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- Research Article
- 10.1016/j.freeradbiomed.2026.01.050
- Mar 1, 2026
- Free radical biology & medicine
- Jiaying Yu + 15 more
Glycine ameliorates aging-related dysfunctions associated with Nmdmc-mediated mitochondrial one-carbon metabolism.
- Research Article
- 10.1002/anie.202525622
- Feb 6, 2026
- Angewandte Chemie (International ed. in English)
- Chenyang Li + 13 more
Selective electrooxidation of glycerol (GLY) to glyceric acid (GLA) offers a promising route for GLY valorization but remains hindered by limited activity and stability. Herein, we report a scalable self-corrosion strategy for large-area fabrication of a Ru-doped Pt/NiFe-LDH catalyst on Ni foam (PtRu/NiFe-LDH) with an area of up to 36 cm2. The incorporation of Ru modulates the electronic structure, enhances the adsorption of both OH- and GLY, and lowers the free energy barrier for OH* formation, thereby significantly boosting catalytic activity to achieve a recorded current density of 439.5mA cm- 2. Furthermore, pulse electrolysis effectively suppresses the formation of PtOx, ensuring long-term stability. When integrated into a GLY oxidation-assisted hydrogen evolution system, this bifunctional catalyst reduces the cell voltage by 1.01V relative to conventional water splitting, while delivering 78.5% selectivity towards GLA and stable operation for over 120h. This work establishes a viable pathway toward the industrialization of selective electrochemical oxidation of GLY to GLA by integrating advanced catalyst design with optimized electrolyzer configuration.
- Research Article
- 10.1002/ange.202525622
- Feb 6, 2026
- Angewandte Chemie
- Chenyang Li + 13 more
ABSTRACT Selective electrooxidation of glycerol (GLY) to glyceric acid (GLA) offers a promising route for GLY valorization but remains hindered by limited activity and stability. Herein, we report a scalable self‐corrosion strategy for large‐area fabrication of a Ru‐doped Pt/NiFe‐LDH catalyst on Ni foam (PtRu/NiFe‐LDH) with an area of up to 36 cm 2 . The incorporation of Ru modulates the electronic structure, enhances the adsorption of both OH − and GLY, and lowers the free energy barrier for OH* formation, thereby significantly boosting catalytic activity to achieve a recorded current density of 439.5 mA cm − 2 . Furthermore, pulse electrolysis effectively suppresses the formation of PtO x , ensuring long‐term stability. When integrated into a GLY oxidation‐assisted hydrogen evolution system, this bifunctional catalyst reduces the cell voltage by 1.01 V relative to conventional water splitting, while delivering 78.5% selectivity towards GLA and stable operation for over 120 h. This work establishes a viable pathway toward the industrialization of selective electrochemical oxidation of GLY to GLA by integrating advanced catalyst design with optimized electrolyzer configuration.
- Research Article
- 10.3390/jox16010022
- Jan 27, 2026
- Journal of xenobiotics
- Yi-Fu Xing + 5 more
Nitrite is a common toxic substance in aquaculture, and microplastics are environmental pollutants capable of adsorbing small molecules/particles. Shrimp rely mainly on the hepatopancreas to accomplish detoxification metabolism. In this study, we investigated the individual and combined effects of nitrite and microplastics on the physiological function of the P. vannamei hepatopancreas. The results demonstrated that both nitrite and microplastics induced morphological damage, with the combined stress exacerbating tissue damage. Oxidative stress biochemical indicators were disrupted, and most enzyme activities and gene expression levels were upregulated to varying degrees in each experimental group. The expression levels of immune genes (cytC, CASP-3, Crus, ALF, and proPO), detoxification metabolism genes (CYP450, EH1, SULT, and UGT), and oxidative-stress-related genes (ROMO1, SOD, GPx, and Trx) exhibited different fluctuations. Nitrite and microplastic stress resulted in altered hepatopancreatic function, mainly involving amino acid biosynthesis and metabolism, ABC transporters, oxidative phosphorylation, and the mTOR pathway. We identified 17 metabolic biomarkers, including 6 lipids (Oleic acid, Prostaglandin G2, Linoleic acid, Palmitic acid, Docosahexaenoic acid, Docosapentaenoic acid), 6 amino acids (L-Leucine, Agmatine, L-Arginine, L-Tyrosine, Ornithine, N-Acetylornithine), and 5 carbohydrates (Glyceric acid, Citric acid, D-Mannose, Sorbitol, Fumaric acid). These findings suggest that nitrite and microplastic stresses cause hepatopancreatic tissue damage and induce oxidative stress, physiological and metabolic dysfunction in the shrimp P. vannamei, thereby impacting its normal physiological functions.
