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Volume 16
Issue 6
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Metabolites, Volume 16, Issue 6 (June 2026) – 86 articles

Cover Story (view full-size image): The nitazenes are an evolving class of highly potent mu-opioid receptor agonists that have emerged as illicit drugs of abuse since 2019. This study examined 23 nitazene-related deaths as part of coronial casework in the Australian state of Victoria from 2021 to 2025. Eighty-seven percent of the deaths were male, with broad polydrug usage evident in all cases. Seven different nitazenes were detected with concentrations ranging from 0.1 to 33 ng/mL, and protonitazene being the most prevalent analogue. Drug toxicity was deemed to be a primary cause of death in nineteen cases, and as a contributing factor in four cases alongside natural disease. This study highlights the ongoing public health threat posed by nitazenes, adding previously unreported toxicological findings that contribute to a greater understanding of these emerging compounds. View this paper
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19 pages, 13658 KB  
Article
Lactate Metabolism Dysregulation Drives the Pathogenesis of Acute Kidney Injury
by Yongchen Li, Jingwen Liu, Diman Mai, Renzhi Tan, Chao Wang and Zengnan Mo
Metabolites 2026, 16(6), 434; https://doi.org/10.3390/metabo16060434 - 22 Jun 2026
Viewed by 267
Abstract
Background: Acute kidney injury (AKI) remains a condition with limited effective therapeutic options, partly due to challenges in early diagnosis and timely intervention. While lactate accumulation is a hallmark of ischemic and septic AKI, the underlying mechanisms remain unclear. Methods: This study integrated [...] Read more.
Background: Acute kidney injury (AKI) remains a condition with limited effective therapeutic options, partly due to challenges in early diagnosis and timely intervention. While lactate accumulation is a hallmark of ischemic and septic AKI, the underlying mechanisms remain unclear. Methods: This study integrated single-cell RNA sequencing data from AKI patients (GEO database) with lactate metabolism-related genes (LMRGs) to identify key therapeutic targets. Results: Collecting duct (CD) cells exhibited the highest LMRG expression. Machine learning algorithms and validation in bilateral ischemia/reperfusion injury (bIRI) and lipopolysaccharide (LPS)-induced AKI mouse models, as well as hypoxia/reoxygenation (H/R)-stimulated renal cells, identified Ldhb as a core gene. Disruption of lactate metabolism via BAY876 (selective GLUT1 inhibitor) or siRNA-mediated Ldhb knockdown significantly attenuated kidney injury, reduced inflammatory cytokines (IL-1β, IL-6, TNF-α), and decreased reactive oxygen species in vitro and in vivo. Conclusions: These findings reveal that lactate metabolism is reprogrammed in AKI, particularly in CD cells, and identify LDHB as a novel potential therapeutic target for this condition, though further mechanistic studies are required to establish causality. Full article
(This article belongs to the Section Advances in Metabolomics)
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17 pages, 1882 KB  
Article
Librarian: An Open-Access Web Application for High-Resolution Mass Spectral Library Assembly
by Jacob Ahlberg Weidenfors, Bénilde Bonnefille and Stefano Papazian
Metabolites 2026, 16(6), 433; https://doi.org/10.3390/metabo16060433 - 22 Jun 2026
Viewed by 660
Abstract
Background: Confident chemical annotation in nontarget small-molecule mass spectrometry critically depends on the availability of high-quality tandem mass spectral (MS2) reference libraries. While community efforts have driven significant expansion of open-access repositories, technical challenges in assembling standardized, metadata-rich records continue [...] Read more.
Background: Confident chemical annotation in nontarget small-molecule mass spectrometry critically depends on the availability of high-quality tandem mass spectral (MS2) reference libraries. While community efforts have driven significant expansion of open-access repositories, technical challenges in assembling standardized, metadata-rich records continue to limit broader participation, underscoring the need for improved computational tools to assist contributors. Methods: To promote the creation and sharing of standardized reference MS2 spectral records, we have developed Librarian, a free, open-access web application designed for rapid and scalable assembly of high-resolution MS2 libraries. Librarian integrates automated retrieval and harmonization of chemical identifiers and metadata from PubChem, compound mixture design for high-resolution mass spectrometry (HRMS) acquisition, and assembly of curated MS2 spectra into repository-ready records compatible with public spectral databases. Results: Through a simple in-browser interface, Librarian offers a flexible end-to-end workflow compatible with popular open-source pre-processing tools to lower technical barriers and facilitate broader community participation in library development. As a demonstration, we used Librarian to create and deposit a spectral library comprising over 1500 new MS2 records into MassBank, which was further applied in retrospective analysis of environmental datasets. Conclusions: Librarian streamlines the creation of standardized, metadata-rich and repository-ready MS2 reference records. Addressing a key bottleneck in community spectral library development and sharing, Librarian supports the continued growth of open-access resources for metabolomics, exposomics, and environmental mass spectrometry. The Librarian web application is publicly accessible via the SciLifeLab Serve platform. Full article
(This article belongs to the Special Issue Open-Source Software in Metabolomics, 2nd Edition)
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14 pages, 568 KB  
Article
Purine Metabolism Alterations in Patients with Chronic Heart Failure: A Cross-Sectional Study of Associations with Iron Status, Oxidative Stress, and Anemia
by Yessen Konysbek, Ayazhan Turar, Vilen B. Molotov-Luchanskiy and Olga A. Ponamareva
Metabolites 2026, 16(6), 432; https://doi.org/10.3390/metabo16060432 - 22 Jun 2026
Viewed by 221
Abstract
Background/Objectives: Anemia and iron dysregulation are common in chronic heart failure (CHF), but additional metabolic mechanisms may contribute to these alterations. This study aimed to evaluate purine metabolism and oxidative stress markers in patients with CHF and to explore their potential relationship [...] Read more.
Background/Objectives: Anemia and iron dysregulation are common in chronic heart failure (CHF), but additional metabolic mechanisms may contribute to these alterations. This study aimed to evaluate purine metabolism and oxidative stress markers in patients with CHF and to explore their potential relationship with anemia. Methods: In this cross-sectional study, 176 patients with CHF and 29 control individuals were included. CHF phenotypes were classified according to left ventricular ejection fraction (HFpEF, HFmrEF, HFrEF). Purine metabolites (guanine, hypoxanthine, adenine, xanthine, and uric acid) were measured using high-performance liquid chromatography, while lipid peroxidation (LPO) and advanced oxidation protein products (AOPPs) were assessed spectrophotometrically. Non-parametric statistical tests with correction for multiple comparisons were applied. Results: Anemia was present in 40.3% of patients with CHF. Serum iron and platelet counts were significantly lower in CHF compared with controls (p = 0.001). Among purine metabolites, adenine levels were higher in CHF (nominal p = 0.009), whereas other metabolites did not differ significantly between groups. LPO levels were lower and AOPP levels were higher in CHF (p = 0.021 and p = 0.008, respectively). No statistically significant associations were observed between hemoglobin levels and purine metabolites. Conclusions: CHF is associated with alterations in iron status and oxidative stress markers, as well as changes in purine metabolism. However, no significant associations between purine metabolites and anemia were identified in this cohort, and these findings should be interpreted cautiously given the exploratory design and sample size limitations. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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19 pages, 1936 KB  
Review
The Gut Microbiome in Heart Failure: Pathways to Inflammation and Therapeutic Targets
by Uday Sankar Akash Vankayala, Ali Sohail, Bivin George, Madhu Singh, Omar Khayat, Malek Kreidieh, Alia Hasham and Luis Quiel
Metabolites 2026, 16(6), 431; https://doi.org/10.3390/metabo16060431 - 19 Jun 2026
Viewed by 378
Abstract
Heart failure (HF) continues to be a major global health burden, with persistent morbidity and mortality despite guideline-directed and device-based therapies. Evidence suggests the gut–heart axis is a critical and underrecognized contributor to HF progression. Alterations in cardiac output and systemic venous congestion [...] Read more.
