Recycling of Glutathione by Glutathione Reductase. Glutathione (GSH) is maintained in a reduced form by glutathione reductase (GR) in a NADPH-dependent manner. Enzymes are labelled in green. Glutathione peroxidases (GPx), glutaredoxin (Grx). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Recycling of Glutathione by Glutathione Reductase. Glutathione (GSH) is maintained in a reduced form by glutathione reductase (GR) in a NADPH-dependent manner. Enzymes are labelled in green. Glutathione peroxidases (GPx), glutaredoxin (Grx). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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Glutathione is the most abundant intracellular low molecular weight thiol in cells and tissues, and plays an essential role in numerous cellular processes, including antioxidant defenses, the regulation of protein function, protein localization and stability, DNA synthesis, gene expression, cell proliferation, and cell signaling. Sexual dimorphisms...

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... of two subunits: catalytic GCLC (73 kDa) and modifier GCLM (31 kDa) [37,46]. Within the cells, levels of reduced GSH are maintained by glutathione reductase (GR), which catalyzes the reduction of glutathione disulfide generated by the antioxidant enzymes glutathione peroxidases (GPx) and during the regeneration of oxidized glutaredoxins (GRX) ( Fig. 3; see section 3.1). Due to the high demand in cysteine in the body, GSH acts as a continuous source and transporter of cysteine throughout the body ...
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... catalyzes the reduction of GSSG to GSH, using NADPH as an electron donor (Fig. 3) [86]. GR is responsible for maintaining the GSH/ GSSG ratio by reducing GSSG generated during states of oxidative stress. The ratio of GSH/GSSG is a sensitive indicator of changes in a cell's thiol redox state and ongoing redox signaling [53]. The GSH/ GSSG ratio is remarkably similar across different cell types, but varies between ...
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... similar across different cell types, but varies between different cellular compartments, and the changes of GSH/ GSSG ratio affect cell functions such as apoptosis, differentiation and proliferation [53,57]. GSSG production increases during the detoxification of reactive oxygen species (ROS) by GPx and during the reactivation of oxidized GRX ( Fig. 3; see section 3.1) [4], resulting in a decrease in the GSH/GSSG ratio [6]. Since GSSG increases can be harmful to cells, the reduction of GSSG by GR is essential for restoring the redox homeostasis ...
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... is maintained during most of their adulthood but was not observed in aged rats. In male rats, concentrations of hepatic vitamin E, the most important antioxidant in cell membranes, are lower than in females but increase during aging. Whether this increase is due to increased GRX recycling, which controls vitamin E regeneration, is not known ( Fig. 3; see section 3.1). Interestingly, female livers show agedependent declines in GR activity. No such changes were observed in male liver cytosolic GR activity during aging [92]. A decline in GR activity was also observed in brain cortex homogenates during early post-natal development in both male and female rats [28], but no significant ...
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... catalyzes the reduction of hydrogen peroxide to water as well as the reduction of other noxious peroxides, including lipid peroxides, into the corresponding alcohols [72]. GPx has also been reported to reduce highly reactive peroxynitrite [106]. In these reactions, GSH serves as the electron donor, resulting in the formation of GSSG [53,76] (Fig. 3). The class of mammalian GPx currently encompasses 8 enzymes, GPx1-GPx8 [15]. Of these, GPx1-4 and GPx6 are seleniumcontaining GPxs, and GPx5, 7 and 8 are non-selenium congeners ...
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... and members of the thioredoxin superfamily [104]. This enzyme exists in multiple isoforms and has been reported in most living organisms [21]. GRX catalyzes the reduction of GSH-protein mixed disulfides. The resulting GRX-GSH mixed disulfide is reduced by GSH, generating active GRX and GSSG, which in turn is reduced by GR and NADPH to GSH (Fig. 3) [34]. Little is known about sex differences in GRX activity or expression levels. The lumbosacral cord of female mice has higher GRX1 mRNA and protein expression levels and greater enzyme activity than male mice ...

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... If the increase of reactive oxygen species level during COV-ID-19 is beyond doubt, the results of the antioxidant status studies of both the glutathione system and SOD activity during SARS-CoV-2 infection are ambiguous [4-8, 14, 15]. The reasons for the ambiguity of these results may be the lack of control groups in the studies, as well as the lack of consideration of age and gender, although these factors may influence the AOD system activity [16,17]. ...
