Astragaloside IV Confers Prophylactic Efficacy Against Depression Associated with the ROS/Nrf2/Keap1 Axis: Modulation of Oxidative Stress and Energy Homeostasis
Restricted accessResearch articleFirst published online June, 2026
Astragaloside IV Confers Prophylactic Efficacy Against Depression Associated with the ROS/Nrf2/Keap1 Axis: Modulation of Oxidative Stress and Energy Homeostasis
Depression is a prevalent mood disorder with significant suffering and heightened suicide risk. Accumulating evidence points to oxidative stress and impaired energy metabolism of the brain as key contributors to the pathogenesis of depression. Astragaloside IV (AIV) has been demonstrated to alleviate neurological damage. The capacity of AIV for antioxidation has also been gradually discovered. Yet, it still just scratches the surface of the antidepression mechanisms of AIV. Our aim was to explore a novel mechanism of action of AIV from the perspectives of redox homeostasis and energy metabolism via the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) axis.
Results:
AIV ameliorated anxiety and cognitive dysfunction in rats with depression-like behaviors. Furthermore, we illustrated that AIV reversed redox dyshomeostasis of rats with depression-like behaviors in terms of decreasing the level of malondialdehyde while increasing the abundances of catalase, superoxide dismutase, and glutathione peroxidase. In addition, AIV significantly increased the levels of indicators of energy metabolism that were interrupted by depression. Furthermore, in vitro, AIV significantly increased the levels of indicators related to the Nrf2/Keap1 signaling pathway in corticosterone-induced PC12 cells.
Innovation:
For the first time, it demonstrates that AIV alleviates depression by modulating the ROS/Nrf2/Keap1 axis and restoring hippocampal energy metabolism in a chronic unpredictable mild stress model.
Conclusion:
The current findings not only offer novel insights into antidepressant-like effects of AIV through the ROS/Nrf2/Keap1 axis but also provide a foundation for enhancing clinical efficiency and enriching drug selection. Antioxid. Redox Signal. 44, 822–842.
BélangerM, AllamanI, MagistrettiP. Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation. Cell Metab, 2011; 14(6):724–738; doi: 10.1016/j.cmet.2011.08.016
2.
BhattS, NagappaAN, PatilCR. Role of oxidative stress in depression. Drug Discov Today, 2020; 25(7):1270–1276; doi: 10.1016/j.drudis.2020.05.001
3.
CalabreseV, CorneliusC, StellaAMG, et al.Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: Role of hormesis and vitagenes. Neurochem Res, 2010; 35(12):1880–1915; doi: 10.1007/s11064-010-0307-z
4.
ChenF, YangD, ChengX, et al.Astragaloside IV ameliorates cognitive impairment and neuroinflammation in an oligomeric Aβ induced Alzheimer’s disease m mouse model via inhibition of microglial activation and NADPH oxidase expression. Biol Pharm Bull, 2021; 44(11):1688–1696; doi: 10.1248/bpb.b21-00381
5.
ChodavadiaP, TeoI, PoremskiD, et al.Prevalence and economic burden of depression and anxiety symptoms among Singaporean adults: Results from a 2022 web panel. BMC Psychiatry, 2023; 23(1):104; doi: 10.1186/s12888-023-04581-7
6.
ContrerasRG, Torres-CarrilloA, Flores-MaldonadoC, et al.Na/K-ATPase: More than an electrogenic pump. Int J Mol Sci, 2024; 25(11):6122; doi: 10.3390/ijms25116122
7.
CoxCS, McKaySE, HolmbeckMA, et al.Mitohormesis in mice via sustained basal activation of mitochondrial and antioxidant signaling. Cell Metab, 2018; 28(5):776–786.e5; doi: 10.1016/j.cmet.2018.07.011
8.
De OliveiraMR. Fluoxetine and the mitochondria: A review of the toxicological aspects. Toxicol Lett, 2016; 258:185–191; doi: 10.1016/j.toxlet.2016.07.001
9.
DengY, ChuX, LiQ, et al.Xanthohumol ameliorates drug-induced hepatic ferroptosis via activating Nrf2/xCT/GPX4 signaling pathway. Phytomedicine, 2024; 126:155458; doi: 10.1016/j.phymed.2024.155458
10.
