Nicotinic acid (NA) facilitates antidepressant effects through promoting neuro-protective transcriptome in the hippocampus.

Major depressive disorder (MDD) is characterized by anhedonia and cognitive deficits. In this study, we investigated the therapeutic effects of nicotinic acid (NA), a nicotinamide adenine dinucleotide+ (NAD+) precursor, in a mouse chronic restraint stress (CRS) model. Behavioral assessments revealed that NA ameliorated depressive-like behaviors, evidenced by restored sucrose preference and reduced immobility in forced swim and tail suspension tests, without affecting motor coordination in the rotarod test. Hippocampal transcriptomic analysis indicated that NA reversed stress-induced gene dysregulation, activated neuroprotective Wnt/β-catenin, cGMP-PKG, and cAMP pathways, and rescued lipid and porphyrin metabolism. In conclusion, NA likely exerts antidepressant effects by remodeling hippocampal gene networks to enhance synaptic plasticity and restore metabolic homeostasis. These findings highlight NA as a promising metabolic antidepressant and support the development of NAD+ precursor-based potential therapies for mood disorders.