DMF is a promising prodrug for the treatment of MDD and for comorbidities such as memory deficit. DMF modulated the neuroinflammatory pathway, ↑ astrocyte expression, ↓ microglia expression and the production of the pro-inflammatory cytokines IL-1β and TNF-α. MMF bound the Keap1 protein → activated Nrf2; it also bound HCAR2 protein, leading to a complex signalling cascade cross-talking with the Nrf2 pathway. It is suggested that one of the mechanisms involved in the AD effect of DMF is NI suppression, triggered by the binding of its metabolite MMF to the HCAR2 protein. This evidence concerns the gene HCAR2 and major depressive disorder.