胆固醇作为性激素合成的前体，其代谢过程与抑郁症发生及抗抑郁药物干预密切相关。研究表明性激素稳态失衡与抑郁症易感性及进展高度相关，胆固醇代谢紊乱可通过破坏脑内性激素微环境稳态导致抑郁症发生。而药物可通过介导胆固醇代谢、调控性激素及其受体水平、恢复脑内性激素微环境稳态发挥抗抑郁作用。通过综述胆固醇介导神经甾体缺乏、下丘脑-垂体-肾上腺轴过度激活、炎症通路激活3个途径的代谢紊乱致脑内性激素稳态失衡的机制；并应用稳定同位素示踪、代谢组学、生物网络调控等技术揭示“胆固醇代谢-性激素稳态-抑郁症发生”的内在机制，及药物干预对抑郁症的调控效应。为从性激素微环境稳态调控角度揭示抑郁症发生及药物干预机制提供研究策略。

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.

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国家自然科学基金面上资助项目（82374153）