Mangiferin Buffers Depressive-Like Behaviors by Modulating Astrocytic DHHC2 in the Hippocampus.

Abstract

Several lines of evidence indicate that mangiferin (MGF) ameliorates chronic stress-induced anxiety- and depressive-like behaviors, yet its precise role and underlying mechanisms remain poorly understood. Here, we show that MGF effectively alleviates anxiety- and depressive-like behaviors in mice exposed to chronic stress, accompanied by reduced synaptic loss and ameliorated hippocampal neurogenesis deficits. Notably, nuclear factor erythroid 2-related factor 2 (Nrf2) expression is preferentially altered in hippocampal astrocytes but not in neurons or microglia after chronic stress and MGF treatment, and knockdown of astrocytic Nrf2 abrogates the antidepressant effect of MGF. Further mechanistic studies showed that MGF reverses reactive astrogliosis by regulating astrocytic DHHC2-Nrf2 signaling, including Nrf2 palmitoylation and its nuclear translocation, thereby protecting Nrf2 from Keap1-mediated ubiquitination and proteasomal degradation and sustaining its transcriptional activity in reactive astrocytes. These findings demonstrate that MGF alleviates chronic stress-induced anxiety- and depressive-like behaviors by engaging the astrocytic DHHC2-Nrf2 signaling, suppressing reactive astrogliosis and reversing hippocampal synaptic and neurogenic deficits, which provides novel insights into the therapeutic potential of MGF for chronic stress-related mood disorders.

Key Findings

• Mangiferin alleviates anxiety- and depressive-like behaviors in mice exposed to chronic stress.
• Nrf2 expression is selectively altered in hippocampal astrocytes after chronic stress and mangiferin treatment.
• Mangiferin modulates astrocytic DHHC2-Nrf2 signaling, enhancing Nrf2 palmitoylation, nuclear translocation, and protecting it from degradation, thereby suppressing reactive astrogliosis and reversing synaptic and neurogenic deficits.

Clinical Significance

Citation

Xia Zhi-Xuan, Zhao Yue-Ling, Tian Danet al.. Mangiferin Buffers Depressive-Like Behaviors by Modulating Astrocytic DHHC2 in the Hippocampus. Pharmacological research. 2026-Nov-07.