Major depressive disorder (MDD) is a heterogeneous psychiatric disease characterized by persistent low mood, diminished interests, and impaired cognitive and social functions. The multifactorial etiology of MDD is still largely unknown because of the complex genetic and environmental interactions involved. Therefore, no established mechanism can explain all the aspects of the disease. In this light, an extensive research about the pathophysiology of MDD has been carried out. Several pathogenic hypotheses, such as monoamines deficiency and neurobiological alterations in the stress-responsive system, including the hypothalamic–pituitary–adrenal (HPA) axis and the immune system, have been proposed for MDD. Over time, remarkable studies, mainly on preclinical rodent models, linked the serum- and glucocorticoid-regulated kinase 1 (SGK1) to the main features of MDD. SGK1 is a serine/threonine kinase belonging to the AGK Kinase family. SGK1 is ubiquitously expressed, which plays a pivotal role in the hormonal regulation of several ion channels, carriers, pumps, and transcription factors or regulators. SGK1 expression is modulated by cell stress and hormones, including gluco- and mineralocorticoids. Compelling evidence suggests that increased SGK1 expression or function is related to the pathogenic stress hypothesis of major depression. Therefore, the first part of the present review highlights the putative role of SGK1 as a critical mediator in the dysregulation of the HPA axis, observed under chronic stress conditions, and its controversial role in the neuroinflammation as well. The second part depicts the negative regulation exerted by SGK1 in the expression of both the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF), resulting in an anti-neurogenic activity. Finally, the review focuses on the antidepressant-like effects of anti-oxidative nutraceuticals in several preclinical model of depression, resulting from the restoration of the physiological expression and/or activity of SGK1, which leads to an increase in neurogenesis. In summary, the purpose of this review is a systematic analysis of literature depicting SGK1 as molecular junction of the complex mechanisms underlying the MDD in an effort to suggest the kinase as a potential biomarker and strategic target in modern molecular antidepressant therapy.

重度抑郁症（MDD）是一种异质性精神病，其特征是持续的情绪低落，兴趣减少以及认知和社会功能受损。由于涉及复杂的遗传和环境相互作用，MDD的多因素病因仍是很大程度上未知的。因此，没有建立的机制可以解释该疾病的所有方面。有鉴于此，已经对MDD的病理生理学进行了广泛的研究。已经为MDD提出了几种致病性假说，例如单胺缺乏和应激反应系统中的神经生物学改变，包括下丘脑-垂体-肾上腺（HPA）轴和免疫系统。随着时间的流逝，主要针对临床前啮齿动物模型的杰出研究 将血清和糖皮质激素调节激酶1（SGK1）与MDD的主要特征联系起来。SGK1是属于AGK激酶家族的丝氨酸/苏氨酸激酶。SGK1被普遍表达，它在几种离子通道，载体，泵和转录因子或调节剂的激素调节中起着关键作用。SGK1的表达受细胞应激和激素（包括糖皮质激素和盐皮质激素）的调节。有力的证据表明，SGK1表达或功能增加与重度抑郁的病原性应激假设有关。因此，本综述的第一部分突出了在慢性应激条件下观察到的SGK1作为HPA轴失调的关键介体的假定作用，以及其在神经炎症中的作用也颇受争议。第二部分描述了SGK1对脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）的表达产生的负调节作用，从而导致抗神经活性。最后，本综述着重于几种抑郁症临床前模型中抗氧化保健食品的抗抑郁样作用，这归因于SGK1生理表达和/或活性的恢复，导致神经发生增加。总而言之，本综述的目的是对文献进行系统的分析，这些文献将SGK1描述为MDD背后复杂机制的分子连接点，以试图阐明该激酶作为现代分子抗抑郁治疗的潜在生物标志物和战略目标。