<p>The nucleus functions not only as a repository of genetic information but also plays a central role in mechanosensing and mechanotransduction in response to external mechanical stimuli. This process is critical for cellular adaptation to diverse mechanical environments and holds significant implications for tissue engineering and regenerative medicine. However, systematic and comprehensive reviews in this field remain scarce, particularly those addressing emerging directions such as AI-assisted research. To fill this gap, we analyzed major contributors and emerging hotspots in the past two decades, including key structural and signaling molecules such as lamin A/C and YAP/TAZ. Building upon this, we summarize recent advances, emphasizing the viscoelastic properties of LMNA and the elastic features of LMNB and condensed chromatin, highlighting their roles as core nuclear mechanical elements in protection, adaptation, and memory. Furthermore, nuclear mechanical dysregulation is closely linked to various diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. We also review experimental approaches for probing nuclear mechanics, such as atomic force microscopy, microfluidics, and high-resolution imaging. While conventional imaging and force-measurement methods face limitations in handling high-dimensional dynamic data, the rapid development of artificial intelligence (AI) provides powerful tools for detecting nuclear abnormalities, predicting nuclear responses, and constructing multiscale models. This review offers a systematic synthesis of nuclear mechanobiology and underscores future opportunities for AI-driven research and clinical translation.</p><p></p>