Heart failure (HF) continues to be a major global health burden, with persistent morbidity and mortality despite guideline-directed and device-based therapies. Evidence suggests the gut–heart axis is a critical and underrecognized contributor to HF progression. Alterations in cardiac output and systemic venous congestion in HF lead to intestinal hypoperfusion, mucosal edema, and loss of barrier integrity, increasing intestinal permeability, gut dysbiosis, and translocation of microbial products. This systemic translocation is associated with chronic low-grade inflammation that activates innate immune pathways that correlate with endothelial dysfunction, oxidative stress, fibroblast activation, and adverse cardiac remodeling. Gut-derived metabolites derived by microbial metabolism modulate cardiovascular health by altering the metabolic profiles. Dysbiosis results in loss of protective short-chain fatty acid (SCFA)-producing bacteria and enriches pro-inflammatory taxa such as trimethylamine N-oxide (TMAO)-producing bacteria. Elevated TMAO is associated with increased mortality and hospitalization in HF, whereas SCFAs enhance barrier integrity and immune tolerance. Secondary bile acids and uremic toxins such as indoxyl sulfate and p-cresyl sulfate further link dysbiosis to fibrosis and vascular stiffness. Circulating markers such as TMAO, lipopolysaccharide-binding protein (LBP), and soluble CD14 carry prognostic value beyond traditional cardiac biomarkers. This review highlights current experimental, translational, and clinical evidence describing gut dysbiosis and its molecular links to HF progression. Targeting the gut–heart axis represents a novel therapeutic approach in HF. Dietary modulation, probiotics/prebiotics, fecal microbiota transplantation, and inhibitors of microbial metabolic pathways show promise. Future research should emphasize microbiota-based interventions in HF management. Full article
(This article belongs to the Special Issue Metabolite Profiles in Inflammatory Diseases)
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22 pages, 14729 KB  
Article
Metabolic Mechanisms of Hexavalent Chromium-Induced Splenic Immune Injury via Oxidative Stress and Ferroptosis Pathways in New Zealand Rabbits
by Junzhao Yuan, Jiaqi Zhang, Jinxing Song, Lingling Liu, Hang Liu, Shuangxing Jin and Xiaoli Ren
Metabolites 2026, 16(6), 430; https://doi.org/10.3390/metabo16060430 - 18 Jun 2026
Viewed by 321
Abstract
Background: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. Methods: In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and [...] Read more.
Background: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. Methods: In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and 50 mg/L Cr(VI) (as potassium dichromate, K2Cr2O7) via drinking water for four weeks to investigate splenic damage and the underlying molecular pathways. Spleen pathological injury was evaluated by hematoxylin and eosin (H&E) staining, and the distribution of T cells, B cells, and macrophages was assessed by immunohistochemistry. Antioxidant enzyme activities and antioxidant substance levels were determined using ELISA, and the relative mRNA expression of immune factor genes, antioxidant-related genes, and ferroptosis-related genes was quantified by quantitative real-time PCR (qRT-PCR). In addition, the distribution of iron in splenic tissue was detected by enhanced Prussian blue staining. Results: Our results demonstrate that high-dose Cr(VI) significantly inhibited body weight gain, induced lymphocyte atrophy, vacuolization, and widening of intercellular spaces in the splenic white pulp. Furthermore, Cr(VI) reduced T and B lymphocyte populations, promoted macrophage infiltration and inflammatory cytokine gene expression in a concentration-dependent manner, impaired total antioxidant capacity, and led to a decrease in glutathione (GSH) levels in the spleen. Additionally, Cr(VI) exposure increased iron accumulation, activated the ACSL4–NOX lipid peroxidation cascade, and downregulated GPX4 expression, ultimately triggering ferroptosis. Conclusions: These findings reveal that Cr(VI) causes splenic immune injury by disrupting oxidative homeostasis and inducing ferroptosis, providing novel insights for evaluating immunotoxicity and identifying metabolic targets under Cr(VI) pollution. Full article
(This article belongs to the Special Issue Animal Nutritional Metabolism and Toxicosis Disease, 2nd Edition)
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13 pages, 4017 KB  
Article
Improving Speed and Efficiency of DESI Imaging with the Xevo MRT Mass Spectrometer for Analyte Mapping
by Mark Towers, Emmanuelle Claude, Lisa Towers, Helen Yates and Joanne Ballantyne
Metabolites 2026, 16(6), 429; https://doi.org/10.3390/metabo16060429 - 18 Jun 2026
Viewed by 440
Abstract
Background: Recent technology improvements have enabled desorption electrospray ionisation (DESI) mass spectrometry imaging to achieve down to 5 µm (pixel) image resolution. However, operating at this resolution introduces challenges, particularly regarding increased total analysis time and the need for sufficient instrument sensitivity to [...] Read more.
Background: Recent technology improvements have enabled desorption electrospray ionisation (DESI) mass spectrometry imaging to achieve down to 5 µm (pixel) image resolution. However, operating at this resolution introduces challenges, particularly regarding increased total analysis time and the need for sufficient instrument sensitivity to detect analytes from very small tissue areas. Methods: High mass and image resolution DESI imaging was performed on rat brain tissue using a Xevo™ MRT benchtop mass spectrometer equipped with a multi-reflecting time-of-flight mass analyser and a DESI XS source. Data acquisition was conducted at speeds of up to 100 Hz. Sensitivity was assessed using a dilution series of five Active Pharmaceutical Ingredients (APIs) spotted onto porcine liver tissue. Signal detection limits were evaluated using extracted ion chromatograms (XICs) with signal-to-noise (S/N) calculations against blank samples. Additionally, enhanced duty cycle (EDC) was applied to evaluate improvements in analyte signal intensity across specific mass ranges in both positive and negative ionisation modes. Results: At acquisition speeds of up to 100 Hz, excellent data quality was achieved, with signal intensity remaining suitable for analytical applications. All five tested APIs were detectable at concentrations of 25 pg/mm2. Three of the five compounds were further detected at concentrations as low as 2.5 pg/mm², with signal-to-noise ratios greater than 5. The application of EDC resulted in a significant increase in analyte signal intensity within the targeted mass ranges, particularly for small molecule endogenous metabolites and lipids, in both ionisation modes. Furthermore, the system demonstrated substantially improved spectral quality, achieving mass resolution up to 100,000 FWHM. This enabled the resolution of previously indistinguishable analytes with significantly improved mass accuracy compared to systems operating at approximately 30,000 FWHM. Conclusions: The Xevo™ MRT mass spectrometer with DESI XS source enables high-resolution DESI imaging at speeds up to 100 Hz without compromising data quality or sensitivity. The system demonstrates excellent detection limits for pharmaceutical compounds and improved performance through enhanced duty cycle operation. Overall, the combination of high spatial resolution, increased mass resolution, and improved spectral quality allows for more accurate analyte differentiation, representing a significant advancement over lower-resolution systems. Full article
(This article belongs to the Special Issue New Technology and Workflows for Advancing Metabolomics)
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18 pages, 3744 KB  
Article
MSTune: A Data-Driven Approach to Parameter Tuning Using Grid Search and Differential Evolution for Gas Chromatography–Mass Spectrometry-Based Compound Identification
by Hunter Dlugas, Jing Li, Xiang Zhang and Seongho Kim
Metabolites 2026, 16(6), 428; https://doi.org/10.3390/metabo16060428 - 18 Jun 2026
Viewed by 248
Abstract
Background/Objectives: In gas chromatography–mass spectrometry (GC-MS) library-based compound identification, spectrum preprocessing and associated tuning parameters critically influence identification performance. These parameters are conventionally optimized using grid search, which requires predefined parameter spaces and becomes computationally inefficient as dimensionality increases, often failing to [...] Read more.
Background/Objectives: In gas chromatography–mass spectrometry (GC-MS) library-based compound identification, spectrum preprocessing and associated tuning parameters critically influence identification performance. These parameters are conventionally optimized using grid search, which requires predefined parameter spaces and becomes computationally inefficient as dimensionality increases, often failing to identify optimal values because of discretization. Differential evolution (DE), a population-based metaheuristic optimization algorithm, provides a flexible alternative through efficient global exploration of the parameter space. This study compared the performance of DE and grid search for optimizing compound identification. Methods: Cosine similarity was applied to the NIST GC-MS library. DE was used to maximize either cross-validated accuracy or mean reciprocal rank (MRR). Results were compared with those from a grid search over five equally spaced parameter values. Identification performance was evaluated using accuracy, MRR, and area under the receiver operating characteristic curve (AUC). Results: When all four parameters were optimized simultaneously, DE achieved slightly higher cross-validated accuracy and MRR than grid search, although the absolute differences were modest. More pronounced differences were observed in specific unidimensional tuning scenarios, particularly for the intensity weight factor. Simultaneous multidimensional parameter optimization yielded better performance than isolated parameter tuning. Conclusions: Grid search may be computationally advantageous when the parameter space is known and limited, whereas DE provides a more flexible approach for unknown or high-dimensional search spaces. Overall, DE achieved comparable identification performance to grid search, with modest improvements observed in some optimization settings. A command line Julia-based tool, MSTune, was developed for spectrum preprocessing parameter optimization and is publicly available on GitHub. Full article
(This article belongs to the Special Issue Open-Source Software in Metabolomics, 2nd Edition)
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25 pages, 822 KB  
Article
Impact of a Dietary Fish Oil Supplementation on the Plasma Lipidome of Healthy Adult Cats
by Nadine Paßlack, Helena Veit, Henri Funk, Jürgen Zentek and Sven Schuchardt
Metabolites 2026, 16(6), 427; https://doi.org/10.3390/metabo16060427 - 18 Jun 2026
Viewed by 354
Abstract
Background/Objectives: Dietary fish oil supplementation has been associated with lower total plasma triacylglycerols in felines. The present study aimed to characterize this effect in more detail, using lipidomic analyses. Methods: Plasma samples of cats (n = 10), receiving a complete [...] Read more.
