Carboxypeptidase E Alleviates Depressive-Like Behaviors in Mice by Regulating BDNF/Nrf2 Axis-Mediated Ferroptosis

Carboxypeptidase E (CPE) may be a therapeutic target for depression. This study investigated the mechanistic insights into the possible regulatory role of CPE in ferroptosis in a mouse model of chronic unpredictable mild stress (CUMS)-induced depression. One week before CUMS exposure, mice received injections of adeno-associated virus-CPE. One week after CUMS induction, the Nrf2 inhibitor ML385 was administered. Behavioral tests were performed 3 weeks after CUMS induction. Ionized calcium-binding adapter molecule 1-positive cells and inflammatory cytokine levels in the CA1 region were assessed by immunofluorescence and ELISA. Hippocampal pathological and neuronal damage were evaluated using H&E and Nissl staining. Additionally, brain-derived neurotrophic factor (BDNF)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, ferroptosis markers, oxidative stress indices, glutathione peroxidase 4 (GPX4), and Fe2+ levels were measured using western blot, RT-qPCR, and biochemical assays. CPE overexpression alleviated CUMS-induced depression-like behaviors and hippocampal damage in mice. CPE overexpression reduced microglial activation, neuronal degeneration, and pro-inflammatory factors. It also attenuated oxidative stress by decreasing malondialdehyde, reactive oxygen species, and lactate dehydrogenase while elevating superoxide dismutase and glutathione-S-transferase activities. Mechanistically, CPE activated the BDNF/Nrf2 axis, increased GPX4 activity, suppressed acyl-CoA synthetase long chain family member 4 expression, and reduced iron accumulation. All protective effects of CPE overexpression were reversed by ML385. CPE overexpression activates the BDNF/Nrf2 signaling axis to inhibit ferroptosis, thereby reducing neuroinflammation and depression-like behaviors in mice. This work further clarifies the pathogenesis of depression, enriches pathophysiological theories, and provides key experimental evidence for early intervention and target development.