Article
The aim. The research was conducted to assess the total antioxidant and glutathione status, superoxide dismutase activity in menopausal women with moderate and asymptomatic COVID-19. Materials and methods . Ninety two women 45 to 69 years old were divided into groups: women without COVID-19, not vaccinated, with no antibodies to SARS-CoV-2 (IgG) – control; women with moderate COVID-19 – main group; women with anti-SARS-CoV-2 IgG in blood but who deny any symptoms of COVID-19 in the last 12 months – asymptomatic COVID-19. Results. A lower glutathione peroxidase (GPx), superoxide dismutase (SOD) activities and a higher glutathione reductase (GR) activity, glutathione S-transferase pi (GSTpi) concentrations were detected in the patients with moderate COVID-19 as compared to control. There were statistically lower oxidized glutathione (GSSG) levels, total antioxidant status (TAS) and higher reduced glutathione (GSH) levels, as well as GSH/GSSG ratio in the group with asymptomatic COVID-19 as compared to control. Significantly a lower GPx, SOD activities and a higher TAS, GR activity, GSTpi concentrations were detected in the patients with symptomatic COVID-19 as compared to group without clinical symptoms. ROC analysis shows the diagnostic significance of TAS (AUC = 0.714; p = 0.048), GSH (AUC = 0.714; p = 0.030), GSSG (AUC = 0.712; p = 0.031), GSH/GSSG (AUC = 0.837; p < 0.001) for group with asymptomatic COVID-19 compared with controls; TAS (AUC = 0.709; p = 0.020), SOD (AUC = 0.760; p < 0.001), GSH/GSSG (AUC = 0.658; p = 0.039), GPx (AUC = 0.774; p < 0.001), GSTpi (AUC = 0.864; p < 0.001) and GR (AUC = 0.871; p < 0.001) for group with moderate COVID-19 compared asympotmatic COVID-19. Conclusions. Antioxidant defense system activity in menopausal women depends on the COVID-19 course.
... GSH acts directly or indirectly in many biological processes, including protein synthesis, maintenance of intracellular redox balance and redox signaling, metabolism and protection cellular, detoxification, regulation of proliferation and apoptosis, and exerts immunobiological functions (Rover Júnior et al. 2001;Traverso et al. 2013;Lu 2013). Gender differences in GSH metabolism in aging and some pathologies, such as neurodegenerative diseases and diabetes, have already been described in the literature, with males being more susceptible to oxidative stress and decreased plasma GSH (Wang et al. 2003(Wang et al. , 2020Liu et al. 2005). The possible gender differences in GSH metabolism in cancer pathology are poorly understood, in this study, only male animals were adopted due to possible greater oxidative stress and GSH depletion, although future studies with female rats would be interesting to understand better the effects of GSH on the intestinal mucosa of female rats with cancer-induced cachexia. ...
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Walker-256 tumor is an experimental model known to promote cachexia syndrome, oxidative stress, and systemic inflammation. This study evaluated the duodenal mucosa of rats with Walker-256 tumor administered with 1% l-glutathione, intending to evaluate the damage caused by cancer-associated cachexia in the gastrointestinal tract and the effects of antioxidant administration on mucosal protection. Twenty-four 55-day-old male Wistar rats were distributed into four groups: control (C); control administered with 1% l-glutathione (C-GSH); Walker-256 tumor (W) and Walker-256 tumor administered with 1% l-glutathione (W-GSH). After 14 days of treatment, the duodenum was harvested for morphometric analysis of the mucosa, proliferation, apoptosis, immunostaining of varicosities immunoreactive (IR) to vasoactive intestinal peptide (VIP) and 5-HT-IR cells, and quantification of mast cells and goblet cells. Walker-256 tumor-bearing rats showed cachexia syndrome, mucosal atrophy, reduced cell proliferation, reduced 5-HT-IR cells, and increased goblet cells and VIPergic varicosities, which were not reversed by l-glutathione. On the other hand, l-glutathione caused a reduction of cells in apoptosis and mast cell recruitment, demonstrating a partial recovery of the damage detected in the intestinal mucosa.
... Antioxidant gene expression is higher in females than in males and is accompanied by lower oxidative damage [3] . In addition, there is considerable evidence that estrogen increases substantially the activities of GPX and Glutamate Cysteine Ligase (GCL), an enzyme in the GSH pathway [5][6][7] . ...
