Search Results (865)

Salt stress is a severe threat to medicinal plants, adversely affecting their growth, yield, and quality. As a key antioxidant tripeptide, glutathione (GSH) confers salinity stress resilience in plants. However, how GSH shapes the plant tolerance to salt stress remains a mystery, especially in medicinal plants, including Pogostemon cablin. In this study, we investigated the regulatory effects of exogenous GSH on P. cablin seedlings under salt conditions. The results showed that GSH significantly improved seedling quality under both normal and salt conditions, evidenced by the increased shoot and root dry weight, plant height, and root length. Moreover, GSH effectively protected the photosynthetic system against salt-mediated damage via raised chlorophyll a, chlorophyll b, carotenoids, quantum yield of photosystem II [Y (II)], and PSII maximum efficiency (Fv/Fm). Furthermore, GSH stimulated the antioxidant defense system, including GSH, AsA, SOD, CAT, APX, POD, and GR, to restrain salt-induced malondialdehyde production and ROS burst. In addition, GSH treatment promoted the biosynthesis of secondary metabolites, including total polyphenol and flavonoid. RNA-seq analysis revealed that the activation of the flavonoid biosynthetic pathway significantly enhanced salt tolerance in P. cablin. Notably, several key regulatory genes within this pathway, including PAL, 4CL, C4H, CHI, ANS, F3′H, and CYP93, were significantly upregulated 24 h following GSH application under salt conditions. Therefore, exogenous GSH alleviates salt-induced oxidative stress in P. cablin via enhancing the antioxidant defense system and flavonoid biosynthetic activation. These findings provide valuable insights into the dual defense strategies of GSH for conferring salt resistance in plants. Full article

Background: Neonatal hypoxic–ischemic encephalopathy remains a leading cause of neonatal mortality and long-term neurodevelopmental disability worldwide. Despite the widespread adoption of therapeutic hypothermia, a substantial proportion of affected infants experience death or significant neurological impairment. Given their metabolic vulnerability, ketogenic diet strategies and ketone bodies have emerged as potential adjunctive neuroprotective interventions. This scoping review aims to critically evaluate the mechanistic rationale, preclinical evidence, and clinical feasibility of ketogenic approaches. Methods: A scoping review of the literature was conducted, including experimental and clinical studies investigating ketogenic diets, endogenous ketosis, and exogenous ketone supplementation in neonatal hypoxia–ischemia. Evidence was synthesized across mechanistic, preclinical, nutritional, and clinical domains, with particular attention to developmental context, timing of intervention, safety considerations, and translational relevance in the contest of therapeutic hypothermia. Results: Preclinical studies consistently demonstrate that ketone bodies enhance cerebral energy metabolism, support mitochondrial function, reduce excitotoxic signaling, and attenuate oxidative stress and neuroinflammation in the immature brain. Neonatal models show preferential utilization of β-hydroxybutyrate over glucose during hypoxic–ischemic stress, suggesting intrinsic metabolic advantages. Emerging evidence also supports potential long-term effects on epigenetic regulation and white matter development, although direct causal validation in neonatal HIE remains limited. Nutritional studies indicate that carefully monitored enteral and parenteral feeding is feasible in critically ill neonates, identifying a potential window for metabolic interventions. Conclusions: Ketogenic strategies represent a plausible, multimodal approach to targeting the metabolic and inflammatory sequelae of neonatal HIE. While current evidence is insufficient to support clinical implementation, this scoping review provides a hypothesis-generating framework to guide future translational research and the design of carefully controlled clinical trials in neonatal neurocritical care. Full article

Our prior research revealed that UV-B stress enhances bioactive compounds’ biosynthesis in buckwheat sprouts while simultaneously increasing oxidative damage. To address this, we searched for an exogenous hormone capable of promoting bioactive compound accumulation while mitigating UV-B-induced oxidative damage. This study investigated the regulatory effects of exogenous melatonin (MT) on secondary metabolite accumulation and antioxidant systems in buckwheat sprouts under UV-B stress. MT (30 μM) treatment significantly increased the contents of bioactive compounds (flavonoids and total phenolics) in buckwheat sprouts under UV-B stress. Moreover, these contents peaked in 3-day-old sprouts, showing increases of 23.1% and 13.6%, respectively, compared to UV-B-treated. Concurrently, combined UV-B and MT treatment significantly elevated key enzyme activities in the phenylpropanoid pathway and upregulated the related gene expression levels. Additionally, exogenous MT significantly enhanced the antioxidant capacity of sprouts under 3-day UV-B stress, increasing DPPH radical scavenging rate and FRAP values by 8.38% and 12.2%, respectively. MT treatment also upregulated superoxide dismutase activity (32.1%), peroxidase activity (10.3%), and catalase activity (27.2%). It further enhanced the expression of antioxidant-related genes. Collectively, these effects reduced the accumulation of malondialdehyde, hydrogen peroxide, and superoxide anions, thereby mitigating UV-B-induced oxidative damage in sprouts. This research suggests a potential strategy for the targeted enhancement of bioactive compounds in buckwheat sprouts. Full article

