The Hepato-Exposome Axis: How Endocrine Disruptors Hijack Liver Receptors to Drive MASLD
Abstract
Metabolically dysfunction-associated steatotic liver disease (MASLD) is rising worldwide at a pace that cannot be fully explained by obesity, diet, or genetics alone. Emerging evidence supports a mechanistic dissection of 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 that regulate lipid metabolism, glucose homeostasis, mitochondrial dysfunction and inflammatory signalling 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.
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BibTeX
@article{martingrau2026hepatoexposome,
title = {{The Hepato-Exposome Axis: How Endocrine Disruptors Hijack Liver Receptors to Drive MASLD}},
author = {M. Martín-Grau and J.H. Kamstra and T. Hyötyläinen and M. Orešič and Y. Song and N. Veličković and A. Djordjevic and D. Vojnović Milutinović and R.F. Jackson and R. van Vorstenbosch and J. Massart and A. Vidal-Puig and S. Carobbio},
journal = {Journal of Hepatology},
year = {2026},
month = oct,
doi = {10.1016/j.jhep.2026.06.021},
url = {https://hal.science/hal-05679115v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The Hepato-Exposome Axis: How Endocrine Disruptors Hijack Liver Receptors to Drive MASLD
AU - M. Martín-Grau
AU - J.H. Kamstra
AU - T. Hyötyläinen
AU - M. Orešič
AU - Y. Song
AU - N. Veličković
AU - A. Djordjevic
AU - D. Vojnović Milutinović
AU - R.F. Jackson
AU - R. van Vorstenbosch
AU - J. Massart
AU - A. Vidal-Puig
AU - S. Carobbio
PY - 2026
DA - 2026/10/23
JO - Journal of Hepatology
DO - 10.1016/j.jhep.2026.06.021
UR - https://hal.science/hal-05679115v1
AB - Metabolically dysfunction-associated steatotic liver disease (MASLD) is rising worldwide at a pace that cannot be fully explained by obesity, diet, or genetics alone. Emerging evidence supports a mechanistic dissection of 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 that regulate lipid metabolism, glucose homeostasis, mitochondrial dysfunction and inflammatory signalling 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.
SN - 0168-8278
SN - 1600-0641
ER -