Multifaceted roles of casein kinase 1 in health and disease: beyond cancer.

Casein kinase 1 (CK1) enzymes, a family of serine/threoninespecific protein kinases, are remarkably conserved throughout evolution and exhibit diverse functionalities across eukaryotic species. While initially characterized by their role in casein (a type of milk protein) phosphorylation, subsequent investigations have unveiled their extensive involvement in fundamental biological processes, including cell division, maintenance of DNA integrity, programmed cell death, and the intricate regulation of gene transcription. Furthermore, CK1 significantly influences circadian rhythm mechanisms, highlighting its systemic regulatory importance. In mammals, multiple CK1 isoforms have been identified, each contributing to both physiological functions and various disease states. Dysregulation of CK1 activity is consistently associated with oncogenesis, where it promotes tumor cell proliferation, survival, metastasis, and resistance to therapeutic interventions. Emerging evidence also points to the critical relevance of CK1 in non-malignant conditions, such as neurodegenerative diseases, metabolic syndromes, and immune dysfunctions. In these conditions, CK1 often mediates pathogenic signaling through aberrant phosphorylation and the disruption of temporal gene expression. This review aims to re-examine the CK1 family as a versatile regulator that interacts with various pathological conditions, extending beyond its traditional classification as merely a signaling kinase. We provide an overview of the structural and functional properties of CK1 isoforms, summarize their relevance across a range of diseases, and explore novel possibilities for therapeutic interventions targeting this kinase family. Moreover, by reviewing the current understanding of CK1, we search for a new perspective on its role in maintaining cellular balance and its contribution to disease mechanisms, thereby proposing novel avenues for future research. [BMB Reports 2026; 59(6): 299-312].