Nucleotide Metabolism in Health and Disease

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic resistance. Despite the growing recognition of these metabolic vulnerabilities, an integrated understanding of how specific enzymatic dysregulations translate into diverse disease phenotypes remains fragmented. This review systematically synthesizes the physiological regulatory mechanisms governing nucleotide metabolism and describes the molecular underpinnings of its dysregulation across malignant, immune, and neurodegenerative disorders. We critically examine how specific metabolic enzymes are exploited to drive pathogenesis and highlight the complex interplay between nucleotide metabolites and inflammatory or oncogenic signaling cascades. Furthermore, we evaluate recent clinical innovations in precision medicine, focusing on novel inhibitors targeting key metabolic nodes. By mapping these intricate metabolic networks, this article provides a crucial basis for overcoming current therapeutic challenges, offering profound insights to accelerate the development of next-generation targeted therapies.