Abstract Description

Metabolomics studies in cancer typically focus on identifying lists of dysregulated molecules, often overlooking the global, systems-level changes in the chemical properties of the metabolome. This approach may miss a higher level of organization in the metabolic reprogramming that defines cancer. This study moves beyond individual biomarkers to characterize the systemic shifts in the chemical and regulatory landscape of colorectal cancer in Homo sapiens, seeking to identify a global "chemical signature" of the disease. The central hypothesis is that the collective physicochemical and quantum-mechanical properties of the metabolome are systematically altered during carcinogenesis and that these shifts are orchestrated by master transcriptional regulators. A publicly available, untargeted metabolomics dataset (MTBLS8090) from 35 paired colorectal cancer (CRC) and adjacent normal tissues was used as the foundation for this analysis. A systems-level chemoinformatic pipeline was developed to enrich the data by programmatically calculating an extensive set of physicochemical and quantum-mechanical (GFN2-xTB) descriptors for statistically significant metabolites. This enriched dataset was then integrated with transcriptomic data from the TCGA-COAD cohort to infer pathway and transcription factor (TF) activities. This allowed for the correlation of upstream regulatory events with downstream shifts in the chemical properties of the metabolome. The analysis revealed a distinct, global chemical signature of CRC. Metabolites that are up-regulated in CRC tissues tend to have, on average, higher molecular complexity and larger dipole moments. Conversely, down-regulated metabolites exhibit higher HOMO energies and a greater fraction of sp ^3hybridized carbons, indicating they are more saturated and electronically distinct. It was further demonstrated that the most dysregulated biological pathways, such as Retinol metabolism and Glycine metabolism, possess unique "chemical personalities" defined by the average properties of their constituent molecules. Finally, these chemical profiles were successfully linked to the activity of master TFs like SP1 and PPARG, whose metabolic targets exhibit divergent structural and electronic properties. A systems-level analysis of the chemical properties of the metabolome reveals a higher-order layer of organization in the metabolic reprogramming of colorectal cancer. The identification of a global chemical signature of the disease, and the linking of these signatures to specific pathways and regulators, provides novel insights into the fundamental chemical strategies employed by cancer cells and establishes a new, property-based direction for future systems biology research.