- Research Article
- 10.1186/s13099-025-00781-6
- Jan 3, 2026
- Gut pathogens
- Cha-Kyung Youn + 9 more
Ulcerative Colitis (UC) is a chronic illness that commonly demands the use of medication, sometimes for long term. In a DSS mouse model, we examined 5-aminosalicylic acid (5ASA) in comparison to a defined polyphenol-rich herbal mixture CSPG: Cirsium japonicum, Scutellaria baicalensis, Paeonia japonica, and Glycyrrhizae radix, using a two-phase approach. In phase 1 (days 1-14, without DSS stimulation), the herbal formula CSPG produced a more gut-friendly preventive profile compared to 5ASA in non-inflammatory condition:Unlike 5-ASA, which decreases microbial diversity as previously reported, CSPG preserved overall diversity and maintained protective taxa such as Ruminococcaceae uncultured ; and reduced inflammatory metabolites (uracil, glyceric acid, succinic acid) more effectively than 5ASA. Next, in phase 2 (days 15-24, with DSS inflammatory stimulation), CSPG matched first-line 5-ASA in suppressing inflammation (reduced colon shortening and procalcitonin). Its PI3K-Akt upregulation-together with NF-κB repression-was associated with more continuous ZO-1/ZO-2/occludin proteins expression and normalization of claudin-2 and MUC1/MUC2/MUC4, indicating barrier-repair capacity, a result supported by in vitro HT-29 experiments. Simultaneously, CSPG corrected DSS-induced dysbiosis more effectively than 5ASA: it increased SCFA-linked taxa (Prevotellaceae UCG-001 and Ruminococcus; 5ASA also rose but to a lesser extent), and reduced inflammation-associated groups ( [Eubacterium] siraeum group, and Erysipelotrichaceae). CSPG restored SCFAs and elevated glycine, proline, pyruvate, and myo-inositol, while reducing succinate and uracil-with stronger effects than 5-ASA for pyruvate, myo-inositol, and succinate, and comparable effects for butyrate. Although CSPG is not a single-target, rationally designed drug like 5ASA, it achieved comparable anti-inflammatory and barrier-repair effects and, unlike 5ASA, also improved gut microbiota composition and metabolite profiles, indicating potential advantages for long-term UC management.
- Research Article
- 10.1016/j.nbd.2025.107221
- Jan 1, 2026
- Neurobiology of disease
- Zhong-Yun Chen + 8 more
Integrated peripheral metabolic and inflammatory biomarker signatures are associated with clinical deterioration in Creutzfeldt-Jakob disease.
- Research Article
- 10.1093/geroni/igaf122.3516
- Dec 1, 2025
- Innovation in Aging
- Araya Cserepy + 1 more
Abstract Alzheimer’s Disease (AD) is a neurodegenerative disorder often marked by amyloid beta and tau accumulation, but metabolic changes can precede clinical onset by several years. Metabolites in particular have been implicated as early indicators of brain dysfunction. As such, this study applied machine learning to identify serum-derived metabolites distinguishing early (EMCI) from late mild cognitive impairment (LMCI). Using publicly available metabolite data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we analyzed baseline profiles from 643 participants (222 EMCI, 421 LMCI) across 104 features. A two-stage feature selection framework combined univariate ANOVA F-testing (top 30 features) with multivariate recursive feature elimination (final 15 features) to find the most important metabolites for diagnosis. This feature selection framework was repeated across different training/testing set splits to ensure the reliability of the features selected. Random Forest classification with balanced weighting addressed dataset imbalance. Across all repetitions, a core panel of five metabolites emerged consistently across validation runs: glyceric acid, hyocholic acid (HCA), hyodeoxycholic acid (HDCA), tauro-muricholic acid (TAMCA), and succinic acid. These metabolites achieved 76% ± 3% accuracy on unseen validation data and 78% ± 6% on development data. Notably, the panel included bile acid metabolites (HCA, HDCA, TAMCA) and energy-related metabolites (glyceric acid, succinic acid), pointing to disruptions in the gut–liver axis and cellular metabolism during disease progression. Overall, this work highlights metabolic alterations that accompany the transition from EMCI to LMCI and demonstrates the potential of machine learning–based metabolomics for early detection and diagnosis in AD.
