Dioxin-associated hepatocarcinogenesis: Multi-omics biomarkers, mechanistic pathways, and translational challenges

Hepatocellular carcinoma represents a poorly monitored axis of hepatocarcinogenesis in clinical laboratory medicine, which may be induced by occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).Traditional surveillance using alphafetoprotein is only 39%-64% sensitive for early-stage disease and has not been tested in occupational cohorts exposed to dioxin.There is a growing need for mechanisminformed serum biomarker strategies.This narrative review systematically evaluates the analytical evidence for serum biomarkers associated with TCDD-induced hepatocarcinogenesis that are detectable in human body fluids, encompassing metabolomics, proteomics, and epigenomics.The diagnostic performance, preanalytical requirements, and interlaboratory harmonization status of candidate analytes, including bile acid profiles, lysophosphatidylcholines, azelaic acid monoesters, multiprotein MRM-MS panels, DNA methylation clock indices, and circulating lncRNAs, were assessed.A conceptual, unvalidated three-tiered occupational surveillance algorithm was developed that combined the use of routine hepatic enzyme panels, high-resolution serum TCDD quantification, and confirmatory multi-omics testing.Even though pre-analytical standardization, certified reference materials, and validation according to ISO 15189 are available, there are still important translation gaps before clinical use.The findings present a conceptual clinical chemistry framework, not a clinically validated model, designed for the early detection and risk stratification of populations occupationally exposed to dioxins, focusing on the potential development of hepatic carcinogenesis.