Eutrema salsugineum is a model species for studying stress resistance, particularly extreme salinity, and is often compared with Arabidopsis thaliana. Previous research has shown that basal salicylic acid (SA) levels are significantly lower in E. salsugineum than in A. thaliana. In this study, subtractive hybridization revealed that SA-related genes were extensively induced in Arabidopsis but not in Eutrema. Using exogenous SA and the biosynthesis inhibitor paclobutrazol (PBZ), we further demonstrated that the low endogenous SA level in Eutrema significantly upregulates dehydroascorbate reductase (DHAR) and glutathione reductase (GR) gene expression, doubling the pools of total ascorbic acid and total glutathione. While SA treatment decreased the ratios of reduced ascorbic acid (ASA) to dehydroascorbate (DHA) and reduced glutathione (GSH) to oxidized glutathione (GSSG), PBZ treatment increased them, correspondingly modulating DHAR and GR activities and gene expression. The resulting enhancement of these key non-enzymatic antioxidants is a critical mechanism underpinning the superior salt tolerance of Eutrema. Full article

Short-term hypothermic storage at 4 °C represents a promising non-freezing alternative for transporting bovine embryos and synchronizing assisted reproductive procedures. However, chilling induces oxidative stress, mitochondrial dysfunction, and apoptosis, which markedly impair post-preservation embryonic viability. Glutathione (GSH), a key intracellular antioxidant, may mitigate these damaging effects, yet its protective mechanisms during bovine blastocyst hypothermic preservation remain unclear. Here, we investigated the impact of exogenous GSH supplementation on the survival, hatching ability, cellular integrity, mitochondrial function, and developmental potential of bovine blastocysts preserved at 4 °C for seven days. Optimization experiments revealed that 4 mM GSH provided the highest post-chilling survival and hatching rates. Using DCFH-DA, TUNEL, and γ-H2AX staining, we demonstrated that 4 °C preservation significantly increased intracellular reactive oxygen species (ROS), DNA fragmentation, and apoptosis. GSH supplementation markedly alleviated oxidative injury, reduced apoptotic cell ratio, and decreased DNA double-strand breaks. MitoTracker and JC-1 staining indicated severe chilling-induced mitochondrial suppression, including decreased mitochondrial activity and membrane potential (ΔΨm), which were largely restored by GSH. Gene expression analyses further revealed that chilling downregulated antioxidant genes (SOD2, GPX1, TFAM, NRF2), pluripotency markers (POU5F1, NANOG), and IFNT, while upregulating apoptotic genes (BAX, CASP3). GSH effectively reversed these alterations and normalized the BAX/BCL2 ratio. Moreover, SOX2/CDX2 immunostaining, total cell number, and ICM/TE ratio confirmed improved embryonic structural integrity and developmental competence. Collectively, our findings demonstrate that exogenous GSH protects bovine blastocysts from chilling injury by suppressing ROS accumulation, stabilizing mitochondrial function, reducing apoptosis, and restoring developmental potential. This study provides a mechanistic foundation for improving 4 °C embryo storage strategies in bovine reproductive biotechnology. Full article

Pulmonary fibrosis (PF) is a group of chronic progressive lung diseases characterized by irreversible remodeling of lung tissue structure, abnormal proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM), among which idiopathic pulmonary fibrosis (IPF) is the most typical subtype. Currently, the only two clinically approved therapeutic drugs (nintedanib and pirfenidone) can only partially slow disease progression without reversing fibrotic lesions, and are associated with varying degrees of adverse effects. Oxidative stress, defined as a pathological imbalance between systemic oxidant and antioxidant systems, has been substantiated by extensive research as a pivotal mechanism driving the pathogenesis and progression of pulmonary fibrosis. This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways. We also specifically highlight the latest progress and challenges in therapeutic strategies targeting oxidative stress, and discuss next-generation therapies, including the modulation of endogenous antioxidant pathways, supplementation of exogenous antioxidants, as well as nanomaterials, exosomes, and combination therapies. We hope this review will deepen the understanding of oxidative stress and pulmonary fibrosis, and provide new directions for improving the clinical efficacy of oxidative stress-targeted therapies. Full article