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Aims: Clinical and experimental evidence has shown that females in humans and other mammals have higher glutathione (GSH) levels than males, which are caused by higher levels of estradiol. Understanding how hepatic GSH level and synthesis velocity depend on the sex hormones is an extremely important question since oxidative stress contributes to the risk for heart disease and cancer, and oxidative stress is reduced by GSH. Our aim is to develop a systems approach to understanding GSH metabolism and use this to explain the causes of GSH differences in males and females, how GSH changes during the menstrual cycle, and why women may be less susceptible to acetaminophen toxicity. Methods: We use mathematical models for hepatic glutathione metabolism, including one-carbon metabolism and acetaminophen detoxification, to investigate how the activation of certain enzymes by estradiol leads to dramatic changes in reaction velocities and metabolite concentrations. Results: The models explain why women of childbearing age have higher glutathione than men, and that this is caused by the balance of activation of glutamyl cysteine synthetase (GCL) and glutathione peroxidase (GPX) by estradiol. The steady-state concentration of glutathione in women depends on the strength of the activation of GCL and GPX and is quite homeostatic over a wide range of activations. Conclusions: During the menstrual cycle, the GSH concentration changes daily but over a relatively narrow range. We explain how this dynamic homeostasis depends on the biochemical network that produces GSH. The model is also consistent with published results that show that female mice are less susceptible than males to hepatotoxicity due to acetaminophen overdose and suggests that this might also be true for humans, though the human epidemiological data are contradictory.
... We searched both ChEMBL and DrugBank Online with GPX3 as a target and identified glutathione in documented clinical trial profiles. Glutathione binds to other drugs to make them more soluble for excretion, and it also serves as a cofactor for certain enzymes involved in protein disulfide bond rearrangement and reducing peroxide production [87]. Due to the molecular characteristics and mechanism of action of glutathione, it is better suited as a supplement rather than a unique ALS treatment. ...
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Background There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. Methods To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. Results Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. Conclusions Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.
... In addition to HPA axis maturation, sexual dimorphism of the GSH metabolism and GSH-dependent responses have been reported [70] and may also be involved in sex-differences regarding internalizing symptoms. Accordingly, we found higher GPx activity in female adolescents as compared to males. ...
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Adolescence is marked by the maturation of systems involved in emotional regulation and by an increased risk for internalizing disorders (anxiety/depression), especially in females. Hypothalamic-pituitary-adrenal (HPA)-axis function and redox homeostasis (balance between reactive oxygen species and antioxidants) have both been associated with internalizing disorders and may represent critical factors for the development of brain networks of emotional regulation. However, sex-specific interactions between these factors and internalizing symptoms and their link with brain maturation remain unexplored. We investigated in a cohort of adolescents aged 13–15 from the general population ( n = 69) whether sex-differences in internalizing symptoms were associated with the glutathione (GSH)-redox cycle homeostasis and HPA-axis function and if these parameters were associated with brain white matter microstructure development. Female adolescents displayed higher levels of internalizing symptoms, GSH-peroxidase (GPx) activity and cortisol/11-deoxycortisol ratio than males. There was a strong correlation between GPx and GSH-reductase (Gred) activities in females only. The cortisol/11-deoxycortisol ratio, related to the HPA-axis activity, was associated with internalizing symptoms in both sexes, whereas GPx activity was associated with internalizing symptoms in females specifically. The cortisol/11-deoxycortisol ratio mediated sex-differences in internalizing symptoms and the association between anxiety and GPx activity in females specifically. In females, GPx activity was positively associated with generalized fractional anisotropy in widespread white matter brain regions. We found that higher levels of internalizing symptoms in female adolescents than in males relate to sex-differences in HPA-axis function. In females, our results suggest an important interplay between HPA-axis function and GSH-homeostasis, a parameter strongly associated with brain white matter microstructure.
... Sexual dysmorphism of GST activity can be observed in various organs. Females have a higher GST-pi detoxification activity, which may be related to female sex hormones [73]. For this reason, separate norms should be prepared for males and females. ...
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Background Serum creatinine, the criterion standard in assessment of renal function, is not reliable for the neonatal period because of its dependence on renal immaturity and maternal creatinine levels. Thus, it is important to study other biomarkers of renal function in neonates. The present study aimed to measure the urinary concentration of renal biomarkers: calbindin, clusterin, GST-pi (glutathione-S-transferase-alpha), KIM-1 (kidney injury molecule 1), MCP-1 (monocyte chemoattractant protein-1), and B2M (beta 2-microglobulin) in healthy term neonates. Material/Methods In the study, we included 80 healthy term neonates – 40 females and 40 males. We collected the neonates’ urine on their first day of life. Urinary concentrations of calbindin, clusterin, KIM-1, MCP-1, and B2M were assessed using an immunoassay for kidney toxicology research. Because dilution of the urine affects the concentrations of urinary biomarkers, we normalized them to the concentration of urinary creatinine (Cr) and present them as biomarker/Cr ratios. Results We obtained the following values of the assessed biomarker/Cr ratios (median [Q1–Q3]): calbindin/Cr.: 197.04 (56.25–595.17), KIM-1/Cr: 0.09 (0.04–0.18), MCP-1/Cr: 0.05 (0.02–0.14), B2M/Cr: 126.12 (19.03–342.48), GST-pi/Cr in boys: 1.28 (0.46–3.77), GST-pi/Cr in girls: 8.66 (2.51–27.82), clusterin/Cr: 4.55 (1.79–12.97) ng/mg Cr. Conclusions We showed the urinary levels of calbindin, clusterin, GST-pi, KIM-1, MCP-1, B2M in white, West Slavic, healthy term neonates. We found that in there is an association between female sex and a higher urinary GST-pi excretion, but urinary excretion of calbindin, clusterin, KIM-1, MCP-1, and B2M is sex-independent. The urinary levels of the assessed biomarkers do not depend on the method of delivery.
