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Micropeptides regulate oncogenic processes including sustained proliferative signaling, growth suppression evasion, and metabolic reprogramming, aligned with cancer hallmarks. 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\n[https://doi.org/10.1007/s00018-026-06151-y](https://doi.org/10.1007/s00018-026-06151-y) Cellular and Molecular Life Sciences  \nREVIEW  \nThe hidden players: LncRNA-Encoded micropeptides in cancer hallmarks  \nXiaoyun Chen1 · Sijie Luo1 · Ruishu Chen2 · Ximo Zhang1 · TiantianYang1 · Qiwei Chen1  \nReceived: 6 November 2025 / Revised: 17 January 2026 / Accepted: 15 February 2026 © The Author(s) 2026  \nAbstract  \nTraditionally, long non-coding RNAs (lncRNAs) were considered non-protein-coding. However, recent studies reveal that their short open reading frames (sORFs) can translate functional micropeptides (10–100 amino acids), forming “bifunctional RNAs” with dual RNA and polypeptide functions. This review summarizes the mechanistic roles and clinical significance of lncRNA-encoded micropeptides in tumor development. By integrating ribosome footprinting sequencing (Ribo-seq), mass spectrometry, and bioinformatic prediction, researchers have identified numerous tumor-associated micropeptides (e.g., APPLE, RBRP, CIP2A-BP) . These micropeptides drive malignant progression by regulating key oncogenic processes, including sustained proliferative signaling (e.g., enhancing translation initiation complex assembly), evasion of growth suppression (e.g., blocking tumor-suppressive pathways), and metabolic reprogramming (e.g., activating ATP synthase) . Notably, micropeptide functions align with Hanahan & Weinberg’s hallmarks of cancer framework, highlighting their centrality in tumor biology. The expression levels of specific micropeptides (e.g., MIAC, SMIM30) correlate significantly with patient prognosis, demonstrating their potential as novel diagnostic biomarkers and therapeutic targets. Although challenges in stability and delivery exist for micropeptide-based drugs, their high specificity and low toxicity offer promising avenues for precision cancer therapy.  \nKeywords Long non-coding RNA (lncRNA) · Micropeptide · Tumorigenesis · Cancer hallmarks · Biomarker · Targeted therapy  \nIntroduction  \nProteins currently represent the predominant class of disease biomarkers and drug targets. However, only about 2% of transcripts in the human genome are protein-coding mRNAs, while the remaining 98% are non-coding RNAs (ncRNAs) [1] . ncRNAs lack canonical open reading frames (ORFs) and comprise diverse types such as tRNA, rRNA, miRNA, circRNA, lncRNA, and piRNA [2]. Among these, long non-coding RNAs (lncRNAs) are defined as transcripts  \nXiaoyun Chen and Sijie Luo contributed equally to this work.  \n􀀍 Qiwei Chen[chenqiwei@dmu.edu.cn](chenqiwei@dmu.edu.cn)  \n1 Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian 116011, China  \n2 First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian 116044, China  \nwithout protein-coding capacity [3] . lncRNAs account for approximately 70–80% of ncRNAs and play crucial roles in immune regulation, developmental differentiation, and disease progression [4–8] . Compared to the relatively limited repertoire of protein targets, lncRNAs offer immense diagnostic and therapeutic potential due to their vast number and functional diversity.  \nTraditionally, lncRNAs were regarded as non-translatable, owing to their low sequence conservation, absence of standard initiation codons, and the presence of only short ORFs (sORFs) typically \u003C 300 nt in length [9–11]. However, recent evidence shows that sORFs within certain lncRNAscan encode functional short peptides with biological significance [12–18] . These active peptides endow the parent RNA with a dual capacity—functioning both as an RNA molecule and as a peptide-encoding transcript—thereby justifying their reclassification as bifunctional RNAs [19, 20] .  \nORF length is a central criterion for distinguishing lncRNAs from mRNAs. To avoid misclassification resulting from random short ORFs, a minimum ORF length  \n1 3  \nthreshold is","cbCainu0m4ooz2bH","https://ap.wps.com/l/cbCainu0m4ooz2bH","pdf",2635023,17,"English","# Abstract\n# Introduction","[{\"question\":\"What are lncRNA-encoded micropeptides and how are they produced?\",\"answer\":\"Certain lncRNAs contain short open reading frames (sORFs) that can be translated into functional micropeptides, typically 10–100 amino acids long.\"},{\"question\":\"How do micropeptides contribute to cancer development according to the review?\",\"answer\":\"They drive malignant progression by regulating key oncogenic processes such as sustained proliferative signaling, evasion of growth suppression, and metabolic reprogramming.\"},{\"question\":\"Why are micropeptide expression levels important clinically?\",\"answer\":\"Expression levels of specific micropeptides correlate with patient prognosis, supporting their potential as diagnostic biomarkers and therapeutic targets.\"}]","The hidden players: LncRNA-Encoded micropeptides in cancer hallmarks | PDF",1790095361,43]