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Nucleophosmin1 (NPM1) proteins, initially recognized as central guardians of nucleolar architecture and function, have recently been redefined as pivotal hubs that integrate diverse forms of chronic cellular stress signaling. Although the roles of NPM1 have been extensively elucidated in tumor biology, its broad involvement in non-communicable chronic inflammatory diseases (NCDs) remains insufficiently and unsystematically summarized. Here, we highlight NPM1 as a key sensor of stress-induced nucleolar disassembly, nucleocytoplasmic translocation, and p53 stabilization. In pathological conditions such as myocardial ischemia, endothelial dysfunction, atherosclerosis, and chemotherapy-associated cardiotoxicity, NPM1 exhibits pronounced context dependence functioning either to initiate cytoprotective responses or to promote inflammation and apoptosis. In parallel, NPM1 plays a central role in maintaining genomic stability by sequestering, mobilizing, and regulating essential enzymes across multiple DNA damage repair pathways, including base excision repair (BER) and translesion synthesis (TLS). Dysregulation of these functions is closely linked to chronic pathological processes driven by metabolic stress, oxidative stress, and proteotoxicity. Collectively, available evidence suggests that NPM1, as a core node of the nucleolus-nucleoplasm signaling axis, may constitute a common molecular pathological basis underlying multiple chronic inflammatory diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders. A deeper dissection of its post-translational modifications, stress-dependent subcellular re-localization, and interactions with partner proteins is expected to provide a novel conceptual framework and therapeutic avenues for the development of NPM1-based targeted interventions. Accordingly, this review synthesizes the core molecular mechanisms of the NPM1 in the maintenance of cellular homeostasis, including regulating nucleolar stress, DNA damage repair, and inflammation, We place a particular emphasis on how these baseline pathways translate into distinct functional phenotypes within the pathological processes of chronic diseases, including cardiovascular, metabolic, and neurodegenerative disorders.