Exploring the risk of sodium dehydroacetate in tumours: a multi-omics investigation from network toxicology to clinical proteomics

Abstract Sodium dehydroacetate (DHA-S) poses an escalating, yet systematically uncharted, cancer threat to populations increasingly exposed through globalised food chains. We integrated network toxicology, pan-cancer multi-omics, and clinical validation to map DHA-S carcinogenicity. 305 cross-targets were mined from PharmMapper, CTD, and SwissTargetPrediction. 61 high-centrality nodes (AKT1, SRC, EGFR, and so on) were extracted from the protein–protein interaction network. 29 core targets intersecting the KEGG “Pathways in Cancer” (hsa05200) were docked to DHA-S (Autodock Vina) and interrogated across 33 TCGA tumours. Prognostic modelling integrated data from multiple Gene Expression Omnibus cohorts (GSE147352, GSE53757, GSE114445, and GSE62452) and the Human Protein Atlas. The analysis revealed that DHA-S docks with HRAS/HSP90AA1 and six oncoproteins. It also demonstrated a pan-cancer pattern of AKT1/HSP90AA1 overexpression alongside PTGS2/ESR2 repression. Furthermore, dysregulation of these targets in LGG, KIRC, SKCM, and PAAD was associated with poor survival (p < .001), linked to PI3K-AKT, ERBB signalling, and immune-evasion pathways as validated by IHC. These findings implicate DHA-S in multi-target, pathway-driven oncogenesis. This study, through multiple approaches such as data mining, network toxicology, molecular docking, and clinical sample analysis, explored the possibility that DHA-S may be associated with the risk of LGG, KIRC, SKCM, and PAAD through multiple targets and signalling pathways under cumulative effects. Future studies should promote well-designed human epidemiological surveillance on DHA-S.