Altered glucocorticoid receptor signaling leading to MASLD progression via insulin resistance-associated endoplasmic reticulum stress

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). 

his adverse outcome pathway (AOP) describes a mechanistic sequence linking altered glucocorticoid receptor (GR) signaling to the progression of metabolic dysfunction–associated steatotic liver disease (MASLD) through insulin resistance–associated endoplasmic reticulum (ER) stress. Disruption of GR signaling promotes systemic insulin resistance, enhanced adipose lipolysis, and increased hepatic free fatty acid (FFA) influx, resulting in hepatocellular lipotoxicity. Lipid overload and impaired insulin signaling induce ER stress, triggering unfolded protein response activation, hepatocyte injury, and inflammatory signaling. Subsequent activation of Kupffer cells, hepatic stellate cells, and TGF-β–mediated profibrotic pathways drives collagen deposition, fibrosis, and progression to cirrhosis. This AOP provides a biologically plausible and regulatory-relevant framework for identifying endocrine-disrupting chemicals (EDCs) that promote MASLD progression through GR-mediated insulin resistance and ER stress pathways.

Endoplasmic reticulum (ER) stress is a central cellular stress response implicated in the progression from simple steatosis to steatohepatitis and fibrosis. In hepatocytes, insulin resistance, lipid overload, and disrupted metabolic signaling converge on the ER, overwhelming protein folding capacity and activating maladaptive unfolded protein response pathways. Chronic ER stress promotes hepatocyte injury, inflammatory signaling, and fibrogenesis.

Glucocorticoid receptor (GR) signaling plays a key role in metabolic homeostasis, insulin sensitivity, and lipid flux regulation. Altered GR signaling—whether due to dysregulation or chemical interference—can induce systemic insulin resistance, increased adipose lipolysis, and hepatic lipid influx, thereby promoting ER stress. This AOP was developed to explicitly capture ER stress as a mechanistically distinct and biologically important mediator linking GR dysregulation to MASLD progression.

The AOP was developed using an expert-driven conceptual framework supported by targeted literature evaluation across endocrinology, metabolism, ER stress biology, and chronic liver disease. Initial scoping identified insulin resistance–associated ER stress as a recurring mechanistic feature in experimental and clinical MASLD progression.

Focused literature searches were conducted to identify evidence supporting:

• GR signaling perturbation and systemic insulin resistance

• Adipose lipolysis and hepatic FFA influx

• Induction of ER stress by lipid overload and insulin resistance

• ER stress–mediated hepatocyte injury and inflammatory activation

• Fibrogenic signaling driven by TGF-β and hepatic stellate cell activation

Evidence from human studies, animal models, and mechanistic in vitro systems was prioritized, with emphasis on chronic and low-dose perturbations relevant to endocrine disruption.

This AOP is biologically plausible and supported by moderate to strong empirical evidence linking insulin resistance, ER stress, and progressive liver injury. The sequence of key events reflects conserved cellular stress and inflammatory mechanisms observed across mammalian species and aligns with established pathological features of MASLD progression.

The AOP is particularly relevant for hazard identification and prioritization of chemicals that interfere with GR signaling and metabolic regulation but may not directly target mitochondrial pathways. It is well suited for integration into AOP networks describing multiple converging routes to MASLD.

This AOP may support:

• Identification of GR-modulating chemicals that induce ER stress–mediated liver injury

• Integration of ER stress biomarkers into MASLD-relevant testing strategies

• Complementary assessment of non-mitochondrial stress pathways in MASLD

• AOP network development capturing converging intracellular stress responses