Background/Objectives: Dietary fish oil supplementation has been associated with lower total plasma triacylglycerols in felines. The present study aimed to characterize this effect in more detail, using lipidomic analyses. Methods: Plasma samples of cats (n = 10), receiving a complete basic diet, with and without the addition of 0.5 g and 1.0 g fish oil/kg body weight/day, each for 21 days, in a randomized crossover design, were analyzed by an FIA MS/MS-based targeted metabolomics approach. Results: The results demonstrated that 360 metabolites were affected by the dietary treatments, predominantly belonging to triacylglycerols (n = 124), phosphatidylcholines (n = 68), phosphatidylethanolamines (n = 63), phosphatidylglycerols (n = 33), and phosphatidylinositols (n = 21). Lowering effects of fish oil supplementation on plasma triacylglycerols could be confirmed. However, increased levels of specific triacylglycerols were also observed, especially of those containing eicosapentaenoic or docosahexaenoic acid. The decreased triacylglycerols showed a lower number of carbons and a lower degree of unsaturation than the enhanced triacylglycerols. Such a lipid profile is assumed to be beneficial in human medicine; its relevance for feline health, however, is unclear so far. Conclusions: In conclusion, the lipidomic analyses provided a detailed characterization of the feline plasma lipidome and its modulation by a dietary fish oil supplementation. The clinical relevance of these findings warrants further investigation. Full article
(This article belongs to the Section Animal Metabolism)
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15 pages, 7280 KB  
Article
TyG Index and Frailty as Composite Biomarkers of Cardiometabolic Risk and Mortality Across CKM Stages 0–3
by Yaocheng Luo, Peng Zeng, Shuoya Huang, Zhenzhen Peng, Jian Zheng, Zumin Shi, Manoj Sharma and Yong Zhao
Metabolites 2026, 16(6), 426; https://doi.org/10.3390/metabo16060426 - 17 Jun 2026
Viewed by 366
Abstract
Background: Cardiovascular disease and mortality are common outcomes of cardiovascular–kidney–metabolic (CKM) syndrome. The integrated role of metabolic dysfunction and frailty, quantified by the triglyceride–glucose–frailty index (TyG-FI), remains insufficiently explored. This study examined the association between TyG-FI and incident composite outcomes among participants [...] Read more.
Background: Cardiovascular disease and mortality are common outcomes of cardiovascular–kidney–metabolic (CKM) syndrome. The integrated role of metabolic dysfunction and frailty, quantified by the triglyceride–glucose–frailty index (TyG-FI), remains insufficiently explored. This study examined the association between TyG-FI and incident composite outcomes among participants with CKM stages 0–3. Methods: Data were obtained from two large cohort studies conducted in China and the United States. The analysis focused on participants classified as CKM stages 0–3. Cox proportional hazards models were used to estimate the relationship between TyG-FI and incident composite outcomes. Nonlinear associations were explored using spline functions. Additional analyses were performed across different subgroups and under varied assumptions. Model performance over time was also assessed. Results: Significant differences in outcome incidence were observed across TyG-FI levels. Higher quartiles showed a gradual increase in risk and displayed a dose–response pattern, with inflection points at 1.01 and 2.29. Associations were consistent across subgroups, and TyG-FI demonstrated moderate discrimination (AUCs 0.714 and 0.744). Conclusions: In the CHARLS and HRS cohorts, higher TyG-FI scores were independently associated with an increased risk of incident composite outcomes among participants with CKM stages 0–3, with a nonlinear relationship observed. Its discriminatory power was moderate, suggesting that TyG-FI may serve as a supplementary indicator for risk stratification in the early to mid-stages, although its clinical predictive value requires further validation. Full article
(This article belongs to the Special Issue Research on Biomarkers for Cardiometabolic Risk in Metabolic Syndrome—2nd Edition)
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12 pages, 12206 KB  
Article
Efficacy of Oral Vitamin K2 Supplementation in Experimental Knee Osteoarthritis
by Emre Uzun, İbrahim Tekeoğlu, Hüseyin Çakıroğlu, Özcan Budak, Elvan Şahin, Kemal Nas, Muhammed Zahid Sahin and Ayhan Kamanlı
Metabolites 2026, 16(6), 425; https://doi.org/10.3390/metabo16060425 - 17 Jun 2026
Viewed by 431
Abstract
Background/Objectives: Although vitamin K has been implicated in osteoarthritis pathophysiology, the specific effects of vitamin K2 (menaquinone) on cartilage degeneration remain poorly characterized. This study aimed to investigate the effect of oral vitamin K2 supplementation in a monosodium iodoacetate-induced osteoarthritis model. Methods [...] Read more.
Background/Objectives: Although vitamin K has been implicated in osteoarthritis pathophysiology, the specific effects of vitamin K2 (menaquinone) on cartilage degeneration remain poorly characterized. This study aimed to investigate the effect of oral vitamin K2 supplementation in a monosodium iodoacetate-induced osteoarthritis model. Methods: Twenty-four male Sprague Dawley rats were included in the study and divided into 3 equal groups: sham group, control (osteoarthritis) group, and treatment group. Saline was applied to the right knee of the sham group, and MIA was applied intra-articularly to the right knee of the control and treatment groups to create an osteoarthritis model. Rats in the treatment group were given 8 micrograms (μg)/day of vitamin K2 orally in addition to the standard diet. After 28 days of follow-up, all rats were euthanized. The right knee articular cartilage was examined histologically with Hematoxylin–Eosin and Safranin O and immunohistochemically with type II collagen alpha 1 and Matrix Metalloproteinase-13. Results: Histological evaluation demonstrated significantly lower Mankin scores in the treatment group (4.25 ± 0.83) compared with the control group (11.10 ± 0.83). Immunohistochemical analysis showed more intense type II collagen staining and reduced matrix metalloproteinase-13 staining in the treatment group relative to the control group. Conclusions: Oral vitamin K2 administration was associated with reduced cartilage degeneration and improved matrix preservation at the 28-day endpoint in an induced MIA osteoarthritis rat model. Full article
(This article belongs to the Section Nutrition and Metabolism)
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17 pages, 12815 KB  
Article
Gut–Liver Axis Mechanisms Underlying Spontaneous Reversal of Liver Fibrosis: A Gut Microbiota-Metabolomics Analysis
by Yuanying Zhao, Hao Chang, Chenxue Hou, Bingqing Yang and Yue Li
Metabolites 2026, 16(6), 424; https://doi.org/10.3390/metabo16060424 - 17 Jun 2026
Viewed by 333
Abstract
Background: The reversal of liver fibrosis is crucial for improving outcomes in chronic liver disease. The gut–liver axis, mediated by the intestinal microbiota, plays a significant role in this process. However, its dynamic changes and mechanisms during reversal remain unclear. This study aimed [...] Read more.
Background: The reversal of liver fibrosis is crucial for improving outcomes in chronic liver disease. The gut–liver axis, mediated by the intestinal microbiota, plays a significant role in this process. However, its dynamic changes and mechanisms during reversal remain unclear. This study aimed to systematically reveal these dynamics and explore the link between gut microbiota and metabolism in a spontaneous reversal model. Methods: Intestinal contents were collected from mouse model groups (fibrosis, 4-week reversal, and 12-week reversal). The use of 16S rRNA gene sequencing was employed to analyze gut microbiota structure, and untargeted metabolomics was used to profile metabolic changes. Differential metabolites and microbial taxa were identified using multivariate statistical analysis, followed by pathway enrichment analysis. Spearman correlation analysis was used to construct metabolite–microbiota association networks across different reversal stages. Results: Metabolomic analysis showed significant alterations in multiple pathways during reversal. Linoleic and α-linolenic acid metabolism had a high impact in later stages. Taurine and biotin metabolism remained active throughout. Branched-chain amino acid degradation was enriched later. Microbiota analysis revealed significant structural shifts via beta-diversity. Bacteroidota decreased while Firmicutes increased in 4 weeks. Butyrate-producing families increased, and Akkermansia was enriched later. Integrated analysis demonstrated significant correlations between specific bacteria and metabolites, indicating a close microbiota–metabolism association during reversal. Conclusions: This integrated multi-omics study delineates the potential dynamic reorganization of the gut microbiota and host metabolism during spontaneous liver fibrosis reversal. These findings provide a theoretical basis for understanding the gut–liver axis mechanism in fibrosis reversal and for developing microbiota-targeted intervention strategies. Full article
(This article belongs to the Special Issue Lipid Metabolism in Chronic Diseases)
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27 pages, 7550 KB  
Article
Malic Enzyme 1 Limits Acetaminophen-Induced Liver Injury by Sustaining Redox and Bioenergetic Homeostasis
by Chang Guo and Zizhi Tang
Metabolites 2026, 16(6), 423; https://doi.org/10.3390/metabo16060423 - 16 Jun 2026
Viewed by 356
Abstract
Background: Acetaminophen (APAP) overdose remains a major cause of acute liver injury. Although N-acetylcysteine (NAC) is the clinically established antidote for APAP toxicity, its efficacy is greatest when administered early, and additional therapeutic strategies are still needed for patients with delayed presentation [...] Read more.
