Nrf2: An all-rounder in depression

Abstract

The balance between oxidation and antioxidant is crucial for maintaining homeostasis. Once disrupted, it can lead to various pathological outcomes and diseases, such as depression. Oxidative stress can result in or aggravate a battery of pathological processes including mitochondrial dysfunction, neuroinflammation, autophagical disorder and ferroptosis, which have been found to be involved in the development of depression. Inhibition of oxidative stress and related pathological processes can help improve depression. In this regard, the nuclear factor erythroid 2-related factor 2 (Nrf2) in the antioxidant defense system may play a pivotal role. Nrf2 activation can not only regulate the expression of a series of antioxidant genes that reduce oxidative stress and its damages, but also directly regulate the genes related to the above pathological processes to combat the corresponding alterations. Therefore, targeting Nrf2 has great potential for the treatment of depression. Activation of Nrf2 has antidepressant effect, but the specific mechanism remains to be elucidated. This article reviews the key role of Nrf2 in depression, focusing on the possible mechanisms of Nrf2 regulating oxidative stress and related pathological processes in depression treatment. Meanwhile, we summarize some natural and synthetic compounds targeting Nrf2 in depression therapy. All the above may provide new insights into targeting Nrf2 for the treatment of depression and provide a broad basis for clinical transformation.

Keywords: Autophagy; Depression; Ferroptosis; Neuroinflammation; Nrf2; Oxidative stress.

Fig. 1

The structure and regulation of Nrf2. (A) The fundamental structure of Nrf2. (B) Keap1 -dependent and -independent regulation of Nrf2.

Fig. 2

Schematic representation of the multifaceted role of Nrf2 in depression. The target molecules of Nrf2 (marked in red) are invovled in oxidative stress, mitochondrial function, autophagy/mitophagy, neuroinflammation and ferroptosis. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)