Receptor for advanced glycation end-product in ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) serves as a pivotal pathological mechanism underlying tissue damage in diverse clinical scenarios, particularly in organ transplantation, and cardiovascular surgery. A key factor in this process is the inflammatory response triggered by the receptor for advanced glycation end-products (RAGE). Emerging evidence reveals that dual roles of RAGE signaling: while the canonical AGEs-RAGE axis drives inflammation, RAGEexhibits ligand- and concentration-dependent pleiotropy, it is now considered a pattern recognition receptor which recognize not only a range of DAMPs, but also PAMPs, modulating divergent downstream pathways that either exacerbate or attenuate inflammatory responses. For instance, S100A6 and S100A12 as well as HMGB1, after being secreted from intracellular space, would interact with RAGE, and this kind of interaction is often indicative of pro-inflammatory effects, while some members of S100 family proteins may also exert beneficial roles in vascular remodeling and in the context of cancer. Additionally, the RAGE signaling pathway has been shown to crosstalk with other signaling networks, a topic explored further in this review. Beyond IRI and inflammatory reactions, RAGE has been implicated in a range of other diseases, positioning it as a potential therapeutic target for multiple conditions. This article provides a comprehensive assessment of RAGE and its possible involvement in the onset and progression of diseases affecting various organs and systems, while also briefly summarizing both existing and novel therapeutic targets for prevention or intervention related to RAGE.