Background: Acetaminophen (APAP) overdose remains a major cause of acute liver injury. Although N-acetylcysteine (NAC) is the clinically established antidote for APAP toxicity, its efficacy is greatest when administered early, and additional therapeutic strategies are still needed for patients with delayed presentation or progressive injury. Because APAP hepatotoxicity involves coupled disturbances in redox control, mitochondrial performance, and cellular metabolism, metabolic enzymes that sustain NADPH availability may critically influence disease severity. Malic enzyme 1 (ME1), a cytosolic NADPH-generating enzyme, has not been functionally defined in this context. Methods: To determine the contribution of ME1 to APAP-induced liver injury (AILI), we used hepatocyte-specific ME1 knockout mice, hepatic overexpression and reconstitution approaches, primary mouse hepatocytes, and an enzymatically inactive ME1 mutant. Liver injury and associated changes in oxidative stress, mitochondrial function, energy metabolism, autophagic flux, and endoplasmic reticulum (ER) stress were evaluated using biochemical, histological, molecular, and ultrastructural analyses, together with pharmacological interventions. Results: Genetic loss of ME1 did not substantially alter early APAP metabolic activation-related indices, including APAP-protein adduct formation, but markedly increased hepatocellular metabolic vulnerability after APAP challenge. This phenotype was characterized by enhanced lipid peroxidation, impaired mitochondrial polarization, reduced ATP availability, defective autophagic flux, and amplified ER stress, leading to more severe liver damage. In contrast, ME1 overexpression or reconstitution promoted a more adaptive metabolic response and limited tissue injury. These effects depended largely on ME1 catalytic activity, as protection was markedly weakened with the mutant enzyme. Pharmacological analyses further supported the involvement of AMPK/mTOR-associated autophagy regulation and ER stress adaptation in the downstream actions of ME1. Malic acid also partially attenuated APAP-induced hepatotoxicity in vivo and in vitro. Conclusions: ME1 functions as an endogenous metabolic factor that influences the outcome of APAP-induced liver injury. Its catalytic activity supports hepatocyte survival primarily by preserving reductive capacity, bioenergetic balance, and adaptive stress responses, rather than by altering APAP metabolic activation. Full article
(This article belongs to the Section Cell Metabolism)
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15 pages, 970 KB  
Article
Sex Differences in the Socioeconomic Gradient of Latent Cardiometabolic Phenotypes in a Working-Age Population from the Balearic Islands (Spain): A Population-Based Analysis
by María Teófila Vicente-Herrero, Pedro J. Tárraga López, Carla Busquets-Cortés, Lluis Rodas Cañellas, Ángel Arturo López González and José Ignacio Ramírez-Manent
Metabolites 2026, 16(6), 422; https://doi.org/10.3390/metabo16060422 - 16 Jun 2026
Viewed by 388
Abstract
Background: Cardiometabolic diseases are shaped by complex interactions between biological and social determinants. While socioeconomic inequalities in cardiometabolic risk are well established, less is known about how these inequalities are distributed across multidimensional cardiometabolic phenotypes and whether they differ by sex. Objective: We [...] Read more.
Background: Cardiometabolic diseases are shaped by complex interactions between biological and social determinants. While socioeconomic inequalities in cardiometabolic risk are well established, less is known about how these inequalities are distributed across multidimensional cardiometabolic phenotypes and whether they differ by sex. Objective: We aimed to examine sex differences in the socioeconomic gradient of cardiometabolic phenotypes using latent class analysis in a working-age population. Methods: A cross-sectional study was conducted in 3108 adults aged 18–65 years undergoing occupational health assessments in the Balearic Islands (Spain). Educational level was used as an indicator of socioeconomic position. Cardiometabolic risk was assessed using obesity, insulin resistance (METS-IR), metabolic dysfunction-associated steatotic liver disease (FLI), atherogenic index of plasma, and metabolic syndrome. Latent class analysis was applied to identify cardiometabolic phenotypes. Multinomial logistic regression models stratified by sex and interaction analyses were used to assess associations between educational level and class membership. Tests for linear trend and predicted probabilities were also estimated. Results: Four cardiometabolic phenotypes were identified: low-risk (40.8%), obesity-dominant (24.1%), dysmetabolic (19.3%), and high-risk multimorbid (15.8%). A clear socioeconomic gradient was observed, with lower educational attainment associated with a higher likelihood of belonging to adverse cardiometabolic profiles. This gradient was stronger among women. For the high-risk multimorbid class, the relative risk ratio comparing low vs. high educational level was 1.82 (95% CI 1.34–2.46) in men and 2.47 (95% CI 1.68–3.64) in women (p for interaction = 0.012). A significant linear trend across educational levels was observed in both sexes (p for trend < 0.001). Predicted probabilities further confirmed a steeper increase in high-risk profiles among women with lower educational attainment. Conclusions: Cardiometabolic risk is structured into distinct phenotypic profiles that are socially patterned. Socioeconomic inequalities are strongly associated with adverse cardiometabolic phenotypes, with a more pronounced gradient among women. These findings highlight the need for gender-sensitive strategies addressing social determinants to reduce cardiometabolic health inequalities. Full article
(This article belongs to the Special Issue Exploring Pathological Mechanisms in Obesity, Diabetes, and Metabolic Syndrome: 2nd Edition)
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16 pages, 590 KB  
Review
Ceramide-Driven Mechanisms in Pulmonary Fibrosis
by Zifan Li, Yaqian Li, Na Mao, Xuemin Gao, Hong Xu, Wenchen Cai and Tian Li
Metabolites 2026, 16(6), 421; https://doi.org/10.3390/metabo16060421 - 16 Jun 2026
Viewed by 394
Abstract
Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a chronic and progressive interstitial lung disease characterized by alveolar epithelial injury, fibroblast activation, and excessive extracellular matrix deposition, which collectively lead to respiratory failure. Despite the availability of antifibrotic agents, disease-modifying therapies remain limited. [...] Read more.
Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a chronic and progressive interstitial lung disease characterized by alveolar epithelial injury, fibroblast activation, and excessive extracellular matrix deposition, which collectively lead to respiratory failure. Despite the availability of antifibrotic agents, disease-modifying therapies remain limited. Emerging evidence has identified dysregulated sphingolipid metabolism, especially ceramide accumulation, as a key driver of fibrotic pathogenesis. Ceramide is a central bioactive lipid in the sphingolipid pathway that regulates multiple cellular processes, including apoptosis, inflammation, endothelial barrier dysfunction, and fibroblast activation, all of which contribute to pulmonary fibrosis. This review is a narrative review that systematically summarizes the biosynthetic and metabolic pathways of ceramide, with an emphasis on chain length-specific functions and the ceramide to S1P rheostat. We further discuss the mechanistic roles of ceramide in alveolar epithelial cell apoptosis, inflammatory responses, and vascular barrier disruption in fibrotic lung disease. Finally, we highlight emerging therapeutic strategies that target ceramide metabolism, including inhibitors of acid sphingomyelinase (ASMase) and serine palmitoyltransferase (SPT), and propose future directions for clinical translation. Full article
(This article belongs to the Special Issue Advances in Immune Metabolism: Lipid Regulation and Disease Outcomes)
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17 pages, 6525 KB  
Article
Melatonin Modulates Macrophage Polarization and Immunometabolic Responses in the Colostrum of Obese Mothers
by Silvia Hannah Bilotti Ratto Gomes da Silva, Danielle Cristina Honorio França, Kênia Maria Resende Silva, Emanuelle Carolina Honorio França, Viviane Francelina Luz, Arce dos Santos Sfredo, Tassiane Cristina Morais, Eduardo Luzía França and Adenilda Cristina Honorio-França
Metabolites 2026, 16(6), 420; https://doi.org/10.3390/metabo16060420 - 15 Jun 2026
Viewed by 326
Abstract
Background/Objectives: Obesity is a major public health problem associated with chronic inflammation and functional alterations in multiple organs and systems. Few studies have examined colostrum from obese mothers, particularly with respect to macrophage function, enzyme and cytokine concentrations, and the role of [...] Read more.
