L-fucose administration ameliorates chronic social defeat stress-induced depressive-like behaviors by restoring GDP-fucose biosynthetic activation and core fucosylation.

Chronic psychosocial stress is a major driver of depression, yet the glycometabolic mechanisms linking stress exposure to neuroinflammation and synaptic dysfunction remain poorly understood. Here, using a chronic social defeat stress (CSDS) model, we demonstrated that L-fucose supplementation markedly attenuated depressive-like behaviors and suppressed neuroinflammation in the hippocampus. L-fucose also reduced Iba1-positive microglial accumulation, inhibited JAK2/STAT3 inflammatory signaling, and restored the stress-induced loss of synaptic proteins, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and postsynaptic density protein 95 (PSD95). Mechanistically, CSDS downregulated hippocampal guanosine 5'-diphosphate (GDP)-fucose levels, thereby impairing core fucosylation. This defect was associated with downregulation of key enzymes in the GDP-fucose salvage biosynthetic pathway, including fucokinase (FUK) and fucose-1-phosphate guanylyltransferase (FPGT), both of which were restored by L-fucose administration. Consistently, pharmacological inhibition of fucosylation with 2-fluorofucose (2FF) suppressed GDP-fucose and Fuk expression, thereby exacerbating depressive-like behaviors and neuroinflammation in the CSDS model. Furthermore, L-fucose or MF30 alleviated CSDS-induced inflammatory responses in distal colon tissues. Taken together, this study clearly identifies a link between GDP-fucose synthesis and chronic stress and, for the first time, shows that alterations in key enzymes in the GDP-fucose salvage pathway play critical roles in CSDS-induced depressive-like behaviors and neuroinflammation, suggesting that restoring GDP-fucose biosynthetic activation may offer a promising therapeutic strategy for stress-related neuropsychiatric disorders.