- Research Article
2
- 10.1016/j.apcatb.2025.125668
- Dec 1, 2025
- Applied Catalysis B: Environment and Energy
- Yiwei Jiang + 5 more
Boosting the glycerol tandem oxidation to glyceric acid via the rate determination step alteration
- Research Article
- 10.21203/rs.3.rs-8052995/v1
- Nov 24, 2025
- Research Square
- Wilson Bamise Adeosun + 3 more
IntroductionThe cysteinyl leukotriene receptor 1 (CysLTR1) is known as a potent lipid mediator with a well-established role in inflammatory regulation and lung disease. While its involvement in immune cell recruitment has been previously reported, its broader impact on pulmonary metabolism remains poorly understood.ObjectivesThe study aims to investigate the metabolic consequences of a CysLTR1 deletion in mice to elucidate its role in pulmonary metabolic homeostasis.MethodsBronchoalveolar lavage fluid (BALF) was collected from CysLTR1 knockout (KO) and wild-type (WT) mice and analysed using standardized untargeted gas chromatography–time-of-flight mass spectrometry (GC-TOFMS) metabolomics.ResultsMetabolomics analyses of the BALF collected from the CysLTR1 KO mice presented significantly reduced levels of glucose, glucosamine, and glyceric acid, indicating the role of the CysLTR in lung glucose uptake and consequently lung glycolysis and gluconeogenesis. This is further supported by reductions in myo-inositol and D-chiro-inositol, also supporting previous findings that this occurs due to insulin resistance. Consequential disruption of various glucose-dependent pathways, including the pentose phosphate pathway (reduced gluconic acid, sedoheptulose and xylose) and purine metabolism (reduced 1-methylinosine) indicates a consequential altered nucleotide turnover, and the significantly reduced concentrations of butanoic acid, decan-2-ol, and 1-hexadecanol, indicate changes to fatty acid metabolism in the lung, as a compensatory response to the initial glucose deficiency induced by the CysLTR1 KO. Lastly, the changes to mandelic acid, glutaric acid, tricarballylic acid, and decan-2-ol, furthermore, indicate the role of CysLTR1 in the composition/metabolism of the microbiome.ConclusionThis study expands our knowledge on the role of CysLTR1 beyond its role in immune regulation, that may later serve towards a better understanding of CysLTR1 associated lung diseases and in the development of improved therapeutic strategies.
- Research Article
- 10.1149/ma2025-02271512mtgabs
- Nov 24, 2025
- Electrochemical Society Meeting Abstracts
- Enina Egiebor + 3 more
Water splitting is a promising method for sustainable hydrogen production. However, the anodic oxygen evolution reaction (OER) is thermodynamically unfavorable and inefficient, requiring expensive platinum metal group (PGM) group catalysts such as iridium oxide. One approach to lowering the energy demand is to bypass the OER entirely and replace it with a more thermodynamically favorable reaction. Selective oxidation of glycerol (GLYOR) is an attractive alternative to water oxidation due to its lower thermodynamic potential and ability to generate value-added products (e.g., glyceraldehyde, dihydroxyacetone, formic acid) at reduced overpotentials. The increasing production of biodiesel has led to a surplus of glycerol, making it a cheap feedstock and optimal candidate for upgrading. Catalytic efficiency in GLYOR can be predicted using Nørskov’s d-band theory, which describes how the bond strength between a molecule and a transition metal surface is governed by the average energy level of metal d-orbitals. Generally, metal binding strength decreases as the d-band center shifts downward. While platinum is considered the most efficient GLYOR catalyst because of its optimal binding energy and low d-band center, its scarcity and high cost limit scalability. Palladium is a promising alternative, though its higher d-band center reduces catalytic activity.To address this, we have developed Pd-M based catalysts to understand and correlate electrochemical activity with Pd’s d-band center. We synthesized a morphology-controlled Pd nanocube catalyst and series of Pd-M (M = Cu, Ag) nanoparticles using a one-pot reduction technique and compared their performance with