Background/Objectives: Obesity is a major public health problem associated with chronic inflammation and functional alterations in multiple organs and systems. Few studies have examined colostrum from obese mothers, particularly with respect to macrophage function, enzyme and cytokine concentrations, and the role of melatonin in immune modulation. This study aimed to evaluate melatonin levels and their effects on macrophage polarization, cytokine concentrations, nitric oxide synthase [iNOS], and arginase in colostrum from obese mothers. Colostrum samples were collected from eutrophic mothers [BMI: 18.5–24.9 kg/m2] and obese mothers [BMI: ≥30 kg/m2]. Methods: Macrophages were isolated by density gradient and treated with melatonin. The expression of M1 and M2 macrophages and cytokine concentrations were assessed by flow cytometry, while melatonin levels in colostrum supernatants, iNOS, and arginase in cell lysates were determined by ELISA. Results: An endogenous increase in melatonin was also observed in the colostrum of obese mothers. Maternal obesity has been shown to reduce M1 and M2 macrophage expression, increase nitric oxide synthase [NOS] activity, and elevate interleukin-6 [IL-6] and interleukin-17 [IL-17] levels. However, melatonin treatment restored M1 and M2 macrophage levels and reduced inducible nitric oxide synthase [iNOS] and arginase production to levels similar to those observed in mothers of healthy weight. Conclusions: these findings suggest that maternal obesity creates a pro-inflammatory environment in colostrum, characterized by altered macrophage polarization, altered cytokine secretion, and an imbalance in the enzymatic activities of iNOS and arginase within the L-arginine metabolic pathway. Both natural and supplemental melatonin exhibited immunomodulatory, antioxidant, and anti-inflammatory effects, helping to restore immune balance in colostrum. These results emphasize the potential benefits of melatonin as an immunometabolic modulator and its contribution to understanding immunometabolic regulation in obese mothers. Full article
(This article belongs to the Special Issue Effects of Nutrition Intake and Lifestyle Intervention on Human Metabolic Health)
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22 pages, 9169 KB  
Article
Identification and Transcriptomic Analysis of Mitochondria-Related Gene Signatures in Obesity
by Hezhang Yun, Chang Liu, Binghong Gao and Peijie Chen
Metabolites 2026, 16(6), 419; https://doi.org/10.3390/metabo16060419 - 15 Jun 2026
Viewed by 392
Abstract
Objectives: This study aimed to identify core genes associated with mitochondria-related transcriptomic signatures and evaluate their potential as computational biomarkers, immune characteristics, regulatory mechanisms, and potential therapeutic relevance. Methods: Obesity-related transcriptome datasets were obtained from the GEO database. Differentially expressed genes [...] Read more.
Objectives: This study aimed to identify core genes associated with mitochondria-related transcriptomic signatures and evaluate their potential as computational biomarkers, immune characteristics, regulatory mechanisms, and potential therapeutic relevance. Methods: Obesity-related transcriptome datasets were obtained from the GEO database. Differentially expressed genes (DEGs) were intersected with mitochondria-related genes (MRGs) to identify obesity-related MRGs. Functional enrichment, protein–protein interaction (PPI) analysis, CytoHubba, LASSO and random forest algorithms were used to screen core genes. External validation, ROC analysis, immune infiltration analysis, regulatory network construction, candidate drug prediction, and molecular docking were further performed. Results: A total of 527 DEGs and 15 differentially expressed MRGs were identified. Enrichment analysis suggested that these mitochondria-related genes were mainly associated with disrupted mitochondrial energy metabolism, lipid metabolic remodeling, and altered substrate utilization. ECHDC2, FASN, NAT8L, and AASS were identified as core MRGs; these genes are respectively associated with mitochondrial metabolic regulation, de novo fatty acid synthesis, N-acetylaspartate-related mitochondrial metabolism, and lysine degradation. These genes were significantly downregulated in obesity and showed good diagnostic performance. Immune infiltration analysis revealed alterations in the immune microenvironment, and the core genes were negatively correlated with multiple immune cell types. Molecular docking showed that Genistein had the lowest predicted binding free energy with NAT8L (−8.89 kcal/mol), suggesting relatively favorable binding among the tested ligand–target pairs. Conclusions: ECHDC2, FASN, NAT8L, and AASS may serve as candidate computational biomarkers, among which FASN represents a known lipid metabolism-related gene, supporting the biological plausibility of the workflow. Full article
(This article belongs to the Special Issue Obesity and Metabolic Health, 2nd Edition)
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22 pages, 25748 KB  
Article
Gαq Is a Heterotrimeric G-Protein Subunit That Directs the Selectivity of PPARγ-Induced Gene Pathways Toward Energy-Related Processes Rather than Adiposity
by Evelyn A. Bates, Zachary A. Kipp, Wang-Hsin Lee, Genesee J. Martinez, Sally N. Pauss, Philipp E. Scherer and Terry D. Hinds, Jr.
Metabolites 2026, 16(6), 418; https://doi.org/10.3390/metabo16060418 - 15 Jun 2026
Viewed by 312
Abstract
Background/Objectives: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gαq, a [...] Read more.
Background/Objectives: Signaling mediators of PPARγ influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPARγ coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gαq, a heterotrimeric G protein subunit, also signals to PPARγ and may significantly affect adipogenesis and glucose sensitivity. Methods: To explore Gαq’s role in adipocytes, we generated CRISPR-mediated Gαq (Gnaq) knockout (Gnaq KO) and scramble control cells from 3T3-L1 preadipocytes. Results: The absence of Gαq resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPARγ. Gαq deficiency also decreased mitochondrial abundance and respiration in response to PPARγ ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated Gnaq KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in Gnaq KO adipocytes. Conclusions: These findings support Gαq as a regulator of adipocyte function, linking kinase signaling pathways to PPARγ-mediated transcription. This research provides mechanistic insights into targeting Gαq as a potential treatment for individuals with obesity and metabolic disorders. Full article
(This article belongs to the Special Issue Interplay Between Metabolism, Oxidative Stress, and Cellular Signaling in Health and Disease)
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19 pages, 347 KB  
Review
Roles of Metabolites Unveiled by Metabolomics in Brassica rapa, B. napus and B. juncea
by Yunong Xia, Silin Su, Xianyu Tang, Lei Qin, Junxing Lu and Shitou Xia
Metabolites 2026, 16(6), 417; https://doi.org/10.3390/metabo16060417 - 15 Jun 2026
Viewed by 440
Abstract
Rapeseed is a major source of vegetable oil and contains a wide variety of metabolites. Recent advances, particularly the integration of metabolomics with other omics approaches, have enabled not only comprehensive but also detailed analyses of key metabolites that respond to specific conditions. [...] Read more.
Rapeseed is a major source of vegetable oil and contains a wide variety of metabolites. Recent advances, particularly the integration of metabolomics with other omics approaches, have enabled not only comprehensive but also detailed analyses of key metabolites that respond to specific conditions. To date, these recent advances in the metabolomics of Brassica crops have not yet been fully clarified. In this review, we seek to summarize the recent progresses in metabolomics studies of Brassica rapa, B. napus and B. juncea, introduce the key metabolites spanning nucleic acids, amino acids, fatty acids, lipids, organic acids, alkaloids, phenylpropanoids, terpenoids, flavonoids and glucosinolates uncovered by this approach, focusing on those associated with growth and development, and abiotic/biotic stresses, including macronutrient availability, temperature, water stress, salt stress, aluminum and cadmium toxicity, and infection of Sclerotinia sclerotiorum, Leptosphaeria maculans, and Plasmodiophora brassicae. Future perspectives and current challenges in metabolomics integrating with other omics are also discussed, along with its potential for breeding applications, especially in new marker discovery, trait prediction, and even metabolic selection, aimed at developing new rapeseed varieties with stable, high-yielding, and quality traits. Full article
(This article belongs to the Special Issue Metabolomics and Plant Defence, 2nd Edition)
24 pages, 16704 KB  
Article
Immunometabolic Stratification of Autism Spectrum Disorder by CD4+ T-Cell Phenotype Reveals Subtype-Specific Energetic Deficit and Coordinated Suppression of Micronutrient Acquisition Pathways
by Albion Dervishi
Metabolites 2026, 16(6), 416; https://doi.org/10.3390/metabo16060416 - 15 Jun 2026
Viewed by 927
Abstract
Background: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic context. Methods: We analyzed whole-blood microarray data from GSE18123 (GPL570: ASD n = 46, controls [...] Read more.
Background: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic context. Methods: We analyzed whole-blood microarray data from GSE18123 (GPL570: ASD n = 46, controls n = 19; GPL6244: ASD n = 68, controls n = 21) using an integrated immunometabolic framework. CD4+ T-cell transcriptional programs were used to assign dominant immune phenotypes (TH1, TH2, TH17, Tfh, FOXP3+ Treg, Tr1-like). Metabolic demand was quantified via the τ-axis; execution capacity was assessed using cytosolic and mitochondrial energy compensation ratios (CECR, MECR). Induction–execution mismatch was captured by three Gap metrics (Cytosolic, Warburg, Global). Functional validation correlated these metrics with transcriptional signatures of folate transport, one-carbon metabolism, receptor-mediated micronutrient uptake (LRP2–CUBN–AMN), cobalamin processing, and vitamin D activation across both platforms. Results: Six immunometabolic CD4+ subtypes were identified within ASD. τ-axis discrimination was strongest for Tr1-like (AUC = 0.811) and Tfh (AUC = 0.825) states, while TH17 profiles were indistinguishable from controls. Despite variation in metabolic demand, CECR and MECR remained relatively preserved, indicating decoupling between induction and execution capacity. Global Gap values were most negative in Tfh and TH1 states and positive in TH17 and controls. Negative Gap states showed coordinated suppression of ATP-intensive micronutrient acquisition pathways, including folate transport (FOLR1/2, SLC19A1), megalin–cubilin-mediated uptake (r ≈ 0.77–0.79), and vitamin D activation (CYP27B1). Intracellular cobalamin processing was upregulated in proportion to metabolic demand (r > 0.9). Findings were directionally replicated across both datasets. Conclusions: These data demonstrate that ASD exhibits structured immunometabolic heterogeneity characterized by subtype-specific demand–capacity imbalance. The Global Gap framework provides transcriptomic evidence of energetic deficit in Tfh- and Tr1-like-dominant states. Future clinical studies should incorporate subtype-stratified assessment of micronutrient status and metabolic execution capacity. Full article
(This article belongs to the Special Issue Computational Modeling of Metabolite-Modulated Cellular Processes)
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17 pages, 777 KB  
Article
Discriminative Ability of TyG, TyG-WC, BAI, FGIR, and QUICKI Indexes in Identifying Metabolic Syndrome in a Pediatric Population with Obesity
by Sofia Tamini, Adele Bondesan, Diana Caroli, Francesca Frigerio and Alessandro Sartorio
Metabolites 2026, 16(6), 415; https://doi.org/10.3390/metabo16060415 - 14 Jun 2026
Viewed by 364
Abstract
Background/Objectives: Pediatric obesity is closely associated with metabolic syndrome (MetS), a condition linked to increased cardiometabolic risk. Early identification of high-risk individuals remains challenging. This study aimed to evaluate the diagnostic performance of selected anthropometric, metabolic dysfunction and insulin resistance indexes for [...] Read more.
