Aerobic Exercise Inhibits Mitochondrial Ferroptosis in a Rat Model of Depression by Activating the SLC7A11/GPx4 Pathway

DOI: https://doi.org/10.62517/jmhs.202505405

Author(s)

Shanshan Xie1, Yong Zhi2,3,*, Wenkai Chao3, Xiaoyang Zhang3

Affiliation(s)

1Xinjiang Key Laboratory of Mental Development and Learning Science, Xinjiang Normal University, Urumqi, Xinjiang , China 2Xinjiang 474 Hospital, Urumqi, Xinjiang, China 3College of Traditional Chinese Medicine,Xinjiang Medical University, Urumqi, Xinjiang , China *Corresponding Author.

Abstract

Objective: Investigate the role of SLC7A11/GPx4-mediated ferroptosis in aerobic exercise's antidepressant effects. Methods: 36 male SD rats were divided into Control (Con), Depression Model (Mod - CUMS), and Aerobic Exercise (AE - CUMS + 4 weeks exercise) groups (n=12 each). Post-intervention, behavioral tests (sucrose preference, OFT) were conducted. Serum ferritin (SF) and mitochondrial 8-OHdG were measured by ELISA. Prefrontal cortex (PFC) pathology was assessed via HE staining and mitochondrial ultrastructure via TEM. PFC protein levels (GPx4, SLC7A11, FPN1, FTH1) were analyzed by Western blot.Results: Compared to Con, Mod rats showed significantly reduced sucrose preference (P<0.01) and OFT crossings/rearings (P<0.05), elevated serum SF and 8-OHdG (P<0.05), neuronal damage (HE), and mitochondrial damage (swelling, cristae disruption) indicative of ferroptosis (TEM). Protein levels (SLC7A11, GPx4, FPN1, FTH1) were significantly lower in Mod (P<0.05). Compared to Mod, AE rats exhibited significantly increased sucrose preference (P<0.01) and OFT activity (P<0.05), reduced SF and 8-OHdG (P<0.05), alleviated neuronal damage (HE), and improved mitochondrial morphology (TEM). Protein levels (SLC7A11, GPx4, FPN1, FTH1) were significantly higher in AE (P<0.05).Conclusion: Aerobic exercise significantly ameliorated CUMS-induced depression in rats. The mechanism likely involves activating the SLC7A11/GPx4 pathway, inhibiting mitochondrial ferroptosis, and improving iron metabolism, suggesting a novel therapeutic target.

Keywords

Aerobic Exercise; Depression; Mitochondria; Ferroptosis

References

[1]Wang G, Tian SS, Zhang L, et al. Research progress and hot issues in depression over the past decade [J]. Chinese Journal of Psychiatry, 2025, 58(2): 94-102. [2]Tao S, Deng R, Wei M, et al. A Meta-Analysis of Magnetic Resonance Spectroscopy Studies on Glutamatergic Neurometabolite Levels in Major Depressive Disorder [J]. Depress Anxiety. 2025: 5180077. [3]Yin YS, Liu JL, Wang JP, et al. Research progress on pathogenesis related to depression [J]. Medical Recapitulate, 2022, 28(12): 2368-2372. [4]Shi Y, Zhang LJ, Zhang RS, et al. Research progress on the pathogenesis of depression and treatment with traditional Chinese medicine based on ferroptosis [J]. World Journal of Integrated Traditional and Western Medicine, 2025, 20(4): 835-840. [5]Huang L, Liu C, Liang Y, et al. Baihe Dihuang Danshen Decoction Alleviates Myocardial Ischemia-Reperfusion Injury in Depression-Induced Rats by Inhibiting Ferroptosis [J]. Comb Chem High Throughput Screen. 2025: 40776654. [6]Maschalidi S, Mehrotra P, Keçeli BN, et al. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes [J]. Nature, 2022, 606(7915): 776-784. [7]Yu P, Zhang J, Ding Y, et al. Dexmedetomidine post-conditioning alleviates myocardial ischemia-reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation [J]. Hum Cell, 2022, 35(3): 836-848. [8]Liu T, Cui Y, Dong S, et al. Treadmill training reduces cerebral ischemia-reperfusion injury by inhibiting Ferroptosis through activation of SLC7A11/GPX4 [J]. Oxid Med Cell Longev, 2022, 2022: 8693664. [9]Wang J, Zhu Q, Wang Y, et al. Irisin protects against sepsis-associated encephalopathy by suppressing ferroptosis via activation of the Nrf2/GPX4 signal axis [J]. Free Radic Biol Med, 2022, 187(4): 171-184. [10]Jiang MR, Wang LY. Research progress on mitochondrial-related mechanisms in depression [J]. Acta Universitatis Medicinalis Anhui, 2023, 58(7): 1233-1238. [11]Zhai L, Sun JZ, Chen XN, et al. Effect of "Tongdu Jieyu" acupuncture on the BDNF/TrkB/CREB pathway in the prefrontal cortex of CUMS depression model rats [J]. Journal of Clinical Acupuncture and Moxibustion, 2024, 40(5): 68-74. [12]Wang T, Zhou X, Yin X, et al. From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy (Review) [J]. Int J Oncol. 2025, 67(3): 76. [13]Wu S, Wang Z, Wang L. USP7 represses ferroptosis in trophoblasts in pre-eclampsia by mediating the xCT/GPX4 axis via deubiquitination of NRF2 [J]. Tissue Cell. 2025, 97: 103050. [14]Liao J, Ge JW, Yu QP, et al. Research status of ferroptosis [J]. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology, 2019, 21(10): 2151-2158. [15]Zhang TT, Qian J, Zong YW. Relationship between serum 8-OHdG, COR, IL-18 levels and post-stroke depression [J]. Shandong Medical Journal, 2024, 64(16): 24-28. [16]Wu Y, Ji Y, Jin X, et al. YLKTT, a potent biopeptide that ameliorates oxygen-glucose deprivation-induced neuronal cell ferroptosis by ACSL4/GPX4 and SLC7A11/GPX4 axis [J]. J Pharm Pharmacol. 2025: rgaf037. [17]Wu R, Wang T, Xu X, et al. Phoenixin-14 Alleviates Premature Ovarian Failure by Inhibiting Ferroptosis Through SLC7A11/GPX4 [J]. Drug Dev Res. 2025, 86(5): e70110. [18]Kong X, Wei P, Meng L, et al. Discovery of a potential anti-ischemic stroke agent by suppressing ferroptosis through the ATF3/SLC7A11/GPX4 pathway [J]. Eur J Med Chem. 2025, 296: 117873. [19]Wang T, Zhou X, Yin X, et al. From mitochondrial dysregulation to ferroptosis: Exploring new strategies and challenges in radioimmunotherapy [J]. Int J Oncol. 2025, 67(3): 76. [20]Wang QX, Feng XY, Huang Y, et al. Ferroptosis in glial cells [J]. Chinese Journal of Pathophysiology, 2024, 40(11): 2166-2172. [21]Zhou B, Li J, Wu A, et al. Insights into targeted ferroptosis in mechanisms, biology, and role of Alzheimer's disease: an update [J]. Front Aging Neurosci. 2025, 17: 1587986. [22]Long R, Liang M, Shen Q, et al. Autophagic regulation of the iron efflux Pump MoFpn1 induces ferroptosis in developing conidia of Magnaporthe oryzae [J]. Autophagy. 2025: 40774826.