RAGE Signalling in Acute Inflammatory Disorders: Therapeutic Potential of Natural Products

Acute inflammatory disorders, including acute lung injury, acute pancreatitis, ischaemia-reperfusion injury, and sepsis, are major clinical challenges characterised by rapid progression, a characteristic cytokine storm, and high mortality rates. The receptor for advanced glycation end-products (RAGE) serves as a pivotal multi-ligand pattern recognition receptor that integrates PAMPs and DAMPs. Excessive RAGE engagement triggers detrimental signalling cascades, notably NF-κB and MAPKs, which exacerbate hyperinflammation and lead to progressive organ dysfunction. Consequently, the RAGE axis represents a potent therapeutic target for mitigating hyperinflammation and improving clinical outcomes in acute inflammatory disorders. While initial pharmacological efforts focused on synthetic inhibitors and biologics, there is a shifting focus toward bioactive alternatives with high safety profiles. Here, we present recent molecular insights into RAGE-mediated pathogenesis in acute inflammatory disorders and evaluate current therapeutic strategies. Furthermore, we emphatically summarise the bioactive natural products, including terpenoids, flavonoids, alkaloids, and a xanthone, that prevent and treat acute inflammatory disorders by disrupting RAGE-ligand interactions and suppressing downstream oxidative stress and cytokine release. Integrating these molecular mechanisms with the pharmacological profiling of natural RAGE modulators provides a robust foundation for the development of next-generation therapeutic strategies to improve clinical outcomes in acute inflammatory disorders.