open reading frames (smORFs), which encode proteins under 100 amino acids, represent an underexplored dimension of the human gut microbiome, despite growing evidence of their essential biological roles. Due to small size and poor annotation, smORFs are typically excluded from metagenomic/metaproteomic analyses. Here, we present a high-resolution multi-omic workflow that integrates smORF prediction into metaproteome searches and enables ultra-deep detection of smORF-encoded proteins (SEPs), without experimental size-based enrichment, utilizing state-of-the-art mass spectrometry instrumentation. Applied to human gut microbiomes, this approach resulted in the largest number of detected SEPs to date, allowing identification of over 25,000 SEPs in the metaproteome, alongside the measurements of the larger proteins. Our multi-omics integrative strategy is critical for advancing human metaproteome research. It also provides a generalizable strategy for comprehensive SEP discovery across diverse microbial ecosystems greatly expanding the previously hidden proteomic landscape.
    DOI:  https://doi.org/10.1038/s41467-026-72762-5
  6. Mol Cell Proteomics. 2026 May 13. pii: S1535-9476(26)00080-0. [Epub ahead of print] 101584
    A proteogenomic approach to discover novel lncRNA-derived microproteins and their potential clinical utility in hepatocellular carcinoma.
    Bingwu Li, Kandarp Joshi, Dan Ohtan Wang.
      Microproteins (i.e., peptides) are increasingly recognized for their functions in versatile biological contexts but their clinical relevance and utility remain largely unexplored. Proteogenomic approaches can accelerate microprotein discovery in clinical samples by integrating proteomic data with genomics and transcriptomics evidence. However, long noncoding RNA (lncRNA)-derived microproteins (lncPeps) remain largely unidentified, resulting in unmatchable MS/MS spectra. To solve this problem, we have used high-quality Ribo-seq translatomic datasets to generate an extensive database of human liver lncRNA-derived open reading frames (lncORFs), which we subsequently applied to proteomics data of tumor-adjacent normal tissue pairs from hepatocellular carcinoma (HCC) patients. Using the new database, we discovered 104 novel lncPeps including 46 lncPeps differentially expressed between tumor and non-tumor tissues, and 13 lncPeps with significant correlation with prognosis. Remarkably, combining the expression of lncPeps with canonical proteins in a LASSO regression model improved predictive performance for recurrence, increasing the AUC by 0.005 to 0.085 across three recurrence time points. These findings suggest that lncPeps discovery contributes to our understanding of the molecular heterogeneity and progression of HCC, and broadens the range of potential biomarker candidates or treatment targets for the disease.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101584
  7. Dev Cell. 2026 May 13. pii: S1534-5807(26)00155-3. [Epub ahead of print]61(5): 973-975
    Additional layers of systemic plant immunity: Apoplastic pH and uORF peptides.
    Hannah Weber, Birgit Kemmerling.
      Plants coordinate systemic immunity through mobile signals that prime distal tissues for enhanced defense. Two recent studies show that an upstream ORF-encoded peptide induces systemic stomatal closure, whereas apoplastic alkalinization enhances immune responsiveness, revealing complementary, systemic acquired resistance-independent mechanisms that integrate peptide signaling and extracellular pH dynamics.
    DOI:  https://doi.org/10.1016/j.devcel.2026.04.008
  8. Proteomics. 2026 May 11. e70142
    iMPI: An Integrative Database for MicroProteins Encoded by Intron Retention in Tumors.
    Jiamin Hu, Yongqiang Zheng, Xin Huang, Zhuoran Liang, Juntong Di, Bijin Cao, Lulu Wang, Junteng Li, Zhe Fu, Hao Li, Han Cheng, Ze-Xian Liu.
      Research advancements made in the last decade have shed light on the dysregulation of cellular mechanisms that lead to aberrant and pathologic intron retention (IR). IR is not merely a mechanism of gene regulation but may also play a potential role in cancer pathogenesis and therapeutic resistance across various human cancers. Despite its potential significance, there remains a notable gap in comprehensive database resources for introns within tumors. Therefore, we investigated whether the retained introns contain undiscovered protein-coding ORFs and whether they can encode proteins. We conducted a genome-wide search for underlying translatable intron ORFs (iORFs) and validated them at the protein level via large-scale proteomic mass spectrometry (MS) data. Furthermore, we developed the first comprehensive resource, iMPI (an integrative database for MicroProteins encoded by introns), to provide an accessible source of iORF-encoded microproteins. Our genome-wide search identified 209,091 introns in the human GRCh38 genome, among which 15,975 were confirmed as candidates with strong coding potential. On the basis of the proteomic MS search, 4751 introns containing a total of 5823 iORFs across 27 cancer types were validated. Detailed annotations, including intron information, coding evidence, subcellular location and structures, were integrated. iMPI is a user-friendly web interface that is freely available at https://impi.omicsbio.info/, making it a valuable tool for researchers investigating the spectrum of IR in human cancers.
    Keywords:  alternative splicing; biological database; cancer; coding potential; intron retention
    DOI:  https://doi.org/10.1002/pmic.70142
  9. Life Sci. 2026 May 12. pii: S0024-3205(26)00261-4. [Epub ahead of print]398 124452
    MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction.
