Metabolic reprogramming-associated genomic instability drives colorectal cancer progression via the UBXN1-NF-κB axis.

Colorectal cancer (CRC) is a common malignancy in clinical practice, and its treatment is greatly challenged by tumor heterogeneity. The most prominent features of CRC heterogeneity are differences in metabolic states and genomic instability, which ultimately lead to unfavorable clinical outcomes. Based on this, the present study aimed to investigate the association between metabolic reprogramming and copy number variation (CNV) in CRC using single-cell datasets. By integrating four publicly available single-cell RNA sequencing datasets, a comprehensive single-cell atlas of CRC was constructed. Subsequently, epithelial cells were specifically analyzed, and consensus non-negative matrix factorization (cNMF) was applied to identify six gene expression programs, covering functional modules such as cell cycle, metabolism, inflammatory stress, and immune interaction. Genomic instability was assessed using the inference of copy number variations (InferCNV) analytical tool, which identified malignant epithelial cells characterized by large-scale CNVs. Meanwhile, metabolic pathway activity at the single-cell level was evaluated using the area under the curve cell (AUCell) method, and predictive performance was further assessed using machine learning algorithms. The results demonstrated that metabolic features could effectively predict the malignant state defined by CNVs, achieving an area under the curve (AUC) of 0.985, with protein metabolism and TP53-related pathways contributing most significantly. Further integrative analysis identified 13 metabolism-related genes associated with clinical prognosis, among which UBXN1 was identified as a central node in the protein-protein interaction network. Functional analysis of UBXN1 revealed that it suppresses the NF-κB signaling pathway, thereby regulating the malignant phenotype of CRC cells. In conclusion, this study systematically elucidates the critical link between metabolic features and genomic instability in CRC, suggesting that UBXN1 may serve as a potential therapeutic target.