Astrocytic AT1R deficiency ameliorates LPS-induced depressive-like behaviors through lactoferrin-mediated astrocyte...

Hypertension is associated with increased vulnerability to depression, and the angiotensin II type 1 receptor (AT1R), a central target of antihypertensive therapy, has also been implicated in mood disorders. The AT1R is abundantly expressed in astrocytes, but the role of astrocytic AT1R in depression pathogenesis remains unknown. Here, we investigated the role of astrocytic AT1R in a lipopolysaccharide (LPS)-induced mouse model of depression. LPS markedly increased AT1R expression in the medial prefrontal cortex (mPFC). Astrocytic AT1R deficiency attenuated depressive-like behaviors, reduced the A1/A2 astrocyte ratio, and restored lactoferrin (LF) expression in the mPFC, potentially via a PPARγ-dependent mechanism. Consistently, AT1R inhibition in primary cultured astrocytes reversed the LPS-induced shift toward the neurotoxic A1 phenotype, while pharmacological blockade of AT1R upregulated LF expression in C6 cells. Moreover, both in vivo and in vitro administration of lactoferrin improved LPS-induced depressive-like behaviors, likely by decreasing the A1 astrocyte level rather than via ferroptosis pathways. These findings reveal an astrocytic AT1R/LF pathway as a novel regulator of reactive astrocyte polarization under inflammatory conditions. Our study highlights astrocytic AT1R as a key therapeutic target bridging neuroinflammation, hypertension, and depression.