Reversal of amino acid metabolism patterns between circulating blood and tumors as a new biomarker for the Zhengxu Xieshi syndrome in patients with esophageal squamous cell carcinoma.

Objective: To uncover the biological foundation of the prevailing TCM syndrome in individuals with Esophageal squamous cell carcinoma (ESCC), Zhengxu Xieshi (ZXXS), which is characterized by a deficiency in vital Qi and an excess in evil Qi.

Methods: We investigated shifts in vital Qi by quantifying systemic metabolic changes in the peripheral blood. Serum metabolomic profiling was conducted on the ESCC cohort 1 along with a matched healthy control cohort. Additionally, we assessed changes in evil Qi by examining metabolic perturbations in ESCC tissues. This analysis involved metabolomic and proteomic surveys of ESCC tissues and paired normal adjacent tissues as controls in an independent ESCC cohort 2.

Results: Serum metabolomic profiling highlighted the prevalent downregulation of differentially expressed metabolites in patient sera, in contrast to the upregulation observed in ESCC tissues, compared to their respective controls. Remarkably, the group of differential metabolites in the ESCC tissues was predominantly composed of amino acids. Thus, we focused on amino acid metabolism. Our integrative analysis showed the downregulation of a significant majority of disturbed amino acids in patient sera relative to the upregulation of an overwhelming proportion of perturbed amino acids within ESCC tissues. Enrichment analysis of these amino acids revealed seven metabolic pathways that contribute to the metabolism of antioxidants, energy intermediates, and biosynthetic precursors. Interestingly, these pathways displayed attenuation in patient sera but augmentation in ESCC tissues. Similarly, the proteomic data confirmed the activation of these pathways in ESCC tissues.

Conclusion: This study presents a new perspective on the prevalence of ZXXS syndrome in patients with ESCC, contextualized within the realm of metabolic reprogramming. Specifically, diminished amino acid metabolism in the circulating blood corresponds to a deficiency in vital Qi. Conversely, hyperactive amino acid metabolism in ESCC tissues signifies an augmentation of local evil Qi. These findings hold potential to enrich the current medical framework and offer a deeper understanding of ESCC management by integrating the principles of ZXXS syndrome.