D-serine: A Multitalented Neuromodulator in Brain Function, Systemic Homeostasis, and Disease.

D-serine is an endogenous D-amino acid and a crucial co-agonist for the N-methyl-D-aspartate (NMDA) receptor, well known as a key regulator of synaptic plasticity, learning, and memory. This review summarizes recent advances that extend beyond this canonical role, positioning D-serine as a dynamic nexus linking brain function to systemic homeostasis. We explore its spatiotemporal dynamics in synaptic microdomains, sophisticated epigenetic and transcriptional regulation, and emerging role as a metabolic sensor linking cellular energetics to neuronal signaling. Furthermore, we highlight novel non-canonical signaling pathways, including its function as a ligand for the glutamate delta-1 receptor (GluD1) and its direct role in peripheral organs like the gut and kidney. The pathophysiological implications of disrupted D-serine homeostasis are detailed across a spectrum of CNS disorders—from schizophrenia and Alzheimer’s disease (AD) to addiction and neuropathic pain—as well as in peripheral conditions including diabetic complications and osteoporosis. Finally, we discuss the translational potential of targeting D-serine pathways through innovative therapeutic strategies—such as serine racemase (SR) modulators, D-amino acid oxidase (DAAO) inhibitors, and gene therapy—and its promise as a biomarker for personalized medicine in neurology and psychiatry.