The study investigates the role of lamin A/C in mechanotransduction and nuclear mechanics. Lamin A/C-deficient mouse embryo fibroblasts were subjected to mechanical strain, and their nuclear mechanical properties and signaling were measured. The results show that *Lmna*^−/−^ cells exhibit increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-κB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in *Lmna*^−/−^ cells despite increased transcription factor binding. These findings suggest that lamin A/C deficiency is associated with defective nuclear mechanics and impaired mechanically activated gene transcription, which may contribute to the tissue-specific effects observed in laminopathies.The study investigates the role of lamin A/C in mechanotransduction and nuclear mechanics. Lamin A/C-deficient mouse embryo fibroblasts were subjected to mechanical strain, and their nuclear mechanical properties and signaling were measured. The results show that *Lmna*^−/−^ cells exhibit increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-κB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in *Lmna*^−/−^ cells despite increased transcription factor binding. These findings suggest that lamin A/C deficiency is associated with defective nuclear mechanics and impaired mechanically activated gene transcription, which may contribute to the tissue-specific effects observed in laminopathies.