Serine metabolism in the central nervous system: advances and challenges on a conditionally essential amino acid

Once considered a non-essential amino acid, L-serine (L-Ser) is now recognized as conditionally essential in the brain, orchestrating a complex network of metabolic and signalling pathways. L-Ser provides carbon units to the one-carbon metabolism, supporting nucleotide synthesis and methylation reactions, and serves as a precursor for phosphatidylserine and sphingolipids. L-Ser plays crucial roles in glutathione and heme metabolism and interfaces with mitochondrial one-carbon pathways, thereby linking it to energy production, redox homeostasis, and epigenetic regulation. Its conversion into glycine and D-serine further supports neurotransmission, synaptic plasticity, and cognitive functions. Throughout the lifespan, L-Ser and its derivatives contribute to maintaining neuronal and glial homeostasis. However, fundamental questions remain regarding how L-Ser biosynthesis, transport, and compartmentalization are coordinated in the intact brain and how their dysregulation contributes to disease. Current knowledge largely derives from cancer biology or in vitro models, and translating these insights to the central nervous system poses major challenges. The lack of specific tools to monitor L-Ser flux in vivo, limited understanding of post-translational regulation of key enzymes and incomplete mapping of transport mechanisms across the blood-brain barrier still hampers deeper mechanistic and translational insight. This review compiles the most recent evidence, emphasizing the translational relevance of L-Ser-based interventions and underscoring the urgent need for systematic clinical trials to fully evaluate its therapeutic potential.