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 ferroptosis in 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.

Keywords: depression.

Figure 1

(A) Timeline of important affairs in ferroptosis discovery. (B) the role of ferroptosis in the pathological processes of different organs. ACSL4, acyl-CoA synthetase long-chain family member 4; CoQ10, coenzyme Q10; CoQH2, dihydroubiquione; DHODH, dihydroorotate dehydrogenase; FSP, ferroptosis suppressor protein; NADPH, nicotinamide adenine dinucleotide phosphate; PDTACs, photodegradation-targeting chimeras; PROTACs, proteolysis-targeting chimeras; PUFA, polyunsaturated fatty acid; xCT, cystine/glutamate antiporter.

Figure 2

(A) Overview of intracellular iron metabolism. This schematic chart illustrates the processes involved in iron uptake, storage, regulation and output. The metabolism of iron is regulated by various factors, including transferrin, TRFC and ferritinophagy. Iron metabolism and its regulators contribute to lipid peroxidation and ferroptosis by increasing intracellular labile iron pool levels. (B) Overview of the intracellular modulation of ROS. This scheme depicts how ROS operates at the intersection of crucial signalling events. They work upstream and downstream of other signalling components, such as membranes, GPX4, FLT-3, ACSL4, CARS, CoQ10, 5-LOX and transcription factors. (C) Metabolic signalling pathways regulating ferroptosis. (D) Overview of ferroptosis modulation. This schematic illustrates that cystine import through the xCT system is essential for GSH synthesis and the proper function of GPX4. The activity of GPX4 prevents the accumulation of ROS. Ferroptosis is initiated through phospholipid peroxidation, which relies on ROS, PUFA-PL and transition metal iron as metabolic products. Intracellular and intercellular signalling events and environmental stimuli can all have a role in the progression of ferroptosis. 5-LOX, 5-lipoxygenase; ACSF2, acyl-coA synthetase Family family member 2; ACSL4, acyl-CoA synthetase long-chain family member 4; BH2, 7,8-dihydrobiopterin; BH4, tetrahydrobiopterin; CoQ10, coenzyme Q10; DFO, deferoxamine; DMT1, divalent metal transporter 1; DPP4, dipeptidyl peptidase 4; Fer-1, ferrostatin-1; FLT-3, fms-like tyrosine kinase 3; FSP1, ferroptosis suppressor protein-1; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; GCH1, GTP cyclohydrolase 1; GPX4, glutathione peroxidase 4; GSH, glutathione; HSPB1, heat shock protein beta 1; IREB2, iron responsive element binding protein 2; Lip-1, liproxstatin-1; NAPDH, nicotinamide adenine dinucleotide phosphate; NOX, nitrogen oxides; NRF2, nuclear factor erythroid 2-related factor 2; PKC, protein kinase C; PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; STEAP3, Six-transmembrane epithelial antigen of the prostate 3; TFR1, transferrin receptor 1; VDAC2/3, voltage-dependent anion channel 2/3; xCT, cystine/glutamate antiporter.

Figure 3

Ferroptosis regulation defence systems. This schematic chart illustrates the main control regulatory systems for ferroptosis, which include the xCT-GSH-GPX4, NAD(P)H/FSP1/CoQ10 and GCH1/BH4 pathways. The canonical axis for ferroptosis control involves the uptake of cystine via the cystine-glutamate antiporter, reducing cystine to cysteine through GSH. GSH is a crucial substrate of GPX4, thus preventing ferroptosis. The FSP1/CoQ10 system in ferroptosis has been identified in two independent genetic screens that fully protect against ferroptosis induced by pharmacological inhibition or genetic deletion of GPX4. Unlike GSH/GPX4, FSP1 prevents lipid peroxidation and associated ferroptosis via the reduction of ubiquinol/α-tocopherol on the level of lipid radicals. Researchers have recently identified a new pathway for regulating ferroptosis, which involves the GCH1/BH4/DHFR axis. BH4 is an effective free radical antioxidant that can be reduced by DHFR and inhibit lipid peroxidation. BH4 also has the potential to stimulate the production of CoQ10. BH4, tetrahydrobiopterin; CoQ10, coenzyme Q10; DHFR, dihydrofolate reductase; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclohydrolase 1; GPX4, glutathione peroxidase 4; GSH, glutathione; GSR, glutathione-disulfide reductase; IPP, intracisternal a particle-promoted polypeptide; MTX, methotrexate; NAPDH, nicotinamide adenine dinucleotide phosphate; xCT, cystine/glutamate antiporter.

Figure 4

The potential role of ferroptosis in depression. The molecular mechanism of ferroptosis is involved in the progression of depression. Chronic stress can induce iron overload and the production of ROS in neurons. ACSL4, acyl-CoA synthetase long-chain family member 4; FPN1, ferroportin 1; GPX4, glutathione peroxidase 4; GSH, glutathione; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; TFR1, transferrin receptor 1.

Figure 5

The structure of small molecule ferroptosis inhibitors. These inhibitors come in various forms, such as (A) iron chelators that hinder intracellular Fe²⁺, (B) radical-trapping antioxidants that impede the role of reactive oxygen species (ROS) and (C) natural compounds that block the acyl-CoA synthetase long-chain family member 4 (ACSL4) protein. THN, tetrahydronaphthyridinols.