AGER, also known as the receptor for advanced glycation end-products (RAGE), is a cell surface transmembrane multiligand receptor. It is encoded by the AGER gene and involves multiple pathways such as NFκB, Akt, p38, and MAP kinases, initiating and perpetuating a pro-inflammatory state. AGER is expressed mainly in the lung and is implicated in multiple biological processes including inflammation, apoptosis, and immunity [3,4].

In pancreatic ductal adenocarcinoma (PDAC), up-regulation of AGER within cancer cells instigates macropinocytosis, leading to resistance to the KRAS-G12D inhibitor MRTX1133. The underlying mechanism involves AGER's interaction with DIAPH1 to drive RAC1-dependent macropinosome formation. Combining MRTX1133 with inhibitors of the AGER-DIAPH1 complex or macropinocytosis was effective in patient-derived xenografts, orthotopic models, and genetically engineered mouse PDAC models [1].

In sepsis, AGER-mediated lipid peroxidation drives caspase-11 inflammasome activation in macrophages. Pharmacologic inhibition of the AGER-ALOX5 pathway or global/conditional depletion of AGER in myeloid cells (Ager-/-or AgerMye-/-) protects against lipopolysaccharide-induced septic death in poly(I:C)-primed mice [2].

In conclusion, AGER is a crucial receptor involved in multiple biological processes and diseases. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its role in PDAC drug resistance and sepsis. These findings enhance our understanding of disease mechanisms and suggest potential therapeutic strategies targeting AGER in these disease areas.

References:

1. Li, Changfeng, Liu, Yuanda, Liu, Chang, Tang, Daolin, Kang, Rui. 2025. AGER-dependent macropinocytosis drives resistance to KRAS-G12D-targeted therapy in advanced pancreatic cancer. In Science translational medicine, 17, eadp4986. doi:10.1126/scitranslmed.adp4986. https://pubmed.ncbi.nlm.nih.gov/39879317/

2. Chen, Ruochan, Zhu, Shan, Zeng, Ling, Tang, Daolin, Kang, Rui. 2019. AGER-Mediated Lipid Peroxidation Drives Caspase-11 Inflammasome Activation in Sepsis. In Frontiers in immunology, 10, 1904. doi:10.3389/fimmu.2019.01904. https://pubmed.ncbi.nlm.nih.gov/31440260/

3. Serveaux-Dancer, Marine, Jabaudon, Matthieu, Creveaux, Isabelle, Blanchon, Loïc, Sapin, Vincent. 2019. Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism. In Disease markers, 2019, 2067353. doi:10.1155/2019/2067353. https://pubmed.ncbi.nlm.nih.gov/30863465/

4. Bakutenko, Ivan Yurievich, Haurylchyk, Irena Dmitrievna, Sechko, Elena Vladimirovna, Sukalo, Alexander Vasil'evich, Ryabokon, Nadezhda Ivanovna. 2021. AGER gene variant as a risk factor for juvenile idiopathic arthritis. In The journal of gene medicine, 24, e3399. doi:10.1002/jgm.3399. https://pubmed.ncbi.nlm.nih.gov/34806241/