ORIGINAL RESEARCH article
Front. Immunol.
Sec. Systems Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1678096
This article is part of the Research TopicDevelopment of Diagnostic and Therapeutic Biomarkers for Tumors and Inflammation Based on Multi-omics Approaches Including Transcriptomics, Proteomics, and MetabolomicsView all 9 articles
Membraneless organelles-based integrative analysis constructs an immune-related prognostic signature and identifies NRG1 as a novel methylation biomarker in colorectal cancer
Provisionally accepted
Jingsong Cheng1
Nanting Chen2Qingyao Yin2
Ziheng Zheng2Xue Chen2Xinyi Zhu2Yuanyuan Wan2Ningxi Wang2Siqi Luo3Chengxi Zhang4Weilong Chen5*Rugang Luo6*- 1Department of Medical Oncology, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
- 2Chongqing Medical University, Chongqing, China
- 3The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- 4Chongqing Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Chongqing, China
- 5Chongqing Liangping District People's Hospital, Chongqing, China
- 6The People's Hospital of Renhuai, Renhuai, China
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Background: The dysfunction of membraneless organelles (MLOs) has been implicated in tumorigenesis and progression by aberrant liquid–liquid phase separation (LLPS). However, the role of MLOs in the prognosis and tumor immune microenvironment (TIME) of colorectal cancer (CRC) remains unclear. Method: We integrated transcriptomic data of MLO-related genes to identify distinct CRC subtypes and constructed a prognostic risk score termed MPRS. Then, we systematically demonstrated the characteristics of MPRS based on multi-omics analyses. We further assessed NRG1's LLPS possibility, prognostic significance, and its correlation with methylation through comprehensive analysis and in vitro experiment. Results: A prognostic signature called MPRS associated with prognosis, tumor ecotypes, genomic alterations, TIME patterns, immunotherapy responses, chemotherapy sensitivity in CRC patients. NRG1, identified as the most important MPRS gene with high predicted LLPS propensity—was significantly downregulated in CRC tissues and correlated with prognosis. Promoter methylation was found to be a crucial mechanism underlying NRG1 downregulation, which could be rescued by 5-Aza-2-deoxycytidine (Aza) treatment. The qRT-PCR, IHC and Aza treatment were utilized for in vitro validation. Conclusion: Our integrated multi-omics analysis constructed the MPRS model to delineate CRC tumor ecology and identified NRG1 as a methylation biomarker with predicted phase-separation propensity, with potential therapeutic implications that warrant prospective validation
Keywords: colorectal cancer, Nrg1, Liquid-liquid phase separation, prognosis, Methylation, membranelessorganelle
Received: 01 Aug 2025; Accepted: 30 Sep 2025.
Copyright: © 2025 Cheng, Chen, Yin, Zheng, Chen, Zhu, Wan, Wang, Luo, Zhang, Chen and Luo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Weilong Chen, 13668489510@163.com
Rugang Luo, 13511837390@163.com
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