Integrated proteomic and single-cell transcriptomic profiling elucidates immunomodulatory effects of L-serine in autism spectrum disorder.

Autism spectrum disorder (ASD) is classified as early-emerging developmental divergences distinguished by aberrant interpersonal interactions as well as inflexible, stereotyped activities with no definitive treatments targeting the core symptoms. Accumulating evidence suggests that immune dysregulation critically contributes to ASD pathophysiology. We aimed to elucidate the potential immunomodulatory effects of L-serine in patients with ASD by investigating proteomic alterations in immune cell communication. Across 12 weeks of daily oral L-serine, we observed improvements in behavioral measures alongside more favorable Clinical Global Impression scores. Plasma extracellular vesicle proteomic profiling showed unique protein changes in immune-related pathways and T cell functions. From single-cell transcriptome sequencing profiling of peripheral blood mononuclear cells, the expression signatures of naive CD4 T cells shifted toward a more typical transcriptional state after L-serine treatment. Overall, integrating proteome-scale measurements with single-cell transcriptomes provided new mechanistic insight into ASD intervention effects and suggests that L-serine can reshape adaptive immune cell states.