The AGE-RAGE Pathway in Endometriosis: A Focused Mechanistic Review and Structured Evidence Map

Area of Science:

• Endocrinology and Metabolism
• Reproductive Immunology
• Pathology

Background:

• Endometriosis lesions involve High Mobility Group Box 1 (HMGB1) and S100 proteins, ligands of the Receptor for Advanced Glycation End-products (RAGE).
• The Advanced Glycation End-products (AGE)-RAGE pathway links metabolic stress (insulin resistance, oxidative stress) to inflammation and fibrosis in other diseases.
• Endometriosis shares drivers of AGE accumulation and is associated with vascular risk, suggesting a potential role for AGE-RAGE.

Purpose of the Study:

• To assess the role of the AGE-RAGE pathway in endometriosis.
• To determine if AGE-RAGE bridges metabolic stress to pelvic lesions and systemic vascular risk.
• To map existing evidence on AGEs, RAGE, and RAGE ligands in endometriosis.

Main Methods:

• Focused review of mechanisms and an evidence map of 29 studies.
• Studies included human samples, cell systems, and animal models.
• Findings were categorized as driver, amplifier, consequence, or parallel role.

Main Results:

• Evidence suggests AGE-RAGE acts as a self-reinforcing loop amplifying inflammation and fibrosis after endometriosis lesions form.
• RAGE expression correlated with lesion remodeling, particularly fibrosis.
• Direct AGE measurement in lesions is limited; RAGE dependence in shared TLR4/NF-κB signaling requires further investigation.

Conclusions:

• The AGE-RAGE pathway is likely a disease amplifier in endometriosis, contributing to chronic inflammation and fibrosis.
• Its role may vary by disease stage and location.
• Future research should focus on direct AGE measurement, longitudinal sampling, receptor-level studies, and intervention trials.