DiY, XueR, LiX, et al.Urolithin a exhibits antidepressant-like effects by modulating the AMPK/CREB/BDNF pathway. Nutrients, 2025; 17(14):2294; doi: 10.3390/nu17142294
11.
DjordjevicA, SpasicS, Jovanovic-GalovicA, et al.Oxidative stress in diabetic pregnancy: SOD, CAT and GSH-Px activity and lipid peroxidation products. J Matern Fetal Neonatal Med, 2004; 16(6):367–372; doi: 10.1080/14767050400018270
12.
DjordjevicJ, DjordjevicA, AdzicM, et al.Alterations in the Nrf2/Keap1 signaling pathway and its downstream target genes in rat brain under stress. Brain Res, 2015; 1602:20–31; doi: 10.1016/j.brainres.2015.01.010
13.
FerreiraMF, CastanheiraL, SebastiãoAM, et al.Depression assessment in clinical trials and pre-clinical tests: A critical review. Curr Top Med Chem, 2018; 18(19):1677–1703; doi: 10.2174/1568026618666181115095920
14.
GaoL, WangJ, LiuX, et al.RinsenosideRg1 and its involvement in Hippo-YAP signaling pathway alleviating symptoms of depressive-like behavior. Sci Rep, 2025; 15(1):14441; doi: 10.1038/s41598-025-99587-4
15.
GuoC, LiY, YangR, et al.Astragaloside IV attenuates glucocorticoid-induced osteoclastogenesis and bone loss via the MAPK/NF-κB pathway. BMC Complement Med Ther, 2025; 25(1):48; doi: 10.1186/s12906-025-04793-2
16.
HeQ, HanC, HuangL, et al.Astragaloside IV alleviates mouse slow transit constipation by modulating gut microbiota profile and promoting butyric acid generation. J Cell Mol Med, 2020; 24(16):9349–9361; doi: 10.1111/jcmm.15586
17.
HuangR, ZhouC, WangT, et al.Lycopene inhibits doxorubicin-induced heart failure by inhibiting ferroptosis through the Nrf2 signaling pathway. Life Sci, 2025; 365:123452; doi: 10.1016/j.lfs.2025.123452
18.
JiangC, ZhouH, ChenL, et al.Problem solving therapy improves effortful cognition in major depression. Front Psychiatry, 2021; 12:607718; doi: 10.3389/fpsyt.2021.607718
19.
KaoC, TsaiS, SuT, et al.Monoamine neurotransmitter-related gene-based genome-wide association study of low-dose ketamine in patients with treatment-resistant depression. J Psychopharmacol, 2025; 39(6):593–602; doi: 10.1177/02698811251326939
20.
KhanMU, KomolafeBO, WeberKT. Cation interdependency in acute stressor states. Am J Med Sci, 2013; 345(5):401–404; doi: 10.1097/MAJ.0b013e318253cb07
21.
KimHJ, KimJH, LeeS, et al.PM2.5 exposure triggers hypothalamic oxidative and ER stress leading to depressive-like behaviors in rats. Int J Mol Sci, 2024; 25(24):13527; doi: 10.3390/ijms252413527
22.
LiJ, WangZ, WangY, et al.The essential oil from the rhizomes of stahlianthus involucratus attenuates the progression of vascular aging and atherosclerosis by regulating Nrf2-mediated mitochondrial quality. Front Pharmacol, 2025; 16:1579333; doi: 10.3389/fphar.2025.1579333
23.
LiM, JiaJ, WangY, et al.Astragaloside IV promotes cerebral tissue restoration through activating AMPK-mediated microglia polarization in ischemic stroke rats. J Ethnopharmacol, 2024; 334:118532; doi: 10.1016/j.jep.2024.118532
24.
LiuJ, WangY, QiaoP, et al.Mechanisms of cisplatin-induced acute kidney injury: The role of NRF2 in mitochondrial dysfunction and metabolic reprogramming. Antioxidants (Basel), 2025a;14(7):775; doi: 10.3390/antiox14070775
25.
LiuM, WangJ, WangR, et al.MRI evaluation of neuroprotective effects of astragaloside IV on rotenone-induced late-stage Parkinson’s disease mice. Neuroscience, 2025b;568:195–201; doi: 10.1016/j.neuroscience.2024.12.046
26.
