Abstract: Beyond the traditional concept of genes as the core regulators of cellular phenotypes, epigenetic modifications - which are largely influenced by the external environment and do not alter DNA sequence - also have a significant impact on gene expression. Mechanical signals serve as key mediators through which cells perceive the physical properties of their microenvironment. By means of structures such as integrins, Piezo channels, and the cytoskeleton-LINC ( Linker of nucleoskeleton and cytoskeleton) complex, physical stimuli like ECM (Extracellular matrix) stiffness and mechanical strain are transmitted to the cell nucleus. By interacting with epigenetic modifications, these signals play a pivotal role in regulating cell fate and disease progression. At the chromatin level, mechanical forces dynamically alter DNA methylation and histone modification states by regulating the enzyme activity of DNMTs, TETs, HDACs, KDM5B, and more, via the cytoskeletal system and mechanosensitive molecules. For instance, during atherosclerosis, mechanical forces from matrix stiffening transmit intracellularly through the DDR1-DNMT1 axis to silence vascular protective genes, accelerating collagen deposition. At the RNA level, mechanical signals regulate m6A (N6-methyladenosine) modification-related factors (such as METTL3/14, FTO, ALKBH5, and YTHDFs) via the cytoskeleton, calcium ions, and YAP signaling pathways, influencing mRNA stability and translation. This contributes to osteogenic differentiation, inflammation, and tumor adaptation. Dysregulation of the mechanical-epigenetic axis forms a vicious mechanical signaling - epigenetic reprogramming - disease-progression cycle, contributing extensively to pathological processes such as atherosclerosis, tumors, fibrosis, and osteoarthritis. This review aims to systematically present the regulation of epigenetic modifications - including DNA methylation, histone acetylation, and RNA methylation - by mechanical signals under physiological and pathological conditions, thereby providing insights for identifying disease molecular targets and developing mechanoresponsive materials.