NRF2 as a novel therapeutic target for depression: Insights from preclinical studies

Depression remains one of the most prevalent and disabling psychiatric conditions worldwide, affecting an estimated 280 million individuals, equivalent to 3.8% of the population, including 5.0% of adults and 5.7% of people over the age of 60 (1). Recent evidence proposes that reduced antioxidant defenses are implicated in the pathophysiology of depression, likely due to a diminished ability to neutralize reactive oxygen species (ROS) and reactive nitrogen species (RNS) (2). Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor that regulates the expression of key antioxidant enzymes (3). The involvement of Nrf2 in depression has received a lot of attention in recent years, reporting the role of oxidative stress and neuroinflammation in depression pathogenesis, placing Nrf2 as a promising target for novel antidepressant strategies. Aims:This systematic review aimed to critically assess the current preclinical evidence regarding the role of Nrf2 in models of depression. Specifically, we intended to (1) evaluate how Nrf2 expression is affected in depressive conditions, and (2) identify the effect of antidepressant and natural compounds on Nrf2 modulation.