LiuM, YinJ, SunR, et al.Discovery of antidepressant active compounds from polygala tenuifolia Willd: An integrated multitarget screening strategy combining network pharmacology with cell membrane chromatography coupled to high performance liquid chromatography. J Ethnopharmacol, 2026; 354:120527; doi: 10.1016/j.jep.2025.120527
27.
LiuX, WangS, WuX, et al.Astragaloside IV alleviates depression in rats by modulating intestinal microbiota, T-immune balance, and metabolome. J Agric Food Chem, 2024; 72(1):259–273; doi: 10.1021/acs.jafc.3c04063
28.
LiuX, WuX, WangS, et al.Microbiome and metabolome integrally reveal the anti-depression effects of cistanche deserticola polysaccharides from the perspective of gut homeostasis. Int J Biol Macromol, 2023; 245:125542; doi: 10.1016/j.ijbiomac.2023.125542
29.
LiuX, YangX, TangS, et al.Study on borneol combined with astragaloside IV and Panax notoginseng saponins promoting bioactive components into brain in cerebral ischemia/reperfusion model of rats. Chin Herb Med, 2019; 50(7):1649–1656; doi: 10.7501/j.issn.0253-2670.2019.07.023
30.
LiuY, YanJ, SunC, et al.Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway. Redox Biol, 2018; 17:143–157; doi: 10.1016/j.redox.2018.04.012
31.
LiuY, ZhangB, ZhouY, et al.Plasma oxidative stress marker levels related to functional brain abnormalities in first-episode drug-naive major depressive disorder. Psychiatry Res, 2024b;333:115742; doi: 10.1016/j.psychres.2024.115742
32.
MaQ, ZhouJ, YangZ, et al.Mingmu Xiaoyao granules regulate the PI3K/Akt/mTOR signaling pathway to reduce anxiety and depression and reverse retinal abnormalities in rats. Front Pharmacol, 2022; 13:1003614; doi: 10.3389/fphar.2022.1003614
33.
MaX, XueS, MaH, et al.Esketamine alleviates LPS-induced depression-like behavior by activating Nrf2-mediated anti-inflammatory response in adolescent mice. Neuroscience, 2025; 567:294–307; doi: 10.1016/j.neuroscience.2024.12.062
34.
MengZ, LiM, WangX, et al.Inula britannica ameliorates alcohol-induced liver injury by modulating SIRT1-AMPK/Nrf2/NF-κB signaling pathway. Chin Herb Med, 2024; 16(4):667–678; doi: 10.1016/j.chmed.2023.12.006
MukherjeeR, RanaR, MehanS, et al.Investigating the interplay between the Nrf2/Keap1/HO-1/SIRT-1 pathway and the p75NTR/PI3K/Akt/MAPK cascade in neurological disorders: Mechanistic insights and therapeutic innovations. Mol Neurobiol, 2025; 62(6):7597–7646; doi: 10.1007/s12035-025-04725-8
37.
PapageorgiouL, ChristouE, LoukaE, et al.ADRA2B and HTR1A: An updated study of the biogenic amine receptors reveals novel conserved motifs which play key role in mental disorders. Adv Exp Med Biol, 2023; 1423:79–99; doi: 10.1007/978-3-031-31978-5_7
RaoJ, JagadeesanV. Lipid peroxidation and activities of antioxidant enzymes in iron deficiency and effect of carcinogen feeding. Free Radic Biol Med, 1996; 21(1):103–108; doi: 10.1016/0891-5849(95)02212-0
40.
RatajczakP, MartyńskiJ, ZiębaJK, et al.Comparative efficacy of animal depression models and antidepressant treatment: A systematic review and meta-analysis. Pharmaceutics, 2024; 16(9):1144; doi: 10.3390/pharmaceutics16091144
41.
RenZ, XiaoL, XieY, et al.Effects of testosterone dose on depression-like behavior among castrated adult male rats. Psychoneuroendocrinology, 2024; 165:107046; doi: 10.1016/j.psyneuen.2024.107046
42.
RigottiM, FingerLF, ScariotFJ, et al.Grape seed extract pretreatment prevents mitochondrial dysfunction and NLRP3 inflammasome-induced inflammatory response in glial cells exposed to paroxetine and quinolinic acid. Mol Neurobiol, 2025; 62(6):7110–7123; doi: 10.1007/s12035-025-04730-x
43.
