Here, by studying Z24−/− muscles and MSCs, we further investigated the potential changes of Sun2 expression and its correlation with nuclear abnormalities/damages in progeria cells under mechanical stress, and the potential effect and mechanism of Sun2 suppression in regulating mechanical stress-induced nuclear abnormalities (i.e., nuclear blebbing and DNA damage), the status of nuclear softening and decoupling, and innate immune activation-associated cellular senescence. Here, SUN2 is linked to progeroid syndrome.