Researchers at NYU Langone Health have discovered a small molecule called RAGE406R that interrupts a harmful interaction between proteins RAGE and DIAPH1, reducing inflammation and tissue damage in diabetes. In mouse models of both Type 1 and Type 2 diabetes, the compound accelerated wound healing and lessened organ stress without lowering blood sugar levels. The findings, published in Cell Chemical Biology, suggest a novel approach to treating diabetes complications.
A team led by Ann Marie Schmidt, MD, at NYU Langone Health identified RAGE406R, a small molecule that prevents the proteins RAGE and DIAPH1 from interacting. This pairing contributes to heart and kidney injury in diabetes and slows wound healing. RAGE, a receptor, responds to advanced glycation end products (AGEs), which accumulate in the blood of people with diabetes and obesity, as well as with age.
In experiments with human cells and mouse models, RAGE406R competed for the binding site on RAGE, reducing swelling in diabetic tissues and promoting repair. The compound limited cell death, eased inflammation, and mitigated both immediate and long-term complications in Type 1 and Type 2 diabetes.
Unlike current treatments that target blood sugar, RAGE406R blocks intracellular RAGE signaling. "There are currently no treatments that address the root causes of diabetic complications, and our work shows that RAGE406R can -- not by lowering the high blood sugar, but instead by blocking the intracellular action of RAGE," said Schmidt, the Dr. Iven Young Professor of Endocrinology at NYU Grossman School of Medicine.
This molecule evolved from an earlier compound, RAGE229, which failed a safety test due to potential DNA-altering risks. RAGE406R was refined to address this concern. In tests on obese mice with Type 2 diabetes, topical application sped up wound closure in both males and females.
The benefits partly arise from reduced levels of CCL2, a proinflammatory molecule, which calmed immune cells called macrophages and supported tissue remodeling. "Our findings point to a promising new pathway for treating diabetes in the future," said co-senior author Alexander Shekhtman, PhD, a professor in the Department of Chemistry at SUNY at Albany.
Contributors included Michaele Manigrasso, Gautham Yepuri, and others from NYU Langone and SUNY Albany. The research was funded by U.S. Public Health Service grants including 1R24DK103032 and 1R01DK122456-01A1. The study appears in Cell Chemical Biology (2025; 32(10): 1197, DOI: 10.1016/j.chembiol.2025.09.010). If validated in human trials, RAGE406R could address gaps in diabetes care, particularly for Type 1.