Metabolites

13 pages, 2946 KB

Open AccessArticle

Aerobic Exercise Alleviates Oxidative Stress and Inflammation to Attenuate High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in ApoE^-/- Mice

by Liang Zhang, Wenxin Wang, Fengting Zheng, Jialu Weng, Yao Lu, Qingbo Li, Ting Li, Wei Li and Lifeng Wang

Metabolites 2026, 16(4), 285; https://doi.org/10.3390/metabo16040285 - 21 Apr 2026

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Abstract

Background/Objectives: The development of non-alcoholic fatty liver disease (NAFLD) is closely linked to oxidative stress and inflammation. Aerobic exercise has been shown to improve NAFLD, although its underlying mechanisms remain incompletely understood. This study utilized ApoE^-/- mice to investigate the role [...] Read more.

Background/Objectives: The development of non-alcoholic fatty liver disease (NAFLD) is closely linked to oxidative stress and inflammation. Aerobic exercise has been shown to improve NAFLD, although its underlying mechanisms remain incompletely understood. This study utilized ApoE^-/- mice to investigate the role of Sestrin2 in aerobic exercise-induced amelioration of NAFLD. Methods: Random assignment of C57BL/6J and ApoE^-/- mice yielded four groups: C (control), CE (aerobic exercise), AS (ApoE^-/- control), and AE (ApoE^-/- aerobic exercise). Aerobic exercise lasting 12 weeks was administered to the CE and AE groups. Serum biomarkers were analyzed by ELISA, liver tissue morphology was assessed via HE and ORO staining, and macrophage polarization was evaluated through immunofluorescence. Additionally, mRNA and protein expression levels were measured by qPCR and Western blot. Results: Aerobic exercise reduced liver wet weight, lipid accumulation, and steatosis in ApoE^-/- mice. Aerobic exercise attenuates hepatic oxidative stress, and upregulated the expression of regulation oxidative stress related gene and proteins of Nrf2, HO-1, CAT, and SOD1 in ApoE^-/- mice. Aerobic exercise promoted a shift in macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype in the liver, and significantly reduced TNF-α and IL-1β levels, accompanied by upregulation of Sestrin2 expression, enhanced AMPK phosphorylation, inhibited mTORC1 in the liver. Conclusions: These findings suggest that aerobic exercise alleviates oxidative stress and inflammation in NAFLD, with Sestrin2 activation playing a central role. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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16 pages, 7279 KB

Open AccessArticle

Quercetin Attenuates Non-Alcoholic Fatty Liver Disease in Association with the Inhibition of Hepatic IL-1β/iNOS and IL-1β/CD45 Axes of Inflammation and Fibrosis Accompanied by Reduced Endogenous Metabolites and Apoptosis

by Saif A. Alqahtani, Hanan H. Alshehri, Hend Ashour, Hend Abdallah, Laila Rashed, Rehab M. Badi, Muataz E. D. Mohammed, Bahjat Al-Ani, Norah M. Alzamil, Alia Albawardi and Basma E. Aboulhoda

Metabolites 2026, 16(4), 284; https://doi.org/10.3390/metabo16040284 - 21 Apr 2026

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Abstract

Background: Liver inflammation and fibrosis are directly associated with non-alcoholic fatty liver disease (NAFLD). Dysregulation of the potent pro-inflammatory cytokine interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and tissue leukocyte infiltration (CD45 +ve) are connected with multiorgan injury and fibrosis. We investigated [...] Read more.

Background: Liver inflammation and fibrosis are directly associated with non-alcoholic fatty liver disease (NAFLD). Dysregulation of the potent pro-inflammatory cytokine interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and tissue leukocyte infiltration (CD45 +ve) are connected with multiorgan injury and fibrosis. We investigated whether the induction of NAFLD can cause dysregulation in the hepatic IL-1β/iNOS and IL-1β/CD45 axes of inflammation and fibrosis, as well as in endogenous metabolites (lipids, glucose, and insulin) and apoptosis, in the presence and absence of the flavonoid quercetin. Methods: The model group of rats was fed with a high-fat and high-carbohydrate diet (HFCD) for 4 weeks. The protective group of rats was given both quercetin (50 mg/kg) and HFCD for 4 weeks. All rats were sacrificed on day 29. Results: NAFLD was induced in rats as demonstrated by dyslipidemia, hyperglycemia, insulin resistance, liver inflammation, and elevation of liver injury enzymes. NAFLD was also associated with the upregulation of hepatic IL-1β, iNOS, CD45, and apoptosis (p53). Biomarkers of fibrosis (TIMP-1 and α-SMA) were also elevated, and fibrosis was confirmed in the model group by increased collagen deposition and elevated stages of fibrosis score (Stage 1 to 2 of Brunt’s NASH classification). All these parameters were significantly (p < 0.01) modulated by quercetin treatment. Additionally, a significant (p < 0.001) correlation between IL-1β and hepatic injury parameters was observed. Conclusions: These findings suggest a potential association between NAFLD and the IL-1β/iNOS and IL-1β/CD45 axes of liver injury and fibrosis, as well as dyslipidemia, glycemia, and apoptosis, with quercetin exhibiting beneficial hepatic pleiotropic effects. Full article

(This article belongs to the Special Issue Biomarkers in Obesity, Metabolic Syndrome, and Weight Loss: Advances in Diagnosis, Risk Stratification, and Personalized Management)

