Integrative Analysis of 4-Hydroxynonenal-Modified Proteins and Plasma Metabolome in Breast Cancer Patients

Breast cancer is a highly heterogeneous malignancy, characterized by diverse genetic, epigenetic, and phenotypic variations, as well as by metabolic reprogramming and oxidative stress. Lipid peroxidation bioactive product 4-hydroxynonenal (4-HNE) plays a significant role in the development and progression of cancer. In this study, we quantified circulating 4-HNE-modified proteins and performed comprehensive untargeted metabolomic profiling of the patients' plasma using LC-ESI-QTOF-MS and GC-EI-QMS, aiming to investigate systemic metabolic pathways associated with oxidative damage in breast cancer. Significantly elevated levels of 4-HNE-modified proteins were detected in breast cancer patients compared to healthy controls, accompanied by distinct metabolomic signatures enriched in lipid metabolism. Several metabolites, including specific long-chain fatty acids, exhibited significant correlations with circulating 4-HNE-modified proteins, suggesting an interaction between lipid peroxidation-driven protein modification and breast cancer-associated metabolic reprogramming. Overall, this study provides evidence of associations between systemic 4-HNE-mediated protein modification and altered metabolic profiles in breast cancer, highlighting oxidative stress-related metabolites as potential biomarkers and pointing to redox-metabolic crosstalk in breast cancer patients.