Pharmaco-therapeutic modulation of the Glo1-Nrf2-RAGE functional network in chronic inflammation: polyphenols in the context of current anti-inflammatory therapy.

Chronic inflammation is a central driver of numerous disorders, including metabolic, cardiovascular, neurodegenerative, autoimmune, and malignant diseases. Although current anti-inflammatory pharmaco-therapeutic strategies, including nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressants, disease-modifying antirheumatic drugs, and biologic agents, can reduce inflammatory burden and improve clinical outcomes, their long-term use is often limited by adverse effects, incomplete disease control, treatment resistance, and poor correction of upstream oxidative and glycation-related mechanisms. In this context, the interconnected Glo1-Nrf2-RAGE network has emerged as a pharmacologically relevant framework that links carbonyl stress, oxidative injury, and inflammatory signal amplification in chronic diseases. This review examines the therapeutic significance of this axis and evaluates polyphenolic compounds as emerging modulators of Glo1-, Nrf2-, and RAGE-associated pathways. Polyphenols such as curcumin, epigallocatechin gallate, resveratrol, and related phenolics exhibit anti-inflammatory effects in preclinical models by enhancing antioxidant defense, attenuating AGE-RAGE signaling, and reducing pro-inflammatory mediators. However, their clinical translation remains constrained by poor bioavailability, variable pharmacokinetics, lack of dose standardization, and limited human evidence. Positioning polyphenols within the broader landscape of anti-inflammatory therapy helps clarify their current value as adjunctive modulators or lead structures for future therapeutic development targeting chronic inflammation.