A Multi-PTM omics atlas uncovers novel aging regulators in colorectal cancer

Aging is a key driver of colorectal cancer (CRC) progression, yet the post-translational modification (PTM) landscape associated with aging in CRC remains largely uncharacterized. In particular, the coordinated influence of multiple PTMs-such as phosphorylation, ubiquitination, and malonylation-on aging-related pathways has not been systematically explored.

In this study, we established a CRC-specific multiomics framework by profiling phosphorylation, malonylation, and ubiquitination in matched tumor and adjacent normal tissues (n = 8 pairs). The differentially modified proteins were subjected to functional enrichment, protein-protein interaction (PPI) network construction, structural mapping, and aging pathway annotation. Key regulatory axes were reconstructed through integration of GO, KEGG, and literature-based evidence.

Aging-related PTMs were extensively dysregulated in CRC, with 162 ubiquitination sites, 64 phosphorylation sites, and 68 malonylation sites altered. LMNB1 has emerged as a multi-PTM protein, indicating coordinated control of the nuclear structure during senescence. PPI network analysis highlighted CDK1, SOD2, and MAPK1 as potential hub PTM-regulated nodes involved in the aging program of CRC. An integrated signaling model further demonstrated how PTM-mediated suppression of the EGFR-RAS axis, along with activation of the p38 and p53 pathways, collectively contributes to shaping the aging phenotype in CRC.

This study presents the first integrative network map of aging regulation in CRC based on multiple PTMs. Notably, hub proteins such as LMNB1 have emerged as key regulatory targets. These findings provide a theoretical foundation for the development of aging-cancer axis-related biomarkers and therapeutic strategies for CRC.