ArticleFrontiers in toxicology2026
Genetic evidence and multi-omics characterization of DEHP-relevant detoxification and metabolic heterogeneity in hepatocellular carcinoma.
Article in Frontiers in toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Human evidence linking di(2-ethylhexyl) phthalate (DEHP) exposure to hepatocellular carcinoma (HCC) is limited, and it remains unclear whether DEHP-relevant detoxification biology captures clinically meaningful HCC heterogeneity. Methods: We integrated two-sample Mendelian randomization, proteomic and phosphoproteomic subtyping, bulk, single-cell and spatial transcriptomics, computational candidate prioritization, molecular docking, and cell-based assays. Genetically proxied MECPP and MEHHP were evaluated for associations with HCC and liver-related outcomes. DPTS-related molecular, cellular, spatial, and experimental patterns were then characterized. Results: MR did not support a causal association of genetically proxied MECPP or MEHHP with HCC. In 165 CPTAC tumors, consensus clustering identified two detoxification-phosphorylation tumor subtypes. Compared with DPTS1, DPTS2 showed coordinated suppression of xenobiotic metabolism, bile acid metabolism, fatty-acid oxidation, phase II conjugation, and transport programs. A transcriptomically projected DPTS2-like state was associated with poorer overall survival in TCGA-LIHC, but this association was not replicated in ICGC-LIRI-JP. Single-cell and spatial analyses localized these programs mainly to hepatocyte-like compartments and showed modest spatial coordination with nine prioritized genes, including ALDH2, EHHADH, and PCK2. LINCS-based screening and molecular docking prioritized PD-0325901, trametinib, and regorafenib, but these predictions did not demonstrate binding or efficacy, and the compounds were not tested experimentally. Basal qPCR and DEHP-treatment experiments showed cell-line-specific expression and phenotypic responses. Conclusion: DPTS defines a DEHP-relevant, detoxification-suppressed HCC molecular phenotype rather than an exposure-defined or DEHP-induced subtype. These findings provide a bounded framework for future mechanistic validation of metabolic vulnerability in HCC.
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