... In our study, APO (NOX inhibitor) showed elevated levels of GSH in mice brains. This response might be due to the utilization of NADPH by glutathione reductase (due to inhibition of NOX) to convert oxidized glutathione (GSSG) to reduced GSH [57], thus protecting against oxidative stress. Evidence from studies found that inhibition of NADPH (which was not certified by peer review) is the author/funder. ...
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Background Motor coordination (MC) and long-term recognition memory (LRM) are affected in people with multiple sclerosis (MS). The exact mechanism underlying the pathogenesis of MS is still unknown. However, oxidative stress is one of the underlying mechanisms of the pathogenesis of MS that is detrimental to myelin due to an imbalance in the levels of antioxidants. Dimethyl fumarate (DMF) is a first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Since OS plays a significant role in MS, in addition to DMF treatment, inhibition of NADPH oxidases (NOXs) may provide surplus glutathione (GSH) to prevent myelin loss. Hence, the objective of this study was to test the effect of a fixed dose of apocynin (50 mg/kg) combined with a fixed-dose DMF (30 mg/kg) on antioxidants, MC, and LRM in cuprizone (CUP)-induced mice model of demyelination. Methods The MC and LRM were evaluated by narrow beam and novel object recognition tests, catalase and superoxide dismutase activity by the degradation of hydrogen peroxide and nitroblue tetrazolium method; malondialdehyde by thiobarbituric acid assay, GSH by high-performance liquid chromatography, and presence of myelin by modified luxol fast blue staining. Results The combination therapy with DMF plus APO in CUP-fed mice preserved LRM and MC with a significant increase in catalase activity (1.15 ± 0.04 U/mg protein; p<0.001), superoxide dismutase activity (9.25 ± 0.10 U/mg protein; p<0.0001), and GSH (195.25 ± 22.75 nmol/mg protein, ****p <0.0001) of the cerebral cortex versus disease control (98.52 ± 8.85 nmol/mg protein). APO plus DMF30 in CUP-fed mice also preserved myelin (p<0.001) at the corpus callosum of mice brains. Conclusions We conclude that APO combination with DMF might have protected myelin by modulating (increasing) the levels of antioxidants to act against CUP-induced oxidative stress and thereby preserved MC and LRM in the cuprizone-induced mice model of demyelination.
... As a result, females may be more vulnerable to lipophilic chemicals that preferentially accumulate in fat tissue [27]. Moreover, there is evidence for sex differences in the activity of various cytochrome P-450 s (CYP450), the class of enzymes involved in the metabolism of toxic chemicals [28][29][30], as well as in the activity of glutathione peroxidase, which protects against oxidative damage [31]. . Differential activity of detoxification mechanisms can place one sex at heightened vulnerability compared with the other depending on the chemical of exposure. ...
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Background Early life exposure to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with lowered IQ in children. In some studies, these neurotoxicants impact males and females differently. We aimed to examine the sex-specific effects of exposure to developmental neurotoxicants on intelligence (IQ) in a systematic review and meta-analysis. Method We screened abstracts published in PsychINFO and PubMed before December 31st, 2021, for empirical studies of six neurotoxicants (lead, mercury, PCBs, PBDEs, OPPs, and phthalates) that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or before age six; and (3) provided effect estimates on general, nonverbal, and/or verbal IQ by sex. We assessed each study for risk of bias and evaluated the certainty of the evidence using Navigation Guide. We performed separate random effect meta-analyses by sex and timing of exposure with subgroup analyses by neurotoxicant. Results Fifty-one studies were included in the systematic review and 20 in the meta-analysis. Prenatal exposure to developmental neurotoxicants was associated with decreased general and nonverbal IQ in males, especially for lead. No significant effects were found for verbal IQ, or postnatal lead exposure and general IQ. Due to the limited number of studies, we were unable to analyze postnatal effects of any of the other neurotoxicants. Conclusion During fetal development, males may be more vulnerable than females to general and nonverbal intellectual deficits from neurotoxic exposures, especially from lead. More research is needed to examine the nuanced sex-specific effects found for postnatal exposure to toxic chemicals.