Drought stress represents a major constraint on global apple production, with the widely used semi-dwarfing rootstock ‘M.26’ being particularly vulnerable to water deficit. Although the osmolyte trimethylamine N-oxide (TMAO) has been shown to improve abiotic stress tolerance in the model plant Arabidopsis, its potential role in enhancing drought resilience in woody fruit trees remains largely unexplored. Under prolonged moderate drought stress, exogenous TMAO application significantly promoted plant growth, mitigating the drought-induced suppression of plant height by 5.3–12.2% compared to untreated drought-stressed controls and alleviating the decline in above-ground biomass. This improvement was underpinned by a substantial alleviation of root growth inhibition, with TMAO restoring total root length and biomass from 37% in the control to only 6.1–9.5%. TMAO also fine-tuned the root-to-shoot ratio to favor resource allocation to roots. Consequently, TMAO-treated plants maintained superior leaf water status, exhibiting higher relative water content (drought-induced reduction limited to ~17.5% with TMAO versus 26.3% in the control). Physiologically, TMAO alleviated the drought-induced stomatal limitation of photosynthesis, sustaining higher net photosynthetic rate, stomatal conductance, and transpiration rate. Crucially, under severe drought stress, TMAO pretreatment markedly enhanced ‘M.26’ survival rates from approximately 39% in the untreated control to 60–68%, representing a relative increase of approximately 74%. Collectively, this study demonstrates that exogenous application TMAO significantly enhances drought tolerance in apple rootstock ‘M.26’, highlighting its potential as an effective and environmentally safe plant growth regulator for more sustainable cultivation of fruit trees under irregular/erratic irrigation conditions. Full article

Salinity is a major constraint that compromises safflower performance by disrupting redox balance and metabolic homeostasis. Although hormonal mechanisms for improving plant resilience to abiotic stresses have been reported, the mechanistic role of gibberellic acid (GA₃)-induced regulation of safflower tolerance to salinity remains unclear. This study aimed to investigate the impact of exogenous GA₃ application under normal and saline conditions to evaluate its effects on growth, physiology, redox regulation, and flavonoid biosynthesis in safflower. Using phenotypic, physiological, biochemical, and gene expression analysis, it is suggested that GA₃ significantly alleviates salt stress by integrating antioxidant defense and flavonoid biosynthesis. The results of phenotypic and physiological assessments showed that GA₃ at 400 mg/L GA₃ in safflower seedlings suggests enhanced vegetative growth and photosynthetic performance. Under salt stress, GA₃ significantly alleviated oxidative damage by reducing H₂O₂, ${\mathrm{O}}_2^{-}$, and malondialdehyde (MDA) levels, while enhancing osmoprotective compounds such as proline, soluble sugars, proteins, and chlorophyll. GA₃ also significantly increased the activity of antioxidant enzymes (SOD, POD, CAT, APX, GST, DHAR, and Prx), accompanied by the transcriptional upregulation of their corresponding genes, indicating GA₃-mediated regulation of redox homeostasis at both biochemical and molecular levels. In parallel, GA₃ enhanced the accumulation of major flavonoids, particularly hydroxy safflor yellow A (HSYA), with strong induction of key HSYA biosynthetic genes (CtF6H, CtCGT, Ct2OGD1), whereas salinity alone suppressed their expression. In contrast, the quercetin branch displayed a regulatory bottleneck at CtF3H, which remained suppressed under all treatments, although upstream genes were GA₃-responsive. Together, these findings demonstrate that GA₃ enhances salinity tolerance in safflower by simultaneously activating antioxidant defenses and stimulating flavonoid biosynthesis, providing mechanistic insight with practical implications for developing salt-resilient safflower varieties. Full article