Background/Objectives: Pediatric obesity is closely associated with metabolic syndrome (MetS), a condition linked to increased cardiometabolic risk. Early identification of high-risk individuals remains challenging. This study aimed to evaluate the diagnostic performance of selected anthropometric, metabolic dysfunction and insulin resistance indexes for identifying MetS in children and adolescents with obesity. Methods: In this retrospective, cross-sectional, single-center study, 758 children and adolescents with obesity (mean age 14.8 ± 2.1 years; 59.9% females) hospitalized for a body weight-reduction program were included. MetS was defined according to International Diabetes Federation criteria, in which central obesity is a mandatory diagnostic component. The triglyceride–glucose (TyG), TyG–waist circumference (TyG-WC), body adiposity index (BAI), fasting glucose-to-insulin ratio (FGIR), and quantitative insulin sensitivity check index (QUICKI) were calculated. Receiver operating characteristic curve analysis was used to assess their discriminative ability. Results: The prevalence of MetS was 27.8% and was significantly higher in males than females (34.9% vs. 23.1%, p < 0.0001). TyG and TyG-WC showed the best discriminative performance (AUC 0.75 and 0.76, respectively), although with only moderate sensitivity and specificity. FGIR and QUICKI demonstrated lower accuracy (AUC 0.64 and 0.63), whereas BAI showed no discriminative ability (AUC 0.48). These findings were consistent across sexes, although sex-specific differences in both MetS prevalence and optimal cut-off values were observed. Correlation analyses confirmed moderate associations between TyG-based indexes and MetS, whereas other indexes showed weaker relationships. Conclusions: In the present cohort of children and adolescents with obesity, TyG and TyG-WC showed the best performance in identifying MetS compared with the other evaluated indexes. However, their performance remained moderate, and the proposed cut-off values require validation in independent populations. These indexes may represent simple supportive screening and risk-stratification tools but should be used alongside comprehensive clinical assessment and established diagnostic criteria rather than as stand-alone diagnostic measures. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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22 pages, 3444 KB  
Article
Temperature-Dependent Modulation of Cardiac Metabolism, Post-Injury Survival and Regenerative Rate in Axolotls
by Anita Dittrich, Sofie Amalie Andersson, Aage Kristian Olsen Alstrup, Pernille Lajer Sørensen, Mette Irene Theilgaard Simonsen, Maibritt Hald Arildsen, Rasmus Roost Aabling and Henrik Lauridsen
Metabolites 2026, 16(6), 414; https://doi.org/10.3390/metabo16060414 - 13 Jun 2026
Viewed by 397
Abstract
Background/Objectives: Cardiac regenerative ability varies in vertebrates. Adult mammals cannot mount a regenerative response, while fetal mammals and some salamanders and teleosts fully regenerate the heart after a cryoinjury mimicking a myocardial infarction. This contrast is suggested to be regulated in part [...] Read more.
Background/Objectives: Cardiac regenerative ability varies in vertebrates. Adult mammals cannot mount a regenerative response, while fetal mammals and some salamanders and teleosts fully regenerate the heart after a cryoinjury mimicking a myocardial infarction. This contrast is suggested to be regulated in part by metabolism, with high regenerative capacity correlating with a comparatively lower mass-specific metabolic rate, ectothermy rather than endothermy and a metabolic phenotype favoring glycolysis in cardiac muscle. Methods: In this physiological study on axolotl salamanders, we altered the housing temperatures from the standard 20 °C to 10 °C, 25 °C and 30 °C and assayed key metabolic parameters as well as cardiac function, survival and regenerative capacity. Results: Our study demonstrated that while axolotls could be housed at temperatures ranging from 10 °C to 30 °C in an uninjured state, signs of a pathological response involving cardiac and metabolic insufficiency and mortality, especially after cryoinjury, increased progressively with increasing temperatures. We observed several metabolic effects, including differences in oxygen consumption, plasma metabolites and cardiac function. Cardiac regeneration after cryoinjury progressed as expected with only a small remaining injury after 60 days at the standard housing temperature of 20 °C. Regeneration was highly reduced in a reversible manner at 10 °C while regenerative rate was not affected at 25 °C. At 30 °C, cardiac regeneration could not be evaluated as the majority of animals (five out of six) did not survive the injury, likely reflecting insufficient cardiac reserve capacity to simultaneously sustain thermal metabolic effects and support tissue repair. Conclusions: The ectothermic axolotl undergoes several metabolic changes when exposed to different housing temperatures, with heart regeneration showing a narrower permissive temperature range than survival of the axolotl in an uninjured state. Full article
(This article belongs to the Special Issue Metabolism of Ectotherms: Insights from Amphibians and Reptiles)
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14 pages, 5665 KB  
Article
High-Intensity Interval Training Attenuates Hepatic Fibrosis by Remodeling Lactate Metabolism in MASLD
by Xuefei Chen, Jie Su, Wenhua Huang, Yanjun Li and Jing Zhang
Metabolites 2026, 16(6), 413; https://doi.org/10.3390/metabo16060413 - 13 Jun 2026
Viewed by 305
Abstract
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global metabolic disorder. As a non-pharmacological intervention, the effects of high-intensity interval training (HIIT) on MASLD and its molecular mechanisms remain poorly understood. This study aimed to investigate whether HIIT could [...] Read more.
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global metabolic disorder. As a non-pharmacological intervention, the effects of high-intensity interval training (HIIT) on MASLD and its molecular mechanisms remain poorly understood. This study aimed to investigate whether HIIT could ameliorate high-fat diet (HFD)-induced liver fibrosis by recalibrating the intrahepatic lactate metabolic axis. Methods: An HFD-induced murine MASLD model combined with HIIT intervention was utilized to evaluate the therapeutic efficacy and underlying mechanisms. Hepatosomatic indices, histological architecture and fibrosis severity were examined. Lactate concentrations within the systemic circulation and hepatic parenchyma, alongside comprehensive lipid profiles, were measured. The expressions of genes and proteins involved in hepatic lactate metabolism were delineated via qPCR and Western blotting. Results: The 8-week HIIT intervention effectively improved liver lipid accumulation, hepatocellular injury, and oxidative stress caused by a high-fat diet. Fibrotic expansion and suppressed hepatic stellate cell activation were restricted markedly, as evidenced by the downregulation of collagen type I alpha 1 chain and alpha-smooth muscle actin(α-SMA). HIIT reversed the HFD-induced accumulation of lactate in both systemic circulation and liver tissues, which was found to positively correlate with hepatic α-SMA. Mechanistically, HIIT regulated the expression of the lactate metabolism-related proteins lactate dehydrogenase A and monocarboxylate transporter 1, while selectively enhancing the expression of the gluconeogenic enzymes. Conclusions: Our findings indicate that HIIT effectively ameliorated MASLD and associated hepatic fibrosis by remodeling the hepatic lactate metabolic axis, specifically through the suppression of lactate production and the enhancement of its clearance. These results indicate that targeting lactate homeostasis might be a promising therapeutic strategy for MASLD. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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16 pages, 4055 KB  
Protocol
Practical Workflow for Building Local Mass Spectral Libraries for Untargeted Metabolomics
by Torbjørn Norberg Myhre, Terkel Hansen, Tetiana Lutchyn, Marie Mardal and Terje Vasskog
Metabolites 2026, 16(6), 412; https://doi.org/10.3390/metabo16060412 - 12 Jun 2026
Viewed by 257
Abstract
Background: Metabolite identification and annotation remain major bottlenecks in untargeted metabolomics because mass spectral features often lack sufficient specificity. High-confidence annotation requires experimental validation using authentic standards analyzed under matched chromatographic and ionization conditions, providing greater reliability than in silico predictions or [...] Read more.