... The KEGG database showed two metabolic pathways, namely glutathione metabolism (51) and arachidonic acid metabolism (52), which were chosen for subsequent analyses (Figure 4). First, in the glutathione metabolism pathway, reduced glutathione (GSH) is converted to oxidized glutathione by the enzymes GPX2 and GPX3 in glutathione metabolism (GSSG). ...
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Introduction Lung cancer is a major cause of illness and death worldwide. Lung adenocarcinoma (LUAD) is its most common subtype. Metabolite-mRNA interactions play a crucial role in cancer metabolism. Thus, metabolism-related mRNAs are potential targets for cancer therapy. Methods This study constructed a network of metabolite-mRNA interactions (MMIs) using four databases. We retrieved mRNAs from the Tumor Genome Atlas (TCGA)-LUAD cohort showing significant expressional changes between tumor and non-tumor tissues and identified metabolism-related differential expression (DE) mRNAs among the MMIs. Candidate mRNAs showing significant contributions to the deep neural network (DNN) model were mined. Using MMIs and the results of function analysis, we created a subnetwork comprising candidate mRNAs and metabolites. Results Finally, 10 biomarkers were obtained after survival analysis and validation. Their good prognostic value in LUAD was validated in independent datasets. Their effectiveness was confirmed in the TCGA and an independent Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset by comparison with traditional machine-learning models. Conclusion To summarize, 10 metabolism-related biomarkers were identified, and their prognostic value was confirmed successfully through the MMI network and the DNN model. Our strategy bears implications to pave the way for investigating metabolic biomarkers in other cancers.
... GSH is the most important and abundant antioxidant to construct an endogenous non-enzymatic antioxidant system in organisms [23,37]. Its synthesis is mainly limited to the synthetic enzymes GCL and GS, among which the former is the first rate-limiting enzyme for GSH synthesis [38]. It has been verified that peroxidative products such as MDA are commonly degraded by GSH, which is assisted by the catalyzation of GSH-Px [39]. ...
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The aim of this study was to investigate the chemical composition and antioxidant capacity of various polar fractions obtained from Dendrobium fimbriatum Hook (DH). First, a 90% ethanol-aqueous extract of DH (CF) was subjected to sequential fractionation using different organic solvents, resulting in the isolation of a methylene chloride fraction (DF), an ethyl acetate fraction (EF), an n-butanol fraction (BF), and a remaining water fraction (WF) after condensation. Additionally, the CF was also subjected to column chromatography via a D101 macroreticular resin column, eluted with ethanol-aqueous solution to yield six fractions (0%, 20%, 40%, 60%, 80%, and 100%). UPLC-Q-Exactive Orbitrap-MS/MS analysis identified a total of 47 chemical compounds from these polar fractions, including fatty acids, amino acids, phenolic acids, flavonoids, organic heterocyclic molecules, and aromatic compounds. Moreover, DF, EF, and the 60%, 80%, and 100% ethanol-aqueous fractions had higher total phenol content (TPC) and total flavonoid content (TFC) values and greater 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS-) and 1,1-diphenyl-2-picrylhydrazyl (DPPH)-scavenging abilities. In H2O2-induced HepG2 cells, the aforementioned fractions could increase the activities of antioxidative enzymes NAD(P)H: quinone oxidoreductase 1 (NQO1), superoxide dismutase (SOD), heme oxygenase-1 (HO-1) and catalase (CAT), stimulate glutathione (GSH) synthesis by increasing the activities of glutamic acid cysteine ligase (GCL) and glutathione synthetase (GS), regulate GSH metabolism by increasing glutathione peroxidase (GSH-Px) and glutathione reductase (GR) activities, and reduce levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Furthermore, the antioxidative stress effect of the DH fractions was found to be positively correlated with the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) protein and the presence of antioxidative chemical constituents. In conclusion, this study highlights the efficacy of both liquid–liquid extraction and macroporous resin purification techniques in the enrichment of bioactive compounds from natural food resources. The comprehensive analysis of chemical constituents and antioxidant effects of different polar fractions from Dendrobium fimbriatum Hook contributes to the understanding of its potential application in functional foods and nutraceuticals.