Reactive oxygen species (ROS) are essential regulators of fertilization and early embryo development in mammals, including humans and various animal models, but they exert detrimental effects when produced in excess. In assisted reproductive technologies (ART), particularly in vitro fertilization (IVF), exposure to non-physiological conditions increases oxidative stress (OS), impairing gamete quality, embryo viability, and clinical outcomes. This review synthesizes experimental and clinical studies describing the endogenous and exogenous sources of ROS relevant to embryo development in IVF. Endogenous ROS arise from intrinsic metabolic pathways such as oxidative phosphorylation, NADPH oxidase, and xanthine oxidase. Exogenous sources include suboptimal laboratory conditions characterized by factors such as high oxygen tension, temperature shifts, pH instability, light exposure, media composition, osmolarity, and cryopreservation procedures. Elevated ROS disrupt oocyte fertilization, embryonic cleavage, compaction, blastocyst formation, and implantation by inducing DNA fragmentation, lipid peroxidation, mitochondrial dysfunction, and apoptosis. In addition, the review highlights how parental health factors establish the initial redox status of gametes, which influences subsequent embryo development in vitro. While antioxidant supplementation and optimized culture conditions can mitigate oxidative injury, the precise optimal redox environment remains a subject of ongoing research. This review emphasizes that future research should focus on defining specific redox thresholds and developing reliable, non-invasive indicators of embryo oxidative status to improve the success rates of ART. Full article

Curcumin, a natural polyphenol derived from turmeric, functions as a potent exogenous antioxidant and exhibits a range of benefits in the prevention and management of metabolic diseases. Despite its extremely low systemic bioavailability, curcumin demonstrates significant bioactivity in vivo, a phenomenon likely attributable to its accumulation in the intestines and subsequent modulation of systemic oxidative stress and inflammation. This article systematically reviews the comprehensive regulatory effects of curcumin on systemic metabolic networks—including glucose metabolism, amino acid metabolism, lipid metabolism, and mitochondrial metabolism—and explores their molecular basis, particularly how curcumin facilitates systemic metabolic improvements by alleviating oxidative stress and interacting with inflammation. Preclinical studies indicate that curcumin accumulates in the intestines, where it remodels the microbiota through prebiotic effects, enhances barrier integrity, and reduces endotoxin influx—all of which are critical drivers of systemic oxidative stress and inflammation. Consequently, curcumin improves insulin resistance, hyperglycemia, and dyslipidemia across multiple organs (liver, muscle, adipose) by activating antioxidant defense systems (e.g., Nrf2), enhancing mitochondrial respiratory function (via PGC-1α/AMPK), and suppressing pro-inflammatory pathways (e.g., NF-κB). Clinical trials have corroborated these effects, demonstrating that curcumin supplementation significantly enhances glycemic control, lipid profiles, adipokine levels, and markers of oxidative stress and inflammation in patients with obesity, type 2 diabetes, and non-alcoholic fatty liver disease. Therefore, curcumin emerges as a promising multi-target therapeutic agent against metabolic diseases through its systemic antioxidant and anti-inflammatory networks. Future research should prioritize addressing its bioavailability limitations and validating its efficacy through large-scale trials to translate this natural antioxidant into a precision medicine strategy for metabolic disorders. Full article

Exercise-induced myokines have emerged as crucial mediators of the beneficial effects of physical activity on neurodegenerative diseases through complex molecular mechanisms involving oxidative stress reduction, neuroinflammation suppression, and synaptic plasticity enhancement. Among these myokines, irisin, encoded by the FNDC5 gene, has gained significant attention as a potential therapeutic target in neurodegenerative conditions due to its ability to cross the blood–brain barrier and exert pleiotropic neuroprotective effects. This review synthesizes current evidence from both preclinical and clinical studies examining the role of exercise-induced irisin in neurodegeneration, with particular emphasis on translational potential and therapeutic applications. A comprehensive search was conducted across PubMed, Web of Science, Scopus, and EMBASE databases (spanning January 2015 to December 2024) to identify peer-reviewed articles investigating irisin’s neuroprotective mechanisms in neurodegenerative diseases. Ten studies met the inclusion criteria (five rodent/primate model studies and five human clinical investigations), which were analyzed for methodological rigor, intervention protocols, biomarker quantification methods, and reported outcomes. Reviewed studies consistently demonstrated that exercise-induced endogenous irisin elevation correlates with improved cognitive function, reduced neuroinflammatory markers, enhanced synaptic plasticity, and modulation of neurodegenerative pathways, with exogenous irisin administration reproducing several neuroprotective benefits observed with exercise training in animal models. However, substantial heterogeneity exists regarding exercise prescription parameters (intensity, duration, frequency, modality), training-induced irisin quantification methodologies (ELISA versus mass spectrometry), and study designs (ranging from uncontrolled human observations to randomized controlled trials in animal models). Critical appraisal reveals that human studies lack adequate control for confounding variables including baseline physical fitness, comorbidities, concurrent medications, and potential sources of bias, while biochemical studies indicate distinct pharmacokinetics between endogenous training-induced irisin and exogenous bolus dosing, necessitating careful interpretation of therapeutic applicability. The translational potential of irisin as a therapeutic agent or drug target depends on resolving methodological standardization in biomarker measurement, conducting well-designed clinical trials with rigorous control for confounders, and integrating findings from molecular/biochemical studies to elucidate mechanisms linking irisin to disease modification. Future research should prioritize establishing clinical trial frameworks that harmonize exercise prescriptions, employ robust biomarker quantification (mass spectrometry), and stratify participants based on disease stage, comorbidities, and genetic predisposition to clarify irisin’s role as a potential therapeutic intervention in neurodegenerative disease management. Full article