regular, monometallic Pd nanoparticles. X-ray photoelectron spectroscopy (XPS) was used to characterize the electronic structure of the catalysts. We observed increased shifts in XPS binding energy, suggesting that the incorporation of metals with a lower d-band center shifts Pd’s d-band center downward. Linear sweep voltammetry (LSV) revealed reduced onset potentials for the alloyed catalysts, which is consistent with the degree of shifting observed in XPS. These catalysts demonstrated excellent stability in an anion exchange membrane (AEM) electrolyzer, operating at <1V for over 500hrs at 20 mA/cm² and at <1.5V at 100 mA/cm². PdCu has displayed the best stability for over 1000 hours at both 20 mA/cm² and 100 mA/cm². We selected PdCu as the best catalyst to construct a PEC reactor, integrating a single-junction perovskite with a zero-gap configuration to achieve solar-to-hydrogen (STH) >20% while producing glyceric acid, glycolic acid, and lactic acid at the anode. These results pave the way for the development of GLYOR catalysts and their integration with green hydrogen PEC systems, enabling the direct conversion of waste feedstocks into value-added products using sunlight. Figure 1
- Research Article
2
- 10.1126/sciadv.adz4136
- Nov 21, 2025
- Science Advances
- Shuguang Xu + 8 more
Accessing optically pure chemicals directly from biomass via chemical catalysis remains challenging because of the need for high selectivity across complex, multistep transformations. Here, we report a robust silver-based catalyst featuring synergistic single atoms and nanoclusters that function as complementary active sites in the anaerobic oxidative carbon-carbon cleavage of bio-derived feedstocks. This catalyst enables the production of optically pure glyceric acid from a broad range of biomass sources including raw biomass with unprecedented yield (59 to 96%) and enantiomeric excess (97 to >99%). Structural and mechanistic studies reveal that silver clusters, stabilized by surface oxygen vacancies, activate dioxygen through π-backbonding, while electron-deficient silver single atoms preferentially bind the chiral substrate via ionic interactions, increasing the energy barrier for mutarotation and preserving its stereochemical identity. Oxygen spillover between the two sites facilitates precise oxidative Cα–Cβ bond cleavage. Together, these features overcome the longstanding dual challenges of low productivity and poor enantioselectivity in chemocatalytic biomass upgrading.
- Research Article
- 10.1002/adsc.70221
- Nov 17, 2025
- Advanced Synthesis & Catalysis
- Yue Tian + 3 more
Glycerol, as the primary by‐product in the biodiesel production process, is abundant and cost‐effective. Its efficient conversion into other chemicals offers a promising strategy for alleviating the energy crisis. Electrocatalytic glycerol oxidation reaction (GOR) holds significant application potential due to its mild reaction conditions and lack of additional oxidants, enabling the production of various value‐added chemicals such as lactic acid (LA), dihydroxyacetone (DHA), glyceric acid (GLA), oxalic acid (OA), and formic acid (FA). When GOR is used to replace the oxygen evolution reaction (OER), it enables the coproduction of high‐value oxidation products and H 2 while minimizing energy consumption and carbon dioxide emissions. This has important research significance and value for the conversion of biomass resources and the energy‐efficient production of “green hydrogen.” Consequently, designing efficient and low‐cost electrocatalysts to achieve high activity and selectivity in GOR is a central research objective. Among these, transition metal materials demonstrate significant advantages. This review introduces the types of transition metal catalysts used for GOR and discusses recent catalyst design strategies to enhance GOR activity and selectivity, including nanostructure regulation, defects and surface engineering, heterostructure construction, and single‐atom catalysts. In addition, the practical applications of GOR as well as sustainability studies are discussed. Finally, we summarize the current challenges facing transition metal catalysts in GOR and discuss future prospects.
