Integrated Spatial Metabolomics and Transcriptomics Decipher the Effect of Chronic Stress on the Progression of Liver Cancer.

Liver cancer is a major global health issue and one of the leading causes of cancer-related deaths worldwide. Its pathogenesis exhibits significant pathological associations with chronic stress-specifically, abnormalities in immune function, metabolism, and microcirculation. However, the mechanisms by which chronic stress influences liver cancer progression remain incompletely understood. In this study, morphological observation, histopathological analysis, and biochemical parameter measurements were used to evaluate the effects of chronic stress on liver cancer progression. A multi-omics strategy combining spatial metabolomics and transcriptomics was applied to systematically decipher the mechanism by which chronic stress affects liver cancer progression. The results showed that chronic stress exacerbates liver histopathological damage and liver function impairment, promotes tumor growth, and aggravates hypothalamic-pituitary-adrenal (HPA) axis dysfunction, immune dysfunction, and energy metabolism disorders in liver cancer model rats. Spatial metabolomics analysis based on Desorption electrospray ionization mass spectrometry (DESI-MSI) revealed that palmitoylcarnitine was significantly altered by chronic stress in the context of liver cancer. Furthermore, transcriptome analysis revealed 377 differentially expressed genes, most of which were enriched in the PPAR signaling pathway. Integrated multi-omics analysis and Western blot analysis results revealed that chronic stress exacerbates liver cancer progression through HIF-1α/PPARα-mediated fatty acid metabolic dysregulation.