The extracellular matrix (ECM) and nuclear lamina are fundamental components of cellular architecture, playing pivotal roles in mechanotransduction and gene regulation. The dynamic interplay between the ECM and lamin proteins profoundly influences chromatin organization, epigenetic modifications, and genomic stability. Variations in ECM stiffness and composition can induce significant alterations in nuclear architecture, including changes in nuclear morphology and lamin A/C expression levels. These structural changes, in turn, modulate histone modifications, DNA methylation patterns, and chromatin compaction, all of which are critical for regulating gene expression. Disruption of this intricate ECM-lamin interaction can lead to aberrant gene expression, increased genomic instability, and the progression of various diseases, particularly cancer. A comprehensive understanding of ECM-lamin dynamics offers valuable insights into the mechanisms underlying epigenetic regulation and genome maintenance, with potential implications in developing novel therapeutic strategies against diseases associated with dysregulation of mechanotransduction.