- Research Article
1
- 10.1002/adfm.202522517
- Nov 2, 2025
- Advanced Functional Materials
- Junqing Ma + 9 more
Abstract Engineering the electronic structure of transition metal catalysts is very important for regulating electrocatalytic reactions yet remains challenging, particularly in modulating the spin state for biomass valorization. Herein, a novel spin‐state engineering strategy is proposed to dramatically enhance the glycerol oxidation reaction (GOR) for selective formate production. It is demonstrated that vanadium (V) doping‐induced lattice distortion in Co 3 O 4 triggers a pivotal low‐spin to high‐spin (t 2g 4 e g 2 ) transition of Co 3+ ions. Through a combination of in situ spectroscopic techniques and theoretical calculations, it is revealed that this high‐spin state effectively tailors the interfacial microenvironment by reducing the population of strongly hydrogen‐bonded water molecules (≈30%) and concurrently strengthens the adsorption of glycerol and key intermediates (e.g., glyceric acid, glycolic acid), thereby optimizing the reaction pathway. As a result, the optimized high‐spin V‐Co 3 O 4 catalyst achieves an exceptionally low overpotential (reduced by 70–150 mV across the range of 10 – 300 mA cm −2 ) and a remarkable format selectivity of 93%, significantly outperforming its low‐spin counterpart (57%). This work not only provides profound atomic‐level insights into the spin‐state‐dependent reaction mechanism but also establishes spin‐state control as a fundamental and powerful paradigm for designing advanced electrocatalysts for sustainable energy conversion.
- Research Article
1
- 10.1016/j.foodchem.2025.145567
- Nov 1, 2025
- Food chemistry
- Jun Shu + 7 more
Identification of rice taste quality markers using metabolomics techniques.
- Research Article
- 10.1016/j.plaphy.2025.110828
- Nov 1, 2025
- Plant physiology and biochemistry : PPB
- Yi Zhang + 4 more
Molecular responses of watermelon seedlings to MgO nanoparticles: transcriptome and metabolome insights.
- Research Article
- 10.1016/j.cej.2025.168225
- Nov 1, 2025
- Chemical Engineering Journal
- Shuguang Xu + 5 more
Continuous steady-state coproduction of glyceric and glycolic acids from biomass with high carbon efficiency
- Research Article
1
- 10.3390/nu17213439
- Oct 31, 2025
- Nutrients
- Imelda Cecilia Zarzoza-Mendoza + 9 more
Background/Objective: Human milk is an irreplaceable source of nutrition and is essential for the infant’s growth and development right after birth and for early life stage survival. This study aims to characterize and compare the metabolite profiles of colostrum and transitional and mature milk using an untargeted GC-MS approach. Additionally, it explores potential correlations between the identified metabolites and maternal nutritional factors. Methods: This was a longitudinal, prospective, and observational study. We included human milk samples from 113 Mexican women who practiced exclusive breastfeeding. Partial least squares-discriminant analysis (PLS-DA) was performed to assess differences among lactation stages. Metabolites showing significant variation across lactation stages were further analyzed using Friedman tests with post hoc Wilcoxon tests and Bonferroni correction. Correlations with maternal anthropometric measures were evaluated. Results: Twenty-three metabolites were identified, including amino acids and derivatives, sugars, fatty acids, and energetic metabolites. Alanine and creatinine levels decreased during lactation, while aspartate, serine, and valine levels increased. Rhamnose level was higher in colostrum, whereas decanoic, dodecanoic, and tetradecanoic acid levels increased over time, and that of 11,14-eicosadienoic acid decreased. Lactic acid levels declined across stages. Negative correlations were found between several amino acids and maternal anthropometric variables, while glyceric acid, rhamnose and lactic acid correlated positively. Conclusions: Human milk metabolomic profiles display distinct, stage-specific variations shaped by maternal characteristics, reflecting the dynamic physiological and nutritional demands of the developing infant
- Research Article
- 10.20517/cs.2025.53
- Oct 22, 2025
- Chemical Synthesis
- Tong Chen + 5 more
Glycerol is an important biomass platform molecule, produced as an abundant side-product in the biodiesel industry. The efficient conversion of glycerol through selective oxidation to value-added fine chemicals has been recognized as one of the most promising routes to meet the demand for escalating energy. However, glycerol oxidation usually involves the oxidation of the primary or secondary C–OH groups of glycerol, cascade oxidation of intermediates, and C–C oxidative cleavage of glycerol or its intermediates, resulting in multiple pathways and varied oxidative products. To achieve the selective conversion of glycerol to a single product is of great challenge. The development of efficient catalysts with precisely-designed active sites for the targeted activation of glycerol and the direct conversion to specific oxidative products is the key. In this review, we focus on the recent research advances of the selective oxidation of glycerol to the highly-desired C<sub>3</sub> value-added chemicals including dihydroxyacetone and glyceric acid over heterogeneous catalysts and the synergistic catalytic mechanism. The strategies for the targeted and efficient activation of glycerol at the primary or secondary position and the direct conversion of the primary or secondary C–OH and C–H bonds are emphasized. At the end of the article, future challenges and development strategies on the selective oxidation of glycerol are also discussed.
