Abstract
While recent studies have highlighted oxidative stress (OS) as a pivotal factor influencing tumor dynamics, its specific interactions within the tumor microenvironment (TME) of colorectal cancer (CRC) remain elusive. This study seeks to unveil the impact of OS on the CRC TME and to develop an advanced OS-related risk signature (OSRRS) model. We analyzed OS-related pathway activities using both single-cell and bulk RNA-seq data. An unsupervised clustering algorithm was utilized to identify OS-related subtypes. Based on genes associated with the OS pathways, we constructed an OSRRS model employing the LASSO Cox analysis. For validation, we employed quantitative real-time polymerase chain reaction (qRT-PCR) coupled with immunohistochemical (IHC) analyses on tissue microarrays (TMA) to confirm the expression of the identified gene. Examination of the single-cell RNA-seq GSE132465 dataset revealed a universal elevation in OS-associated pathway activities within malignant cells. By integrating this with the bulk RNA-seq TCGA-CRC dataset, we identified two unique OS-specific clusters. This led to the establishment of a 12-gene OSRRS using the LASSO Cox method. The robustness of our model was further verified using the GSE39582 and GSE17538 cohorts. Notably, increased expression of the UCN gene was observed in CRC specimens, as confirmed by qRT-PCR and IHC assays on TMA. In this research, we delineated two distinct subtypes of CRC associated with OS. The developed OSRRS holds promise as a candidate prognostic and stratification tool for CRC management. Collectively, these results shed light on the intricate role of OS in CRC pathology.
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Data availability
This study utilized publicly available data for analysis. This study utilized four colorectal cancer datasets: the TCGA-CRC dataset, GSE132465 dataset, GSE39582 dataset, and GSE17538 dataset. All datasets are freely accessible and available for download. For any additional data requests or inquiries related to this study, please contact the corresponding author.
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Funding
This work was supported by The Youth Project of Shandong Provincial Natural Science Foundation (No. ZR2024QH655 and No. ZR2023QH414).
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L.M., W.L., and H.G. conceptualized and designed the study. E.L., S.Z., L.Z. and Z.L. interpreted the data. S.Z. and Q.G. conducted the experiment. L.M. and W.L. draft the initial manuscript. W.L., Z.L. and H.G. revised the manuscript.
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Ma, L., Luo, W., Liu, E. et al. Deciphering oxidative stress-related heterogeneity and developing a prognostic signature for colorectal cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46560-4
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DOI: https://doi.org/10.1038/s41598-026-46560-4
