The hepato-exposome axis: How endocrine disruptors hijack liver receptors to drive MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide at a pace that cannot be fully explained by obesity, diet, or genetics alone. Emerging evidence provides mechanistic insight into how defined endocrine-disrupting chemicals (EDCs) rewire hepatic transcriptional and metabolic networks relevant to MASLD. This review focuses on the molecular interfaces through which major EDC families intersect with hepatic metabolic regulation. We propose the "hepato-exposome axis" as a receptor-centric framework that maps specific EDC classes to nuclear receptors (NRs) and key metabolic pathways involved in lipid metabolism, glucose homeostasis, mitochondrial function, and inflammatory signalling that are implicated in MASLD progression. We summarise key EDC groups linked to liver disease, including organochlorine pesticides, pyrethroids, bisphenols, phthalates, organophosphate esters, and per- and polyfluoroalkyl substances (PFAS). We then integrate current understanding of hepatic metabolic and xenobiotic pathways in homeostasis and MASLD, emphasising xenobiotic-sensing and metabolic NRs (AhR, PXR, CAR, PPARs, FXR, LXRs, RXR) as convergence points for EDC action. Drawing on in vivo and in vitro studies, we show that distinct EDC families imprint overlapping molecular signatures onto pathways that control de novo lipogenesis, β-oxidation, glucose handling, antioxidant defences, and inflammatory/immune signalling, collectively fostering a pro-steatotic and pro-inflammatory hepatic milieu. We further discuss vulnerable populations, critical windows of exposure, mixture effects, and sex-specific responses, positioning EDCs as environmental modifiers of the MASLD trajectory across the life course. Finally, we outline priorities for mechanistic and translational research, including mixture toxicology, multi-omics exposome profiling, and biomarker discovery, to better quantify and mitigate endocrine disruptors' contribution to the global MASLD burden.