The cell nucleus is a dynamic and mechanically active organelle whose physical properties significantly influence genome organization, gene regulation, and cellular identity. Over the past two decades, research has increasingly focused on the concept of nuclear mechanotransduction, a process by which the nucleus responds to mechanical signals from both the extracellular microenvironment and the intracellular cytoskeleton. Emerging evidence now positions epigenetic regulation as a central architect of these mechanical properties. This review synthesizes current understanding of how nuclear architecture defines mechanical homeostasis and how mechanical signals are transduced into biochemical and transcriptional responses. We highlights how epigenetic mechanisms, such as histone modifications, chromatin remodeling complexes, and DNA methylation, actively program nuclear mechanics by modulating chromatin stiffness, lamina integrity, and chromatin-envelope coupling. We further examine how this epigenetically encoded mechanical identity influences key biological processes including stem cell differentiation, tissue development, and aging, and contributes to diseases characterized by nuclear dysfunction, such as laminopathies and cancer metastasis. By integrating recent advances, this review underscores the epigenetic-mechanical axis as a core regulatory framework through which cells establish and maintain nuclear mechanical homeostasis in both physiological and pathological contexts.
Keywords: Epigenetic regulation; epigenetic mechanisms; mechanical signals; nuclear architecture; nuclear mechanics; nuclear mechanotransduction.