bims-micpro 2025-06-01 papers

WIREs Mech Dis. 2025 May-Jun;17(3):17(3): e70001

Harnessing Noncanonical Proteins for Next-Generation Drug Discovery and Diagnosis.

Nachiket Rajinikanth, Ruchi Chauhan, Sudhakaran Prabakaran.

Noncanonical proteins, encoded by previously overlooked genomic regions (part of the "dark genome"), are emerging as crucial players in human health and disease, expanding our understanding of the "dark proteome." This review explores their landscape, including proteins derived from long non-coding RNAs, circular RNAs, and alternative open reading frames. Recent advances in ribosome profiling, mass spectrometry, and proteogenomics have unveiled their involvement in critical cellular processes. We examine their roles in cancer, neurological disorders, cardiovascular diseases, and infectious diseases, highlighting their potential as novel biomarkers and therapeutic targets. The review addresses challenges in identifying and characterizing these proteins, particularly recently evolved ones, and discusses implications for drug discovery, including cancer immunotherapy and neoantigen sources. By synthesizing recent findings, we underscore the significance of noncanonical proteins in expanding our understanding of the human genome and proteome, and their promise in developing innovative diagnostic tools and targeted therapies. This overview aims to stimulate further research into this unexplored biological space, potentially revolutionizing approaches to disease treatment and personalized medicine.

Keywords: alternative open reading frames; dark genome; dark proteome; neoantigens; noncanonical proteins; novel cancer biomarkers; novel drug discovery; novel psychiatry biomarkers; proteogenomics; ribosome profiling

DOI: https://doi.org/10.1002/wsbm.70001

Cell Rep. 2025 May 28. pii: S2211-1247(25)00544-3. [Epub ahead of print]44(6): 115773

Unveiling the evolution of antimicrobial peptides in gut microbes via foundation-model-powered framework.

Wenhui Li, Baicheng Huang, Menghao Guo, Zihan Zeng, Tao Cai, Linqing Feng, Xinpeng Zhang, Ling Guo, Xianyue Jiang, Yanbin Yin, Ercheng Wang, Xingxu Huang, Jinfang Zheng.

Antimicrobial resistance poses a major threat to public health, prompting the development of alternative therapies such as antimicrobial peptides (AMPs). Protein language models (PLMs) have advanced protein structure and function predictions, facilitating AMP discovery. We developed antimicrobial peptide structural evolution miner (AMP-SEMiner), an AI-driven framework that integrates PLMs, structural clustering, and evolutionary analysis to systematically identify AMPs encoded by small open reading frames and AMP-containing proteins in metagenome-assembled genomes. AMP-SEMiner identified over 1.6 million AMP candidates across diverse environments. Experimental validation showed antimicrobial activity in 9 of the 20 tested candidates, with 5 surpassing antibiotic effectiveness; variant peptides derived from these candidates similarly demonstrated strong antimicrobial efficacy. AMPs from human gut microbiomes revealed both conserved and adaptive evolutionary strategies, reflecting their dynamic ecological roles. AMP-SEMiner thus represents a valuable tool for expanding AMP discovery and has significant potential to inform the development of alternative antimicrobial treatments.

Keywords: CP: Microbiology; antimicrobial peptides; evolution; human gut microbiota; protein language model; protein structure

DOI: https://doi.org/10.1016/j.celrep.2025.115773

Int J Chron Obstruct Pulmon Dis. 2025 ;20 1543-1553

A Peptide Encoded by lncRNA HOXB-AS3 Promotes Cigarette Smoke-Induced Inflammation in Bronchial Epithelial Cells via EZH2-Mediated H3K27me3 Modification.

Mei Lin, Xiaoman Zhou, Yixiu Yang, Pingdong Xie, Quanni Li, Chanyi He, Qi Lin, Xingwei Wei, Yipeng Ding.