Background: Metabolite identification and annotation remain major bottlenecks in untargeted metabolomics because mass spectral features often lack sufficient specificity. High-confidence annotation requires experimental validation using authentic standards analyzed under matched chromatographic and ionization conditions, providing greater reliability than in silico predictions or database matching alone. This study aimed to develop a practical and scalable workflow for constructing a high-quality mass spectral library using a commercially available analytical standards kit. Methods: A total of 603 metabolites from the MSMLS kit were organized into 42 mixtures, each containing approximately 15 compounds. Mixture design was based on molecular mass and distribution coefficient values, specifically logD at pH 3.1, with a minimum logD spacing of 0.15 to improve chromatographic separation and reduce co-elution. This strategy was used to minimize the total number of injections while maintaining spectral quality. The resulting spectra were evaluated against online spectral resources and in silico fragmentation predictions. A preliminary proof-of-concept analysis was also performed using human serum samples. Results: Using this workflow, 471 metabolites, corresponding to approximately 78% of the standards, were successfully detected and incorporated into the spectral library. Comparison with online resources and in silico fragmentation predictions demonstrated improved spectral quality and reliability. The proof-of-concept serum analysis enabled identification of endogenous metabolites using the constructed library. In addition, the robustness and applicability of the workflow were further supported by a method validation study using metabolites derived from this library. Conclusions: This workflow provides a scalable strategy for constructing mass spectral libraries that balances spectral quality with analytical throughput. By using rational mixture design and authentic standards analyzed under matched experimental conditions, the approach enables substantial metabolite coverage while maintaining data reliability and minimizing experimental effort. Full article
(This article belongs to the Collection Advances in Metabolomics)
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37 pages, 3490 KB  
Review
Multi-Targeted Intervention of Eucommia ulmoides and Its Bioactive Constituents Against Metabolic Syndrome: From Molecular Mechanisms and Gut Microbiota Modulation to Clinical Translation
by Fanjia Cheng, Chenghao Lv, Yuhang Yi, Dongsheng Wang, Wenbo Wang, Tao Li, Runze Zhou, Qili Li and Si Qin
Metabolites 2026, 16(6), 411; https://doi.org/10.3390/metabo16060411 - 12 Jun 2026
Viewed by 347
Abstract
Background/Objectives: Metabolic syndrome (MetS) is a pressing global health challenge comprising obesity, hyperglycemia, hypertension, and hyperlipidemia. Conventional polypharmacy often presents long-term compliance issues and side effects. Eucommia ulmoides Oliv., a traditional medicinal and edible plant rich in iridoids, lignans, flavonoids, and polysaccharides, has [...] Read more.
Background/Objectives: Metabolic syndrome (MetS) is a pressing global health challenge comprising obesity, hyperglycemia, hypertension, and hyperlipidemia. Conventional polypharmacy often presents long-term compliance issues and side effects. Eucommia ulmoides Oliv., a traditional medicinal and edible plant rich in iridoids, lignans, flavonoids, and polysaccharides, has emerged as a promising natural intervention. This review aims to systematically summarize the bioavailability and multifaceted pharmacological mechanisms of E. ulmoides and its bioactive components in alleviating MetS. Methods: We comprehensively reviewed the recent in vitro and in vivo literature to map the functional evidence, specific signaling pathways, and gut microbiota–host interactions associated with E. ulmoides extracts and its key phytochemicals (e.g., asperuloside) against various metabolic dysfunctions. Results: Current evidence indicates that E. ulmoides operates through a “multi-component, multi-target, and multi-pathway” paradigm. For hyperlipidemia and obesity, it activates hepatic lipid metabolism (PPARα/CPT1A, FXR/CYP7A1) and mitigates oxidative stress (Nrf2/ARE). Furthermore, it dose-dependently reshapes the gut microbiota by enriching beneficial bacteria like Akkermansia and increasing butyrate production, exerting profound gut–liver axis regulation. It also ameliorates hypertension by activating the ACE2-Ang-(1–7)-Mas axis, improves insulin resistance via the AMPK/PI3K/Akt cascade, and manages hyperuricemia by modulating XOD and renal transporters. Notably, the low oral bioavailability of its glycosides highlights the crucial role of gut microbial hydrolysis in its efficacy. Conclusions: E. ulmoides holds substantial therapeutic potential as a multi-target natural supplement for MetS. However, future translational applications necessitate large-scale randomized clinical trials, multi-omics studies to further clarify host–microbiome interactions, and the development of standardized formulations to ensure clinical efficacy. Full article
(This article belongs to the Special Issue The Impact of Polyphenols on Metabolic Health and Disease)
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27 pages, 3122 KB  
Review
Exploring the Health Effects of Phytoestrogens
by Vladimír Kraus, Anna Birková, Miroslava Majerníková and Beáta Čižmárová
Metabolites 2026, 16(6), 410; https://doi.org/10.3390/metabo16060410 - 12 Jun 2026
Viewed by 317
Abstract
Background/Objectives: Phytoestrogens are secondary plant metabolites produced via the phenylpropanoid pathway. They include a broad spectrum of chemical compounds, such as phenolics, flavonoids, isoflavones, coumestans, lignans, and others. Their chemical structures resemble those of estradiol, and they exhibit biological effects similar to those [...] Read more.
Background/Objectives: Phytoestrogens are secondary plant metabolites produced via the phenylpropanoid pathway. They include a broad spectrum of chemical compounds, such as phenolics, flavonoids, isoflavones, coumestans, lignans, and others. Their chemical structures resemble those of estradiol, and they exhibit biological effects similar to those of human estrogens, influencing many physiological processes throughout life in both men and women—including the timing and progression of puberty. Methods: The literature search included databases such as PubMed, Scopus, Web of Science, and Google Scholar with the use of specific keywords. Studies were considered eligible if they reported original findings from observational studies (cohort, case–control, and cross-sectional) or from experimental studies. Results: Phytoestrogens can modulate estrogenic activity and interact with a variety of biological pathways. These compounds may play a role in human development and pubertal processes, contribute to overall health, and potentially help alleviate menopausal symptoms and reduce the risk of certain cancers. Conclusions: Phytoestrogens have numerous positive effects on the human body across various stages of life. Their overall impact and potency, however, seem to be influenced by factors such as intake level, individual genetic variability, and the specific phytoestrogen class consumed. Full article
(This article belongs to the Special Issue Effects of Secondary Plant Metabolites on Human Health)
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11 pages, 2695 KB  
Article
Functional Role of AveC Residues Ser138 and Ala139 for Avermectin and Doramectin Biosynthesis in Streptomyces avermitilis
by Zhangqun Li, Ling Zhang, Xiaofang Li, Mingjie Li and Haiyang Xia
Metabolites 2026, 16(6), 409; https://doi.org/10.3390/metabo16060409 - 12 Jun 2026
Viewed by 295
Abstract
Background: Doramectin (CHC-B1) is an excellent antiparasitic drug produced by feeding cyclohexanecarboxylic acid (CHC) to Streptomycesavermitilis bkd− mutants. AveC, a bifunctional enzyme encoded by aveC (sav_0940), catalyzes the stereospecific spiroketalization and selective dehydration of dihydroxy ketone polyketide intermediates and [...] Read more.
Background: Doramectin (CHC-B1) is an excellent antiparasitic drug produced by feeding cyclohexanecarboxylic acid (CHC) to Streptomycesavermitilis bkd− mutants. AveC, a bifunctional enzyme encoded by aveC (sav_0940), catalyzes the stereospecific spiroketalization and selective dehydration of dihydroxy ketone polyketide intermediates and modulates both the yield and the proportion of avermectin/doramectin in Streptomyces avermitilis. In our previous work, we constructed a strain harboring a synthetic aveC* gene encoding ten amino acid mutations, which produced nearly pure doramectin. However, the doramectin yield achieved only approximately 60% of the total doramectin and CHC-B2 output observed in the parental strain. Methods: To investigate the roles of Ser138 and Ala139 of AveC in the biosynthesis of doramectin and avermectin, site-directed mutagenesis was performed at both sites. The production and proportion of avermectin and doramectin were determined using high-performance liquid chromatography (HPLC). AlphaFold2-based molecular docking simulations were used to interpret the results. Results: Among the tested mutants, S138G, S138T, and A139H exhibited the highest doramectin production, achieving 143.87%, 151.22%, and 153.36% of the control level, respectively. Unfortunately, almost none of the tested mutants showed a positive effect on avermectin production. Molecular docking simulations revealed distinct affinities of these mutants for the dihydroxy ketone polyketide intermediate, both with and without a cyclohexyl group. Notably, all three mutants displayed larger substrate-binding cavity volumes compared with the wild-type enzyme, which likely facilitates doramectin synthesis by effectively accommodating the cyclohexyl moiety. Docking results further indicated that Ser138 and Ala139 are positioned within the binding cavity but probably do not directly participate in the dehydration activity. Conclusions: These findings suggest that optimizing cavity size through residue substitutions can enhance substrate specificity for doramectin production while preserving catalytic functionality. Full article
(This article belongs to the Section Microbiology and Ecological Metabolomics)
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18 pages, 3135 KB  
Review
Elabela in Lipid-Related Cardiometabolic Dysfunction: A Critical Narrative Review
by Zuzanna Chęcińska-Maciejewska, Ewa Pruszyńska-Oszmałek, Paweł Kołodziejski, Andrzej Ciborek and Hanna Krauss
Metabolites 2026, 16(6), 408; https://doi.org/10.3390/metabo16060408 - 11 Jun 2026
Viewed by 312
Abstract
Elabela (ELA/APELA/Toddler) is an endogenous peptide ligand of the apelin receptor APLNR (also known as APJ) and, together with apelin, forms the apelinergic signalling system. Its role in embryonic development, the cardiovascular system, the kidneys and the endothelium is becoming increasingly well characterised, [...] Read more.
