Modulating the AGE-RAGE Signaling Pathway in Degenerative Processes: Molecular Mechanisms and Therapeutic Prospect of Phytochemicals

The Receptor for Advanced Glycation End Products (RAGE) is a multifunctional cell-surface receptor capable of binding a broad range of ligands, including advanced glycation end products (AGEs). While RAGE is constitutively expressed in various tissues, AGEs arise from non-enzymatic reactions between reducing sugars and proteins, lipids, or nucleic acids. The AGE–RAGE interaction activates multiple redox-sensitive and pro-inflammatory signaling pathways, thereby contributing significantly to ageing, chronic inflammatory conditions, and metabolic degenerative diseases. Consequently, targeting the AGE–RAGE axis has become an important focus of contemporary biomedical research. Although substantial progress has been made in elucidating this pathway and developing synthetic AGE–RAGE inhibitors, many of these agents present limitations related to safety, bioavailability, or therapeutic efficacy. Phytochemicals such as polyphenols, alkaloids, and tannins have exhibited promising antiglycation, antioxidant, and anti-inflammatory activities that may attenuate AGE–RAGE mediated cellular dysfunction. However, direct evidence of their capacity to inhibit RAGE at the receptor level remains limited. This review identifies critical knowledge gaps and demonstrates that structure-guided computational modeling combined with targeted experimental validation represents a promising strategy for the rational development of phytochemical-based RAGE modulators. These findings highlight the potential of natural products as safer and mechanistically informed therapeutic candidates for attenuating AGE–RAGE-mediated degenerative disease progression.