Salinity stress severely limits crop productivity worldwide. While plant growth-promoting rhizobacteria (PGPR) are known to alleviate abiotic stress, the specific mechanisms mediated by their volatile organic compounds (VOCs) remain largely elusive. In this study, an in vitro split-plate system was used to investigate the effects of VOCs emitted by Bacillus velezensis SQR9 on Arabidopsis thaliana seedlings under salt stress. Exposure to SQR9 VOCs significantly enhanced Arabidopsis salt tolerance, evidenced by increased biomass and root growth. Mechanistically, SQR9 VOCs mitigated salt-induced damage by increasing chlorophyll content, modulating osmolytes, and reducing malondialdehyde (MDA) levels. SQR9 VOCs alleviated oxidative stress by decreasing ROS (H₂O₂, O₂⁻) accumulation and enhancing antioxidant enzyme (SOD, CAT, POD) activities. Furthermore, SQR9 VOCs maintained ion homeostasis by significantly reducing leaf Na⁺ accumulation, maintaining a high K⁺/Na⁺ ratio, and upregulating key ion transporter genes. Analysis of the headspace from SQR9 cultured on MSgg medium identified 2,3-butanediol (2,3-BD) as a major active VOC. Exogenous application of 2,3-BD successfully mimicked the growth-promoting and salt-tolerance-enhancing effects of SQR9. Our findings demonstrate that SQR9 VOCs, particularly 2,3-BD, systemically prime Arabidopsis for salt tolerance by co-activating the antioxidant defense system and the SOS ion homeostasis pathway. Full article

Understanding the molecular basis of heat tolerance in microalgae is crucial for developing resilient strains for industrial biotechnology. This study identified two desert Chlorella strains, XDA024 (thermotolerant) and XDA121 (heat-sensitive), through short-term thermal screening. The thermotolerant strain XDA024 survived exposure to 50 °C for 3 h, whereas XDA121 succumbed within 1 h at 40 °C. Physiological analyses revealed that the superior heat resistance of XDA024 was associated with enhanced activities of key antioxidant enzymes, including superoxide dismutase, catalase, and peroxidase, which effectively mitigated oxidative damage, alongside an elevated proline content contributing to osmoregulation. Transcriptomic profiling under acute heat stress (45 °C, 3 h) revealed that the unique thermotolerance of XDA024 was underpinned by the upregulation of genes related to photosystem stability and lipid synthesis, processes supported by activated calcium signaling and antioxidant pathways. In contrast, XDA121 exhibited significant downregulation of photosynthesis-related genes and promoted lipid degradation, resulting in membrane instability. Exogenous application of phosphatidylethanolamine (PE) and monoethanolamine (MEA) markedly increased the survival rate of XDA121 by more than threefold, primarily by alleviating membrane damage through enhanced membrane integrity and modulated antioxidant enzyme activities. These findings indicate that thermotolerance in desert Chlorella (Chlorophyta) is governed by the integrated coordination of antioxidant defense mechanisms, lipid metabolism, and photosystem protection. This research provides crucial insights and practical strategies for engineering heat-resistant microalgal strains for sustainable biofuel and bioproduct production. Full article

