As the precursor of sex hormone synthesis, depression is profoundly influenced by metabolic pathways, which also affect how patients respond to antidepressants. In addition, when sex hormones are dysregulated, it significantly increases both the risk of developing depression and the likelihood of its worsening over time, and the disorder of cholesterol metabolism can lead to depression by disrupting the homeostasis of sex hormone microenvironment in the brain. Therefore, drugs can exert antidepressant effects by mediating cholesterol metabolism, regulating the levels of sex hormones and their receptors, and restoring the homeostasis of brain sex hormone microenvironment. This article aims to review the mechanism of the imbalance of brain sex hormone homeostasis caused by cholesterol mediated metabolic disorders of neurosteroid deficiency, hypothalamic-pituitary-adrenal axis hyperactivation, and inflammatory pathway activation. Furthermore, stable isotope tracing, metabolomics, biological network regulation and other technologies were applied to reveal the internal mechanism of “cholesterol metabolism sex hormone homeostasis depression”, as well as the regulatory effect of drug intervention on depression. It provides novel research strategies for revealing the mechanism of depression and drug intervention from the perspective of homeostatic regulation of sex hormone microenvironment.

disruption of cholesterol metabolism  /  sex hormone homeostasis  /  depression  /  antidepressant drugs  /  research strategies  /  Cuscutae Semen  /  Chaigui Granules