RivadeneiraDB, ThosarS, QuannK, et al.Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer. Immunity, 2025; 58(10):e00371–e2540.e5; doi: 10.1016/j.immuni.2025.08.008
44.
Selva-ClementeJ, MarcosP, González-FuentesJ, et al.Interneurons in the CA1 stratum oriens expressing αTTP may play a role in the delayed-ageing Pol μ mouse model. Mol Cell Neurosci, 2024; 130:103960; doi: 10.1016/j.mcn.2024.103960
45.
SheeranFL, PepeS. Mitochondrial bioenergetics and dysfunction in failing heart. Adv Exp Med Biol, 2017; 982:65–80; doi: 10.1007/978-3-319-55330-6_4
46.
ShojiH, MaedaY, MiyakawaT. Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice. Mol Brain, 2024; 17(1):79; doi: 10.1186/s13041-024-01146-x
47.
SongMT, RuanJ, ZhangRY, et al.Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARγ/NF-κB/NLRP3 inflammasome axis. Acta Pharmacol Sin, 2018; 39(10):1559–1570; doi: 10.1038/aps.2017.208
48.
Villavicencio-TejoF, OlesenMA, AmpueroE, et al.Sulforaphane prevents cognitive decline and mitochondrial failure induced by hippocampal expression of caspase-3 cleaved tau. Neurochem Int, 2025; 187:105991; doi: 10.1016/j.neuint.2025.105991
49.
WangZ, WangX, LiY, et al.Integrated multi-omics analysis reveals immune and metabolic dysregulation in a restraint stress-induced depression model. Biomedicines, 2025; 13(9):2183; doi: 10.3390/biomedicines13092183
50.
WuW, LiaoY, LiangJ, et al.A network pharmacology approach confirms Biejiaxiaozheng pills combat hepatic fibrosis by modulating macrophage inflammation and hepatic stellate cell activation. Sci Rep, 2025; 15(1):24638; doi: 10.1038/s41598-025-09002-1
51.
YanK, ChenYB, WuJR, et al.Current rapid-onset antidepressants and related animal models. Curr Pharm Des, 2018; 24(22):2564–2572; doi: 10.2174/1381612824666180727115222
52.
YangT, LinX, LiH, et al.Acetyl-11-keto-beta boswellic acid (AKBA) protects lens epithelial cells against HO-induced oxidative injury and attenuates cataract pogression by activating Keap1/Nrf2/HO-1 signaling. Front Pharmacol, 2022; 13:927871; doi: 10.3389/fphar.2022.927871
53.
YaoR, HeC, XiaoP. ‘Food and medicine continuum’ in the East and West: Old tradition and current regulation. Chin Herb Med, 2023; 15(1):6–14; doi: 10.1016/j.chmed.2022.12.002
54.
YuanM, YangB, RothschildG, et al.Epigenetic regulation in major depression and other stress-related disorders: Molecular mechanisms, clinical relevance and therapeutic potential. Signal Transduct Target Ther, 2023; 8(1):309; doi: 10.1038/s41392-023-01519-z
55.
ZhangH, XueX, PanJ, et al.Integrated analysis of the chemical-material basis and molecular mechanisms for the classic herbal formula of lily bulb and rehmannia decoction in alleviating depression. Chin Med, 2021; 16(1):107; doi: 10.1186/s13020-021-00519-x
56.
ZhouZ, HuangL, WuD, et al.Menaquinone-4 ameliorates abdominal aortic aneurysm by suppressing ferroptosis through NRF2/GCLM axis. Gene, 2025; 970:149785; doi: 10.1016/j.gene.2025.149785
57.
ZhuY, FanZ, ZhaoQ, et al.Brain-type glycogen phosphorylase is crucial for astrocytic glycogen accumulation in chronic social defeat stress-induced depression in mice. Front Mol Neurosci, 2021; 14:819440; doi: 10.3389/fnmol.2021.819440
58.
ZouY, TangY, FanW, et al.Cognition impairment of rat in undersea environment. Int J Environ Health Res, 2022; 32(4):829–839; doi: 10.1080/09603123.2020.1799955
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
