General Information of the Disease (ID: DIS00066)
Name
Depressive disorder
ICD
ICD-11: 6A70
Full List of Target(s) of This Ferroptosis-centered Disease
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Depression [ICD-11: 6A70]
Responsed Drug Sodium hydrosulfide Investigative
Responsed Regulator Cystathionine beta-synthase (CBS) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model BV-2 cells Normal Mus musculus CVCL_0182
In Vivo Model
Adult male 22-24 g C57BL/6J mice were purchased from the Vital River Laboratory Animal Technology Co., Ltd. Mice were randomly divided into four groups, the control group (CON group, n = 8), diabetes mellitus group (DM group, n = 8), DM + sodium hydrosulfide (DM + 5.6 mg/kg NaHS, n = 8) group, and CON + sodium hydrosulfide (CON + 5.6 mg/kg NaHS, n = 8) group. In this experiment, mice have received daily intraperitoneally injection of NaHS during the last 4 weeks. Then, all mice were tested by the open field test (OFT), elevated plus maze test (EPM test), forced swimming test (FST), and tail suspension test (TST).

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Response regulation Sodium hydrosulfide (NaHS) ameliorated the ferroptosis via increasing the protein expressions of SLC7A11, glutathione peroxidase 4 (GPX4), and cystathionine -synthase (CBS), reducing the pro-inflammatory cytokines, decreasing the levels of Fe2+, MDA, ROS, and lipid ROS. In conclusion, NaHS did alleviate anxiety and depression.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Depression [ICD-11: 6A70]
Responsed Drug Xiaoyaosan Investigative
Responsed Regulator Phosphatidylethanolamine-binding protein 1 (PEBP1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model mHTs (Mouse hippocampus tissues)
In Vivo Model
The specific-pathogen free (SPF) male C57BL/6 mice (8-week-old, SCXK (Beijing) 2016-0006) were purchased from Beijing Vital River Laboratory Animal Technology Limited Company. A total of 48 mice were randomly assigned to 4 groups (n = 12): a control group (no stress + physiological saline), a CUMS group (CUMS + physiological saline), a Xiaoyaosan group (CUMS + Xiaoyaosan treatment) and a fluoxetine group (CUMS + fluoxetine treatment).

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Response regulation The activation of ferroptosis might exist in the hippocampi of CUMS-induced mice. The PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan. It also implied that ferroptosis could become a new target for research into the depression mechanism and antidepressant drugs.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Depression [ICD-11: 6A70]
Responsed Drug Edaravone Approved
Responsed Regulator NAD-dependent protein deacetylase sirtuin-1 (SIRT1) Suppressor
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model hBCs (Brain cells)
In Vivo Model
Male C57BL/6J mice (aged 7-8 weeks) and retired male CD-1 mice (aged 16-20 weeks) were obtained from the Experimental Animal Centre of Chongqing Medical University (Chongqing, China). The experimental animals were housed in cages under a 12 h light/12 h dark cycle (lights on at 8:00 a.m.), 60 ± 5% humidity, and a temperature of 23 ± 1 with access to water and food freely. All experimental procedures were conducted in accordance with the Ethics Committee of Chongqing Medical University. EDA was purchased from Sigma-Aldrich (St. Louis, USA) and was dissolved in Vehicle (NaCl, 0.9%) at a dosage of 10 mg/kg. EX527 (a Sirt1 inhibitor) and ML385 (a Nrf2 inhibitor) were obtained from MedChemExpress (New Jersey, USA).

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Response regulation The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.
References
Ref 1 Hydrogen sulfide alleviates the anxiety-like and depressive-like behaviors of type 1 diabetic mice via inhibiting inflammation and ferroptosis. Life Sci. 2021 Aug 1;278:119551. doi: 10.1016/j.lfs.2021.119551. Epub 2021 May 1.
Ref 2 Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus. Neuropsychiatr Dis Treat. 2021 Apr 6;17:1001-1019. doi: 10.2147/NDT.S302443. eCollection 2021.
Ref 3 Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J Neuroinflammation. 2022 Feb 7;19(1):41. doi: 10.1186/s12974-022-02400-6.