Fig. 3: Hypothetical mechanism of ferroptosis in bipolar disorder pathogenesis.

BD shows high glutamate levels, which can increase the LIP by increasing expression of DMT1 through the NF-κB/PKC. The increased LIP, which could happen through higher iron importation by TFR1 and DMT1 or less exportation by FPN1, can promote the cytotoxicity of dopamine byproducts which is already increased in BD. The increased LIP can promote lipid radical formation (PUFAOOH^•) through a Fenton-like reaction, which ends up in lipid peroxidation and ferroptosis. Mitochondrial dysfunction in BD can lead to overwhelming the antioxidant defence system with ROS production. The high dopamine levels in BD can also participate in the increased ROS levels. The antioxidant failure in BD can cause disturbance in GSH, GPX4, and NrF2 which leads eventually to high ROS, lipid peroxidation, and ferroptosis. BD shows decreased sensitivity of glucocorticoid receptors along with high basal levels of corticosterone, while dexamethasone can induce ferroptosis by activation of p53, which decreases the expression of SLC7A11 and, therefore, the entry of cystine and production of GSH. Epigenetic modulation of circadian transcriptional factors (BMAL1 and Clock) is a prominent event in BD and their degradation (clockophagy) induces ferroptosis. FADS2 is strongly implicated in both BD pathogenesis and ferroptosis induction. Multiple BD treatments inhibit ferroptosis. ECT inhibits ferroptosis by activating NrF2, which increases the expression of SLC7A11 and loads Fe⁺² into ferritin, decreasing the LIP. ECT also activates GPX4 and inhibits ACSL4 and lipid peroxidation. Lithium inhibits ferroptosis by inhibiting the GSK3-β that inhibits NrF2, increasing the expression of SLC7A11. Lithium inhibits lipid peroxidation and ferroptosis by inhibiting both COX-2 and GSK3- β. Carbamazepine inhibits lipid peroxidation and ferroptosis by inhibiting COX-2. Clozapine N oxide, a metabolite of clozapine inhibits ferroptosis through inhibition of NCOA4-mediated ferritinophagy, which decreases ferritin degradation and build-up of the LIP. Haloperidol can inhibit iron dysregulation and thereby ferroptosis. Valproic acid inhibits HDAC, which in turn inhibits the epigenetic modulation of ferroptosis genes and ferroptosis. N -acetylcysteine inhibits ferroptosis by increasing both SLC7A11 and GSH. Both olanzapine and haloperidol inhibit ferroptosis through ROS scavenging action. Lamotrigine decreases the availability of PUFA. BD bipolar disorder, LIP labile iron pool, Fe⁺² ferrous iron, Fe⁺³ ferric iron, DMT1 divalent metallic transporter 1, TFR1 transferrin receptor 1, TF transferrin, FPN1 ferroportin 1, NF-κB nuclear factor kappa B, PKC protein kinase C, NCOA4 nuclear receptor co-activator 4, ECT electroconvulsive therapy, NrF2 nuclear factor erythroid 2-related factor 2, HDAC histone deacetylase, BMAL1 brain and muscle ARNT-like 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1, CLOCK circadian locomotor output cycles kaput, ROS reactive oxygen species, GSH glutathione, GPX4 glutathione peroxidase 4, SLC7A11 solute carrier family 7 member 11, ACSL4 acyl-coenzyme A synthetase long-chain family member 4, GSK3- β glycogen synthase kinase-3 beta, PUFA polyunsaturated fatty acid, FADS1/2 fatty acid desaturase1/2, COX-2 cyclooxygenase-2.