Non-enzymatic RNA Glycation is a Metabolic Sensor of Cellular Stress

Non-enzymatic RNA modifications expand the epitranscriptome, encoding a rapid and chemistry-driven response to cellular stress. While methylglyoxal, a reactive glycolytic byproduct of metabolic stress, has been shown to modify proteins and DNA, its impact on RNA has remained unexplored. Here, we identify mRNA as a dynamic substrate of MGO, whose modification is actively regulated by DJ-1 and the glyoxalase detoxification system. We show that mRNA glycation impairs translation and engages both the integrated stress response and the ribotoxic stress pathway, culminating in compromised pancreatic β-cell function and reduced insulin secretion. Notably, this phenotype is alleviated by the frontline antihyperglycemic agent metformin. Together, our findings position mRNA as a direct sensor of metabolic stress and establish RNA glycation as a mechanistic link between glycolytic imbalance, translational stress and disease.