Altered glucocorticoid receptor signaling leading to MASLD progression via insulin resistance-associated mitochondrial dysfunction

You Song¹, Jorke H. Kamstra², Matej Oresic^3,4

¹ Norwegian Institute for Water Research, Økernveien 94, Oslo, Norway

² Utrecht University, Institute for Risk Assessment Sciences (IRAS), Utrecht, the Netherlands

³ Örebro University, School of Medical Sciences, Örebro, Sweden

⁴ University of Turku, Turku Bioscience Centre, Turku, Finland

Acknowledgement: This project was supported by the “Investigation of endocrine-disrupting chemicals as contributors to progression of metabolic dysfunction-associated steatotic liver disease” (EDC-MASLD) consortium funded by the Horizon Europe Program of the European Union (Grant Agreement 101136259). 

This adverse outcome pathway (AOP) describes a mechanistically coherent sequence linking altered glucocorticoid receptor (GR) signaling to the progression of metabolic dysfunction–associated steatotic liver disease (MASLD), including steatosis, steatohepatitis (MASH), fibrosis, and cirrhosis. The pathway integrates endocrine disruption–induced perturbations in GR signaling with systemic insulin resistance, dysregulated adipose lipolysis, increased hepatic free fatty acid (FFA) influx, hepatocellular lipotoxicity, mitochondrial dysfunction, oxidative stress, and inflammatory and fibrogenic responses within the liver. Downstream activation of Kupffer cells, hepatic stellate cells, and TGF-β signaling drives extracellular matrix deposition and fibrotic remodeling, culminating in advanced liver disease outcomes. This AOP is particularly relevant for the identification and prioritization of endocrine-disrupting chemicals (EDCs) that interfere with GR signaling and contribute to MASLD progression, supporting its application in screening, hazard identification, and the development of integrated testing strategies.

MASLD is a highly prevalent chronic liver disease driven by metabolic dysfunction, insulin resistance, and lipotoxic stress, with increasing evidence that endocrine signaling perturbations play a critical upstream role. Glucocorticoid receptor (GR) signaling is central to the regulation of glucose and lipid metabolism, adipose tissue lipolysis, mitochondrial function, and inflammatory responses. Dysregulation of GR signaling—whether through chronic activation, impaired feedback control, or chemical interference—has been linked to systemic insulin resistance and altered lipid fluxes that place a metabolic burden on the liver.

This AOP was developed to capture the biological plausibility and mechanistic continuity between altered GR signaling and MASLD progression, with a specific emphasis on insulin resistance–associated mitochondrial dysfunction as a unifying driver of disease advancement. The pathway reflects clinically relevant disease stages and aligns with regulatory interest in identifying upstream endocrine-mediated mechanisms contributing to chronic metabolic liver disease.

The development of this AOP was informed by expert-driven scoping combined with targeted literature evaluation across endocrinology, metabolic disease, toxicology, and hepatology. Initial pathway framing was based on well-established physiological roles of GR signaling in metabolic homeostasis and on clinical and experimental evidence linking glucocorticoid dysregulation to insulin resistance and fatty liver disease.

Focused literature searches were conducted to identify evidence supporting individual key events (KEs) and key event relationships (KERs), including:

• Altered GR signaling and insulin resistance

• Adipose tissue lipolysis and hepatic FFA influx

• Hepatocellular lipotoxicity and mitochondrial dysfunction

• Oxidative stress, cell injury, and inflammatory activation

• Fibrogenic signaling pathways and disease stage progression

Priority was given to peer-reviewed human, animal, and mechanistic in vitro studies demonstrating causal or concordant relationships between upstream and downstream events. Evidence was screened for biological plausibility, consistency across models, and relevance to regulatory toxicology and EDC assessment.

This AOP is biologically plausible and supported by a substantial body of empirical evidence linking endocrine disruption, insulin resistance, mitochondrial dysfunction, and MASLD progression. The sequence of events reflects conserved metabolic and inflammatory processes observed across species, with strong concordance between experimental models and human disease pathology.

The AOP is well-suited for regulatory applications focused on hazard identification and prioritization, particularly for chemicals that modulate GR signaling but may not induce overt liver toxicity in short-term assays. While quantitative understanding varies across individual KERs, the overall weight of evidence supports the use of this AOP in integrated testing and assessment frameworks rather than as a stand-alone risk assessment tool.

This AOP may support:

• Screening and prioritization of GR-modulating chemicals as potential MASLD contributors

• Development of integrated testing strategies combining endocrine, metabolic, and hepatic endpoints

• Grouping and read-across of EDCs with shared GR-mediated modes of action

• Identification of high-value key events for assay development and refinement