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

Area of Science:

• Environmental Health
• Hepatology
• Endocrinology

Background:

• Metabolically dysfunction-associated steatotic liver disease (MASLD) is increasing globally, with factors beyond obesity, diet, and genetics implicated.
• Endocrine-disrupting chemicals (EDCs) are emerging as key environmental contributors to MASLD pathogenesis.
• EDCs can disrupt hepatic transcriptional and metabolic networks, influencing liver health.

Purpose of the Study:

• To review the molecular mechanisms by which EDCs interact with hepatic metabolic regulation in MASLD.
• To propose the "hepato-exposome axis" framework linking EDCs to nuclear receptors and metabolic pathways.
• To highlight EDCs as environmental modifiers of MASLD progression.

Main Methods:

• Literature review focusing on EDC classes (pesticides, bisphenols, phthalates, PFAS, etc.) and their impact on liver metabolism.
• Integration of data on hepatic metabolic and xenobiotic pathways, emphasizing nuclear receptors (AhR, PXR, CAR, PPARs, FXR, LXRs, RXR).
• Analysis of in vivo and in vitro studies detailing EDC effects on lipogenesis, glucose metabolism, mitochondrial function, and inflammation.

Main Results:

• Specific EDC families imprint overlapping molecular signatures on key metabolic and inflammatory pathways in the liver.
• EDCs promote a pro-steatotic and pro-inflammatory hepatic environment, contributing to MASLD.
• The
• hepato-exposome axis
• framework effectively maps EDC actions to nuclear receptors and metabolic disruption.

Conclusions:

• EDCs are significant environmental contributors to MASLD, acting through nuclear receptor-mediated pathways.
• Factors like exposure timing, mixtures, and sex-specific responses modulate EDC impact on MASLD.
• Further research priorities include mixture toxicology, exposome profiling, and biomarker discovery to address the EDC-MASLD link.