Reproductive-stage drought arrests silk elongation, causing a greater anthesis-silking interval and subsequent kernel loss in maize. Exogenous brassinolide (BR) is known to increase drought tolerance; however, its influence on silk growth under water deficit remains unresolved. Here, we subjected maize to drought before tassel emergence (V13) and then applied foliar BR at concentrations of 0, 0.1, 0.5, or 1 mg mL⁻¹, with distilled water-sprayed plants serving as controls. Silk elongation under water-deficit stress was partially restored by 0.1 and 0.5 mg mL⁻¹ BR but suppressed by 1 mg mL⁻¹, with 0.5 mg mL⁻¹ increasing silk length by 2.9-fold compared to the stress control, recovering it to 26.5% of the well-watered level. This protection was underpinned by elevated antioxidant capacity (POD, SOD, and CAT by 31–77%, 12–46%, and 20–33%, respectively) and a 25–76% rise in proline relative to the distilled water-sprayed, which collectively curtailed oxidative damage, as evidenced by 36–67% reductions in O₂⁻ and H₂O₂ levels and a 24% decrease in MDA content. Critically, BR reprogrammed sugar metabolism: sucrose phosphate synthase (SPS) activity declined, while sucrose synthase (SS-I) and vacuolar invertase (VIN) activities surged, thereby shifting carbon partitioning from sucrose toward hexoses to sustain energy supply for silk growth. Genome-wide RNA-seq identified 6171 upregulated and 3295 downregulated genes, significantly enriched in 20 pathways, including starch/sucrose metabolism, glycolysis/gluconeogenesis, and phenylpropanoid biosynthesis. The expression of key genes, including sucrose invertase (INV) and hexokinase (HK), was significantly upregulated by 2.4- to 8.7-fold and 2.3- to 4.0-fold, respectively, compared to the distilled water-sprayed control. This multi-level analysis demonstrates that BR mitigates drought-induced silk growth arrest by orchestrating antioxidant defense, osmotic regulation, and metabolic reprogramming into a coordinated network, providing mechanistic insights into brassinosteroid-mediated reproductive stress adaptation in maize. Full article

Background: Existing exercise metabolomics studies have predominantly focused on changes in the type and abundance of metabolites, while rarely addressing the toxicity risk of differential metabolites. Metabolic toxicity refers to the potential of endogenous or exogenous metabolites to induce oxidative stress, cell death, and other forms of biological damage when excessively accumulated and serves as a key driver of metabolic disorders. This study aims to characterize the toxicity risk of plasma differential metabolites before and after a single session of moderate-intensity running, so as to investigate the exercise-induced changes in metabolic toxicity. Methods: A single-group self-pretest–posttest control design was adopted in this study. Participants were recruited from Wuhan Sports University, China, with the inclusion criteria of healthy females aged 22–30 years and BMI 18.5–24.9. Individuals with a history of metabolic diseases or who met other exclusion criteria were excluded, and 5 females were finally enrolled. The exercise protocol consisted of a single 40 min session of moderate-intensity running on a treadmill. We collected plasma samples from five healthy females before and after exercise and performed untargeted LC-MS/MS metabolomic profiling. The gap-Δenergy algorithm was applied to calculate the toxicity scores of differential metabolites, and the proportion of metabolites with high toxic potential (score > 0.6) was compared. Results: Plasma metabolic profiles underwent notable remodeling after exercise. Thirty-two metabolites were upregulated and the phosphosphingolipid SM(d18:2(4E,14Z)/16:0) was the most significant. Meanwhile 32 metabolites were downregulated and the phosphosphingolipid PC(18:1(9Z)/14:0) was the most significant. The 64 differential metabolites were enriched in 9 KEGG pathways including amino acid metabolism and lipid metabolism. Moreover, we systematically evaluated the toxicity of these metabolites using the gap-Δenergy algorithm and found that the downregulated metabolites exhibited a significantly higher toxicity score compared to the upregulated ones. In addition, 37.5% of the downregulated metabolites had a high toxicity score, while the proportion of high toxicity in the upregulated group was only 15.6%. Conclusions: This study demonstrates that moderate-intensity running may confer metabolic health benefits to individuals by reducing metabolic toxicity, specifically through the downregulation of metabolites with high toxic potential. These findings offer novel evidence for exercise’s role in improving metabolic health. They also open a new direction for exercise-based interventions in metabolic disease–toxicity regulation. Full article