Methylglyoxal-derived glycation tunes nuclear viscoelasticity

Abstract Reactive carbonyl metabolites such as methylglyoxal (MGO) accumulate in diabetes, aging, and metabolic disease, conditions frequently associated with pathological stiffening of human cells and tissues. While glycation of extracellular matrices and cytoskeletal proteins is known to contribute to these mechanical changes, whether the nucleus itself is a direct mechanical target of carbonyl stress remains unknown. Here, by combining advanced atomic force microscopy-based nanomechanical probing with correlative confocal imaging, we show that MGO-derived glycation directly remodels isolated cell nuclei, increasing stiffness, reducing fluidity, and restricting intranuclear deformation propagation. MGO-derived adducts accumulate prominently at the nuclear envelope, and perturbation of lamin A/C and chromatin state reveals that both structures contribute to glycation-induced stiffening. In cells, chronic MGO exposure induces nucleus-intrinsic stiffening and biases YAP nuclear localization in a substrate-stiffness-dependent manner, linking nuclear glycation to altered mechanosensitive regulation. In vivo , cardiac nuclear stiffening is only observed along with increased immunodetected MGO-adduct burden, while nuclear fluidity remains largely preserved. Together, these findings establish nonenzymatic glycation as a metabolic mechanism that remodels nuclear mechanics and alters cellular mechanosensing, revealing a previously unrecognized physical consequence of carbonyl stress.