Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder

Abstract

Depression is a major contributor to poor global health and disability, with a recently increasing incidence. Although drug therapy is commonly used to treat depression, conventional antidepressant drugs have several disadvantages, including slow onset, low response rates and severe adverse effects. Therefore, developing effective therapies for depression remains challenging. Although various aetiological theories of depression exist, the underlying mechanisms of depression are complex, and further research is crucial. Moreover, oxidative stress (OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis. Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders, and investigation of the mediators involved in these processes has emerged as a prominent and active research direction. One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression, and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosisin vivo, suggesting an important role of ferroptosis in the pathogenesis of depression. Hence, our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved, specifically concerning ferroptosis and OS in the context of depression, along with promising prospects for using molecular mediators to target ferroptosis. We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression, most notably reactive oxygen species and iron overload. Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders, delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

Ferroptosis: a new antidepressant pharmacological mechanism

“…Depression is a prevalent mental disorder characterized by persistent symptoms such as low mood and reduced interest, with severe cases sometimes leading to suicidal tendencies, and has been a major contributor to poor global health and disability, with a recently increasing incidence ( ZHANG X. et al, 2022 ; SHAHBAZI et al, 2022 ; SU and SI, 2022 ; YAO et al, 2022 ). Despite the continuous development of antidepressants, the treatment options for depression remain limited, often failing to provide sufficient relief for patients ( WANG L. et al, 2023 ). Therefore, there is an urgent need to explore new strategies for developing antidepressant drugs ( LEVENBERG and CORDNER, 2022 ).…”

“…Therefore, there is an urgent need to explore new strategies for developing antidepressant drugs ( LEVENBERG and CORDNER, 2022 ). Recent research progress on the mechanism of ferroptosis suggests a close association between ferroptosis dysregulation and the pathological mechanism of depression ( MAES et al, 1995b ; WANG et al, 2019 ; LIANG et al, 2020 ; BERTHOU et al, 2021 ; WANG L. et al, 2023 ). This paper explored the efficacy of TCM ingredients, compound formulas, and antidepressant chemicals in regulating ferroptosis to combat depression, based on a thorough review of relevant literature reports.…”