- Research Article
- 10.3390/catal15100963
- Oct 8, 2025
- Catalysts
- Zhiqing Wang + 7 more
Thermal valorization of surplus biomass-derived feedstocks such as glycerol into high-value chemicals represents a sustainable strategy for biomass utilization and decarbonization of chemical manufacturing. However, conventional glycerol conversion processes are often restricted to low-value C1 products owing to rapid C–C bond cleavage during thermo-oxidation. Herein, we report highly efficient Au-Pt bimetallic alloy catalysts supported on mixed-oxide catalysts that enable the selective oxidation of glycerol under ambient conditions in the absence of a base. The synergistic interaction between Au and Pt promotes preferential oxidation of the terminal hydroxyl groups while preserving the C3 backbone, thereby affording the desirable C3 product, glyceric acid. The single-factor experiments and response surface analysis demonstrated that the Au-Pt bimetallic alloy catalysts supported on the mixed oxide MgO-Al2O3 exhibited a glycerol conversion of up to 82.0% and a glyceric acid selectivity of 62.1% under favorable reaction conditions. Kinetic studies further indicated that the activation energy of this catalyst in the reaction system is 32.7 kJ/mol.
- Research Article
1
- 10.1128/mbio.02447-25
- Oct 7, 2025
- mBio
- Jia-Yu Du + 15 more
Major depressive disorder (MDD) and irritable bowel syndrome (IBS) exhibit high comorbidity, yet their shared pathophysiology remains unclear. Previous studies have primarily focused on the psychological health in the IBS population, without considering psychiatric diagnoses or stratifying different psychological states, potentially leading to biased findings. This study employed multi-omics approaches to characterize gut microbiota and serum metabolites in 120 MDD patients (47 with IBS and 73 without IBS) and 70 healthy controls (HCs). MDD with IBS patients showed significantly higher depression (Hamilton depression scale [HAMD-17]) and anxiety (Hamilton anxiety scale [HAMA-14]) scores than MDD-only patients (P < 0.05). Metagenomic sequencing of fecal samples revealed increased alpha diversity (Chao1/Shannon indices) and Firmicutes dominance in both MDD groups vs HC, while Actinobacteria enrichment specifically marked MDD with IBS. Functionally, MDD with IBS uniquely activated D-amino acid/glycerolipid metabolism pathways (Kyoto Encyclopedia of Genes and Genomes). Serum metabolomics identified comorbid-specific perturbations: downregulation of bile acids (CDCA, GCDCA, GCDCA-3S) and upregulation of glyceric acid/glutaconic acid. Our study also found that Eggerthella lenta and Clostridium scindens are differentially abundant bacteria that are involved in bile acid metabolism, and that microbial genes (e.g., K03738) are associated with glyceric acid production. These findings implicate gut microbiota-driven bile acid/glyceric acid dysregulation in MDD with IBS comorbidity, supporting the gut-brain axis as a therapeutic target for probiotics or microbiota transplantation.IMPORTANCEMajor depressive disorder (MDD) exhibits a high comorbidity rate with irritable bowel syndrome (IBS). Our study, conducted on 120 MDD patients (47 of whom were comorbid with IBS) and a control group of 70 individuals, revealed that MDD-IBS comorbid patients demonstrated significantly higher depression/anxiety scores. Multi-omics analysis indicated substantial alterations in the gut microbiota (e.g., Firmicutes, Actinobacteria) and serum metabolites (e.g., bile acids, glyceric acid) among MDD-IBS patients, which were associated with specific metabolic pathways. Therefore, the new aspect of this study was the inclusion of patients with MDD but without IBS symptoms, which provided a deeper understanding of the intestinal microbiota dysregulation associated with comorbid IBS and MDD. These findings suggest that there may be involvement of the gut-brain axis, providing new research directions for potential therapeutic targets.CLINICAL TRIALSThis study is registered with the Chinese Clinial Trial Registry as ChiCTR2100041598.