AEBP1 targets DDR2 to induce ferroptosis and microglial activation through the STAT3/P53 signaling pathway,...

This study investigated the role of Discoidin Domain Receptor 2 (DDR2) in depressive behavior, neuroinflammation, and ferroptosis in the Chronic Unpredictable Mild Stress (CUMS) mouse model, as well as its regulatory mechanisms in LPS-induced BV2 microglial cells. First, the CUMS model successfully induced depressive-like behavior in mice, accompanied by hippocampal neuronal damage, DDR2 activation, and neuroinflammatory responses. The experimental results showed that DDR2 expression was significantly increased in the CUMS mouse model, and LPS stimulation exacerbated ferroptosis and inflammatory responses in microglial cells. Further experiments indicated that DDR2 knockdown significantly alleviated depressive-like behavior, neuroinflammation, and ferroptosis in the mice. In in vitro experiments, LPS-induced BV2 microglial cells exhibited significant ferroptosis characteristics. DDR2 knockdown effectively alleviated these changes and restored the expression of ferroptosis-related proteins SLC7A11 and GPX4. Additionally, DDR2 knockdown suppressed M1 microglial activation and promoted M2 polarization, highlighting its key role in microglial polarization regulation. Intervention through the STAT3/P53 pathway further confirmed that DDR2 promotes LPS-induced oxidative stress and ferroptosis by regulating the STAT3/P53 signaling pathway. Furthermore, Adipocyte Enhancer Binding Protein 1 (AEBP1) directly binds to the DDR2 promoter to regulate its transcription, exacerbating LPS-induced ferroptosis, inflammation, and M1 polarization. DDR2 knockdown effectively counteracted these pathological effects promoted by AEBP1. In summary, DDR2 plays a crucial role in the pathogenesis of depression by regulating ferroptosis and microglial polarization, providing potential targets for future treatments.