    Shu-Hong Li, Shi-Qi Chen, Tao Lu, Jia-Hao Wang, Jia-Xin Wang, Ya-Xian Wu, Qing-Feng Pang, Dan Chen.
       AIMS: Hyperoxia-induced oxidative stress is a primary cause of neonatal injury. Neonatal heart shows a particular susceptibility to hyperoxic toxicity, yet mechanisms and effective therapeutic strategies remain limited. Oxeiptosis is a ROS-specific programmed cell death. Mitochondrial-derived peptide MOTS-c possesses well-known anti-oxidative effect. This study investigated the cardio-protective role of MOTS-c in hyperoxia exposed neonatal mice and its mechanism.
    MAIN METHODS: Neonatal mice exposed hyperoxia (85% O2) were used to establish the hyperoxic cardiac injury model. Additionally, the rat cardiomyocyte cell line H9C2 were subjected to hyperoxic conditions as an in vitro model. Serum MOTS-c content was measured using enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, Real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to evaluate the effects of MOTS-c on hyperoxia-induced cardiac insufficiency.
    KEY FINDINGS: We found that hyperoxia exposure in neonatal mice led to significant cardiac hypertrophy, fibrosis, and dysfunction, concomitant with decreased serum MOTS-c content. Administration of MOTS-c markedly ameliorated these pathological changes and restored cardiac function. In vitro and in vivo experiments revealed that hyperoxia triggers oxidative stress and oxeiptosis via activating KEAP1-PGAM5-AIFM1 axis, and MOTS-c inhibited oxeiptosis. Mechanistically, MOTS-c could potentially interact with KEAP1, thereby maintaining the KEAP1-PGAM5 interaction, and inhibiting the downstream nuclear translocation of AIFM1. Notably, KEAP1 overexpression abrogated the protective effects of MOTS-c, confirming KEAP1 as a critical target of MOTS-c in hyperoxia-induced cardiac injury.
    SIGNIFICANCE: MOTS-c attenuates hyperoxic cardiac injury by inhibiting KEAP1-mediated oxeiptosis, highlighting its potential as a novel therapeutic agent for neonatal cardiomyopathy.
    Keywords:  Hyperoxia; MOTS-c; Myocardial injury; Oxeiptosis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2026.124452
  10. Int Urol Nephrol. 2026 May 13.
    MOTS-c is associated with oxidative stress and arterial stiffness in peritoneal dialysis patients: a pilot study.
    Michela Musolino, Athanasios Roumeliotis, Stefanos Roumeliotis, Mariateresa Zicarelli, Federico Ruosi, Marta Greco, Roberta Misiti, Daniela Patrizia Foti, Vasiliki Sgouropoulou, Gordana Kocic, Andrej Veljkovic, Ioannis E Neofytou, Ioannis Alekos, Efthymios Papas, Anila Duni, Davide Bolignano, Evangelia Dounousi, Vassilios Liakopoulos.
       PURPOSE: Oxidative stress (OS) and endothelial dysfunction are major drivers of cardiovascular disease (CVD) in peritoneal dialysis (PD). MOTS-c, a mitochondria-derived peptide, is emerging as a key regulator of skeletal muscle health, metabolic homeostasis, and vascular function, yet its role in the uremic environment remains unexplored. We investigated the relationship between MOTS-c levels, OS markers, and vascular stiffness in PD patients.
    METHODS: This pilot, clinical study included 32 stable PD patients (mean age 60.7 ± 1.2 years, 62.5% male). MOTS-c levels were quantified in serum (sMOTS-c), urine (uMOTS-c), and peritoneal dialysate (dMOTS-c). Systemic oxidative status was assessed via plasma Advanced Oxidation Protein Products (AOPPs). Vascular function was evaluated by carotid-femoral Pulse Wave Velocity (PWV), and left ventricular systolic function was assessed echocardiographically.
    RESULTS: Urinary MOTS-c (uMOTS-c) levels were inversely correlated with serum AOPPs (R = - 0.592, p = 0.012) and a positive association with PWV (R = 0.708, p = 0.001) and left ventricular systolic function (R = 0.440, p = 0.04). Conversely, dialysate MOTS-c (dMOTS-c) were strongly and inversely correlated with PWV (R = - 0.717, p = 0.019) as well as systolic and diastolic blood pressure (R = -0.5, p < 0.01).
    CONCLUSION: Ηigher urinary MOTS-c was linked to lower systemic oxidative stress, suggesting a potential protective role, and associated with greater arterial stiffness, potentially reflecting a compensatory response to vascular injury. In contrast, higher peritoneal MOTS-c levels were associated with an improved vascular profile. These findings suggest a novel 'Mitochondrial-Vascular Axis' in uremia, highlighting MOTS-c as a potential biomarker.
    Keywords:  AOPPs; MOTS-c; Oxidative stress; Peritoneal dialysis; Pulse wave velocity
    DOI:  https://doi.org/10.1007/s11255-026-05198-x
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