Elabela (ELA/APELA/Toddler) is an endogenous peptide ligand of the apelin receptor APLNR (also known as APJ) and, together with apelin, forms the apelinergic signalling system. Its role in embryonic development, the cardiovascular system, the kidneys and the endothelium is becoming increasingly well characterised, whilst its function in metabolic regulation remains unresolved. Elabela activates pathways essential for metabolic homeostasis—PI3K/Akt, AMPK-related pathways, redox regulation, inflammatory control and pro-survival cascades—but no study has shown that it directly regulates adipocyte lipid metabolism. This narrative review categorises the evidence at the receptor, organ, immunometabolic and intra-adipocyte levels, and also considers the adipose tissue microenvironment as a distinct level of potential relevance. The available data support a role for Elabela as a candidate mediator of lipid-related metabolic dysfunction—via anti-inflammatory, antioxidant and tissue-protective mechanisms—with macrophage lipid metabolism representing the most informative immunometabolic interface. Human studies remain scarce, heterogeneous and limited by a lack of standardisation in assay methods and the unresolved specificity of isoforms. Elabela should therefore be regarded as a candidate indirect modulator of metabolic homeostasis and a candidate biomarker of cardiometabolic stress or adaptation—not as a confirmed direct regulator of adipocyte lipid metabolism. Full article
(This article belongs to the Special Issue Human Nutrition and Metabolic Health)
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17 pages, 3707 KB  
Article
Exogenous Melatonin Alleviates NaCl-Induced Salinity Stress in Forage Pea (Pisum sativum L.): Concentration Optimization and Genotype-Specific Responses
by Melih Okcu, Zuhal Okcu, Funda Kaya and Kamil Haliloglu
Metabolites 2026, 16(6), 407; https://doi.org/10.3390/metabo16060407 - 10 Jun 2026
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Abstract
Background/Objectives: Soil salinity is a major constraint on legume productivity worldwide, threatening forage pea (Pisum sativum L.) cultivation in semiarid regions. This study evaluated the effect of exogenous melatonin in attenuating NaCl-induced salinity stress across diverse forage pea genotypes. Methods: [...] Read more.
Background/Objectives: Soil salinity is a major constraint on legume productivity worldwide, threatening forage pea (Pisum sativum L.) cultivation in semiarid regions. This study evaluated the effect of exogenous melatonin in attenuating NaCl-induced salinity stress across diverse forage pea genotypes. Methods: A three-factor factorial experiment was conducted under greenhouse conditions, testing three NaCl levels (0, 100 and 200 mM) and four melatonin concentrations (0, 100, 150 and 200 µM) across 13 genotypes with three replications (468 pots). Nine vegetative traits were measured and analyzed by factorial ANOVA and Tukey’s HSD test. Results: Increasing NaCl from 0 to 200 mM reduced plant height by ~28% and node number by ~32%. Application of 100 µM melatonin under 100 mM NaCl reduced canopy temperature from 28.1 °C to 23.7 °C and restored SPAD values from 21.7 to 26.5 under 200 mM NaCl. By contrast, 200 µM melatonin under severe salinity paradoxically suppressed SPAD to 8.9 and reduced root length. Emirbey and Kirazlí showed the greatest vegetative growth, while Özkaynak exhibited the highest chlorophyll content. Conclusions: 100 µM melatonin emerged as the optimal concentration for alleviating moderate salt stress in forage pea, and genotype selection is critical when deploying melatonin as a biostimulant under saline conditions. Direct measurement of biomass, yield, and forage quality under field conditions remains an essential next step before agronomic deployment. Full article
(This article belongs to the Special Issue Bioactive Compounds: Plant Stress Responses, Metabolic Regulation, and Therapeutic Insights)
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25 pages, 2988 KB  
Article
Comparative Analysis of Components and Biological Activities in Different Parts of Gastrodia elata Blume
by Yuru Zhang, Hong Zhang, Xue Meng, Yu Zhang, Di Wang and Juan Chen
Metabolites 2026, 16(6), 406; https://doi.org/10.3390/metabo16060406 - 10 Jun 2026
Viewed by 325
Abstract
Background: Gastrodia elata Blume (GE) is a widely used plant with both medicinal and edible properties. Besides the underground tubers, its above-ground parts also have certain medicinal potential. However, most of these resources are frequently discarded during production and processing. The differences [...] Read more.
Background: Gastrodia elata Blume (GE) is a widely used plant with both medicinal and edible properties. Besides the underground tubers, its above-ground parts also have certain medicinal potential. However, most of these resources are frequently discarded during production and processing. The differences in chemical composition and bioactivity among different parts of GE remain unclear. Methods: In this research, the non-targeted metabolomics method was used to detect the metabolites in the stem (ST), capsule shell (CS), seed (SE), arrow end (AE), middle end (ME), and navel end (NE) of GE. Differential metabolites were screened by multivariate statistical analysis. The pathway enrichment analysis of differential metabolites was carried out by the Kyoto Encyclopedia of Genes and Genomes (KEGG) platform. The antioxidant and α-glucosidase inhibitory activities of extracts from six different parts of GE were determined in vitro, followed by correlation analysis between biological activities and key metabolites. Results: Metabolites in different parts of GE were significantly different, including lipids, organic acids, organoheterocyclic compounds, phenylpropanoids, benzenoids, and organic oxygen compounds. The characteristics of metabolites in the underground and above-ground parts of GE were clearly distinct. The contents of lipids, organoheterocyclic compounds, and organic acids were the highest in SE, SE and CS, ST, and AE, respectively. The KEGG pathway enrichment analysis preliminarily suggested that the differences in metabolites from different parts of GE might be related to the arginine biosynthesis pathway, which involves seven metabolites, including L-glutamic acid, L-arginine, L-ornithine, and L-aspartate. Compared with the tuber (the conventional medicinal part), ST and CS exhibited excellent antioxidant properties and inhibitory activity against α-glucosidase. Correlation analysis indicated that L-arginine and L-aspartate were positively correlated with the biological activity of GE and may be components preliminarily associated with its difference in activity. Conclusions: This study provided preliminary comparative evidence for the metabolite characteristics from different parts of GE, thereby facilitating the further development and utilization of its above-ground resources. Full article
(This article belongs to the Section Plant Metabolism)
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18 pages, 2828 KB  
Article
Relationship Between Calcium and Gut Microbial Composition and Metabolic Pathways in Children with Autism
by Jialin Li, Xinjie Xu, Huinuo Wang, Rui Gao, Bing Li and Xin You
Metabolites 2026, 16(6), 405; https://doi.org/10.3390/metabo16060405 - 10 Jun 2026
Viewed by 308
Abstract
Background/Objectives: Trace elements may influence autism spectrum disorder (ASD) severity through interactions with the gut microbiota and microbial metabolic functions, but calcium-related evidence remains limited. This cross-sectional study examined associations among hair calcium, gut microbial taxa, metabolic pathways, and behavioral phenotypes in children [...] Read more.
Background/Objectives: Trace elements may influence autism spectrum disorder (ASD) severity through interactions with the gut microbiota and microbial metabolic functions, but calcium-related evidence remains limited. This cross-sectional study examined associations among hair calcium, gut microbial taxa, metabolic pathways, and behavioral phenotypes in children with ASD. Methods: We analyzed 183 children with ASD who had behavioral assessments, hair calcium measurements, and fecal shotgun metagenomic sequencing data. Participants in the lowest and highest calcium quartiles were first compared to characterize group-level microbiome differences. Full-sample analyses then tested associations among continuous hair calcium, microbial taxa, metabolic pathways, and behavioral measures after covariate adjustment. Benjamini–Hochberg false discovery rate correction was applied for multiple testing. Results: Hair calcium was positively associated with CARS, ATEC-Total, ATEC-1, and ATEC-3 scores, with the strongest associations involving ATEC-1 and ATEC-3. Alpha and beta diversity did not differ significantly between calcium quartile groups, but group-based microbiome analyses identified 63 differential species and 22 differential MetaCyc pathways. Full-sample integrated analyses connected calcium-associated microbial taxa, metabolic pathways, and ASD behavioral measures. Conclusions: Hair calcium was associated with ASD behavioral severity, selected gut microbial species, and microbial metabolic pathways. These findings support an association framework connecting longer-term calcium-related mineral profiles, gut microbial functional potential, and behavioral phenotypes, providing a basis for future longitudinal and multi-omics studies. Full article
(This article belongs to the Special Issue Gut Microbiota-Host Metabolic Axis: From Diet to Systemic Health)
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