Background: Chronic obstructive pulmonary disease (COPD) primarily results from cigarette smoke (CS)-induced chronic inflammation. Although numerous long non-coding ribonucleic acids (lncRNAs) have been extensively studied for their crucial roles in COPD, the peptides encoded by these lncRNAs have garnered limited attention. This study aimed to investigate the role of a peptide encoded by lncRNA HOXB-AS3 in cigarette smoke extract (CSE)-induced inflammation and in 16HBE cells.
Methods: Open reading frames (ORF) Find software was utilized to predict the encoding potential of HOXB-AS3. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the levels of peptide HOXB-AS3-32aa in peripheral blood mononuclear cells (PBMCs) from both healthy controls and COPD patients and in 16HBE cells exposed to different CSE. To establish an in vitro inflammatory cell model of COPD, 16HBE cells were treated with 2% CSE. Enzyme-Linked Immunosorbent Assay (ELISA) measured inflammatory cytokines, while CCK-8 assay assessed cell viability. Flow cytometry was employed to assess cell apoptosis. Western blot analysis was performed to measure the expression of HOXB-AS3-32aa, EZH2, and H3K27me3 proteins. Co-Immunoprecipitation (Co-IP) was conducted to verify the interaction between EZH2 and HOXB-AS3-32aa.
Results: Our findings revealed elevated expression of HOXB-AS3-32aa in PBMCs of COPD patients compared to controls. CSE treatment dose-dependently increased HOXB-AS3-32aa expression. Overexpression of HOXB-AS3-32aa exacerbated CS-induced inflammation in bronchial epithelial cells, leading to inhibited cell proliferation and increased cell apoptosis. Furthermore, HOXB-AS3-32aa suppressed EZH2 and H3k27me3 protein levels in 16HBE cells. Co-IP results confirmed the interaction between HOXB-AS3-32aa and EZH2 protein.
Conclusion: Our results demonstrate that the novel peptide HOXB-AS3-32aa encoded by lncRNA HOXB-AS3 promotes CS-induced inflammation and apoptosis in 16HBE cells via EZH2-mediated H3K27me3 modification.

Keywords: EZH2; H3K27me3 modification; HOXB-AS3-32aa; chronic obstructive pulmonary disease; inflammation

DOI: https://doi.org/10.2147/COPD.S495581

Methods Mol Biol. 2025 ;2923 197-214

Ribo-ITP: A Method for Ribosome Profiling in Single Cells and Low-Input Samples.

Shilpa Rao, Tori Tonn, Can Cenik.

Transcriptome-wide translation can be measured using ribosome profiling, a technique which relies on deep sequencing of ribosome protected fragments. This method enables comprehensive measurement of in vivo translation; however, it involves multiple steps and thereby demands high-input samples. Here, we describe Ribo-ITP (RIBOsome profiling via IsoTachoPhoresis), which utilizes the principles of isotachophoresis coupled with a stringent size selection strategy in a microfluidic chip to isolate ribosome-protected fragments. Ribo-ITP allows quantitative measurement of translation from rare populations like cancer stem cells, early embryonic stages, and other ultralow input samples including single cells.

Keywords: Isotachophoresis; Microfluidic; Ribo-ITP; Ribosome profiling; Translation

DOI: https://doi.org/10.1007/978-1-0716-4522-2_12

Sci Rep. 2025 May 27. 15(1): 18460

MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3.

Feilong Chen, Zhiyu Li, Tutu Wang, Yu Fu, Lei Lyu, Chengyuan Xing, Shunchang Li, Li.

Liver fibrosis is a common complication of T2DM(Type 2 diabetes mellitus). Appropriate intervention (exercise or drugs) in the early stage of liver fibrosis can slow down or even reverse liver fibrosis. MOTS-c (Mitochondrial open reading frame of the 12 S r RNA type-c ) has been described as an exercise-mimicking substance, and its effects are similar to those achieved by aerobic exercise; however, the exact mechanism remains to be elucidated. In this study, liver function was impaired in a T2DM rat model, leading to the aggravation of liver fibrosis. T2DM rats with liver fibrosis were subjected to MOTS-c, aerobic exercise therapy, or their combination. HE staining, Masson's trichrome staining and immunohistochemistry were used for histopathological examination. Transcriptome sequencing, q-PCR and WB were used to detect the expression of Keap1 (Kelch-like ECH-associated protein 1), Nrf2 (Nuclear factor erythroid 2-related factor 2 ), Smad2/3/4 and other genes. MOTS-c and aerobic exercise therapy improved T2DM-induced liver fibrosis. Additionally, cells were transfected with MOTS-c overexpression or interference plasmids or MOTS-c was added to the culture medium. MOTS-c overexpression or MOTS-c addition to the culture medium inhibited ROS levels, increased the mRNA and protein expression of Keap1-Nrf2 pathway genes and decreased the expression of TGF-β1(Transforming growth factor-beta1)/Smad pathway genes. Our findings demonstrate that MOTS-c modulates the progression of T2DM complicated by liver fibrosis through a Keap1-Nrf2-Smad2/3 signaling pathway-dependent mechanism.

Keywords: Aerobic exercise; Keap1-Nrf2-Smad2/3 pathway; Liver fibrosis; MOTS-c; T2DM

DOI: https://doi.org/10.1038/s41598-025-03526-2