Formononetin alleviates corticosterone-induced myelin damage through activating ERα and promoting the differentiation of oligodendrocyte precursor cells in the prefrontal cortex

Depression is frequently accompanied by myelin damage in the prefrontal cortex (PFC), and promoting remyelination may alleviate depressive symptoms. This study investigated the antidepressant mechanism of formononetin (FMN), a natural isoflavone phytoestrogen, in a corticosterone (CORT)-induced depression mouse model. FMN significantly improved depression-like behaviors and alleviated demyelination in the PFC. Proteomic analysis suggested the involvement of estrogen signaling in the antidepressant effects of FMN. Molecular docking, target capture, drug affinity responsive target stability (DARTS), and surface plasmon resonance (SPR) identified estrogen receptor alpha (ERα) as a direct target of FMN. FMN promoted ERα nuclear translocation and upregulated myelin basic protein (MBP). Edu assays indicated that FMN promoted oligodendrocyte precursor cells (OPCs) differentiation without affecting cell proliferation. Notably, its pro-differentiation effects were abolished by the ERα antagonist methylpiperidino pyrazole (MPP). Moreover, FMN did not induce proliferation or metastasis in breast cancer cells or promote tumor growth in vivo. These findings support FMN as a promising and safe therapeutic candidate for depression by targeting ERα to promote remyelination.