Bufotenidine attenuates astrocyte ferroptosis in depressive-like behaviors through targeting GluA1 to reduce neuronal lipid synthesis.

Abstract

Depression is a highly prevalent mental illness, causing global disease burden. Bufotenidine is an active constituent of traditional Chinese medicine Chansu. However, the role of bufotenidine against depression remains unclear. In this study, we investigated the antidepressant effect of bufotenidine in corticosterone-induced mice and the underlying mechanism. We identified AMPA receptor subunit GluA1 as a target of bufotenidine. Mechanistically, bufotenidine binding to GluA1 upregulated the ferroptosis-suppressing proteins GPX4 and SLC7A11, attenuated lipid peroxidation, and prevented astrocyte death. Notably, bufotenidine reduced the enzymatic activity in alpha-linolenic acid and phosphatidylcholine biosynthesis pathways, thereby diminishing neuronal lipid secretion. This reduction subsequently decreased the production of peroxidized PUFA-containing phospholipids and palmitic acid in astrocytes, ultimately suppressing astrocyte ferroptosis. These protective effects were abrogated by the AMPA receptor antagonist NBQX. Furthermore, bufotenidine-mediated suppression of neuronal lipid synthesis was dependent on mTOR-autophagy signaling. Our findings establish GluA1 as a promising therapeutic target for depression and reveal a previously unrecognized neuron-astrocyte lipid metabolic axis, providing new mechanistic insights for antidepressant drug development.