What is it about?
High Mobility Group Box 1 (HMGB1) and S100 proteins are major ligands of Receptor for Advanced Glycation End-products (RAGE) and have causal roles in endometriosis lesions. Yet the AGE-RAGE pathway that unifies Advanced Glycation End-products (AGEs) with these ligands has not been assessed in endometriosis. In diabetes, atherosclerosis, and chronic kidney disease, AGE-RAGE links insulin resistance and oxidative stress to inflammation, fibrosis, and organ harm.Endometriosis shares key drivers of AGE accumulation, including insulin resistance, oxidative stress, and chronic inflammation. Endometriosis is also linked to higher vascular risk and arterial stiffness. We asked whether AGE-RAGE could bridge metabolic stress to pelvic lesions and systemic risk. We did a focused review of mechanisms and an evidence map of studies on AGEs, RAGE, or known RAGE ligands in endometriosis. We grouped findings as most consistent with a driver, amplifier, consequence, or parallel role. We included 29 studies across human samples, cell systems, and animal models. Few studies measured AGE adducts directly.
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Photo by Helio E. López Vega on Unsplash
Why is it important?
Most work tracked RAGE ligands (mainly HMGB1 and S100 proteins) and downstream immune and angiogenic programs. Across models, this pattern fits best with a self-reinforcing loop after lesions form. RAGE expression often aligned with lesion remodeling, especially fibrosis. Blood and skin readouts of AGE burden were mixed and varied by cohort and sample type. A central gap is receptor proof. Many models point to shared Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB) signaling, but few test RAGE dependence. Overall, current evidence supports AGE-RAGE as a disease-amplifying loop involved in chronic inflammation and fibrosis rather than an initiating trigger. Its effects likely vary by stage and site.
Perspectives
Priorities now include direct lesion AGE measurement, paired systemic-pelvic sampling over time, receptor-level studies, and trials testing diet or drug interventions against clear endpoints. Outcomes could include fibrosis, angiogenesis, immune state, pain, and oocyte and follicle function.
Dr Salvatore Cortellino
Scuola Superiore Meridionale
Read the Original
This page is a summary of: The AGE–RAGE Pathway in Endometriosis: A Focused Mechanistic Review and Structured Evidence Map, International Journal of Molecular Sciences, January 2026, MDPI AG,
DOI: 10.3390/ijms27031396.
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