Abstract Sodium dehydroacetate (DHA-S) poses an escalating, yet systematically uncharted, cancer threat to populations increasingly exposed through globalized 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, etc.) were extracted from the PPI network. 29 core targets intersecting the KEGG “Pathways in Cancer” (hsa05200) were docked to DHA-S (Autodock Vina) and interrogated across 33 TCGA tumors. Prognostic modeling integrated data from multiple GEO cohorts (GSE147352, GSE53757, GSE114445, 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 (p0.001), linked to PI3K-AKT, ERBB signaling, 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 signaling pathways under cumulative effects. Future studies should promote well-designed human epidemiological surveillance on DHA-S.
Xu et al. (Sat,) studied this question.