Mechanism of action of REDD1 in depression and its targeted intervention

Depression is a chronic and recurrent mental disorder characterised by depressed mood, social isolation, and anhedonia. Despite its increasing prevalence, the underlying biological mechanisms, particularly those driven by genetic factors, remain largely unknown. Regulated in development and DNA damage responses 1 (REDD1), also known as RTP801/Dig2/DDIT4, is a stress-inducible protein expressed in both neuronal and non-neuronal cells that shows significant changes in expression levels under conditions of hypoxia or cerebral ischaemia. REDD1 has a negative regulatory effect on mammalian target of rapamycin (mTOR), which plays a key role in synaptic development and plasticity maintenance, and is therefore a potential pharmacological intervention target for various neurological disorders. Studies have demonstrated that REDD1 protein is elevated in the prefrontal cortex of patients with depression. Furthermore, animal models of depression have shown that REDD1 modulates depression-like behaviours in mice by inhibiting the protein kinase B (Akt)/mTOR signalling pathway. However, the specific mechanism by which REDD1 regulates depression remains unclear. Therefore, we herein focus on elucidating the role of REDD1 in the pathogenesis of depression. Collectively, our review highlights the critical role of REDD1 in the neurobiological mechanisms underlying depression, suggesting that this protein represents a promising therapeutic target for depression treatment.