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13 pages, 703 KB

Open AccessArticle

Comparative Analysis of Two Dietary Saturated Fat Types on Metabolite Profiles Crossing the Blood–Brain Barrier of Poultry Chicks

by Oluteru E. Orimaye, Paul C. Omaliko, Nathanael I. Lichti, Bruce R. Cooper and Yewande O. Fasina

Metabolites 2026, 16(4), 283; https://doi.org/10.3390/metabo16040283 - 20 Apr 2026

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Abstract

Background: The dorsal raphe nucleus (DRN) produces and distributes serotonin, while the hypothalamus (HYP) uses serotonergic signals to regulate physiological processes in chickens. Coconut oil (COCO), rich in medium-chain fatty acids, is rapidly absorbed without re-esterification. Methods: Day-old broilers (Ross 708 male, n [...] Read more.

Background: The dorsal raphe nucleus (DRN) produces and distributes serotonin, while the hypothalamus (HYP) uses serotonergic signals to regulate physiological processes in chickens. Coconut oil (COCO), rich in medium-chain fatty acids, is rapidly absorbed without re-esterification. Methods: Day-old broilers (Ross 708 male, n = 160) were distributed into two dietary treatments with five replicates of 16 birds each. The birds were fed a corn–soybean meal (SBM) basal diet supplemented with 3% of poultry fat (CON) or coconut oil (COCO). The body-weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) were recorded over a 3-week period, and the data were subjected to a t-test. Untargeted metabolomic analysis by high-performance liquid chromatography (HPLC-MS) was used to evaluate the influence of the type of dietary fat on metabolite profiles in the DRN, HYP, and plasma of broiler chickens. Principal component analysis (PCA) was used to identify unique metabolites, and ANOVA was used to identify the metabolites that were significantly abundant (p < 0.05). The metabolites were then annotated using the KEGG and HMDB databases. Results: Birds in the COCO treatment gained more weight on average (0.8446 kg/bird) than birds in the CON group (0.8132 kg/bird; p = 0.0496). Five metabolites associated with multiple significant cellular processes, such as brain function, energy metabolism, and neurotransmission, showed similar differential expression patterns, while two metabolic pathways (butanoate metabolism and alanine, aspartate and glutamate metabolism) were identified. Conclusions: The dietary inclusion of COCO improves BWG in poultry and enhances their overall well-being by modulating metabolite profiles, supporting neurotransmission, and enriching the metabolic pathways essential for growth and brain function. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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18 pages, 9235 KB

Open AccessArticle

Critical Role for Malic Enzymes in MYC-Mediated Cellular Adaptation to Glutamine Depletion

by Yufan Si, Wei Li, Yang Chen, Jiayang Yuan, Chenrui Hu, Yanan Liu and Li Li

Metabolites 2026, 16(4), 282; https://doi.org/10.3390/metabo16040282 - 20 Apr 2026

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Abstract

Background/Objectives: MYC-driven tumors exhibit significant glutamine addiction, but the metabolic adaptation mechanisms enabling their survival under glutamine deprivation remain incompletely understood. Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate while generating NADPH, linking central carbon metabolism to redox homeostasis. This study [...] Read more.

Background/Objectives: MYC-driven tumors exhibit significant glutamine addiction, but the metabolic adaptation mechanisms enabling their survival under glutamine deprivation remain incompletely understood. Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate while generating NADPH, linking central carbon metabolism to redox homeostasis. This study investigates whether and how ME1 and ME2 mediate cell adaptation to glutamine starvation and explores their functional division in relation to p53 status. Methods: Using MYC-amplified, p53-mutant (G266E) SF188 glioblastoma cells, we performed siRNA-mediated knockdown, overexpression, and rescue experiments. Cell survival was assessed by trypan blue exclusion and Annexin V/PI staining. ROS levels and NADP⁺/NADPH ratios were measured by DCFH-DA fluorescence and enzymatic assays. Metabolite tracing was conducted using [U-¹³C₅] glutamine followed by LC-MS. Key findings were validated in additional cell lines including HCT116, U2OS and MDA-MB-231. Results: ME1 and ME2 promote SF188 cell survival under glutamine deprivation, an effect that depends on their catalytic activity but is independent of TCA cycle anaplerosis. ME1 maintains redox balance by generating NADPH, and antioxidant treatment rescues the survival defect caused by ME1 knockdown. In contrast, ME2 does not contribute to redox regulation but stabilizes mutant p53 (G266E) via proteasome inhibition. Both of these pro-survival functions are attenuated upon MYC knockdown, suggesting a dependency on MYC expression. Across all cell lines tested, ME1 and ME2 also promote survival through redox maintenance, although the isoform responsible for antioxidant function differs. Conclusions: ME1 and ME2 support metabolic adaptation to glutamine starvation through distinct, isoform-specific mechanisms that depend on MYC expression and p53 mutation status. These findings suggest malic enzymes as potential therapeutic targets in MYC-driven, p53-mutant tumors. Full article

(This article belongs to the Section Cell Metabolism)

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13 pages, 2754 KB

Open AccessArticle

Selected Brain Metabolites and Mitochondrial DNA Copy Number as Potential Markers of Ongoing Neurodegeneration in Patients with Wolfram Syndrome

by Ewa Zmysłowska-Polakowska, Tomasz Płoszaj, Sebastian Skoczylas, Julia Grzybowska-Adamowicz, Dobromiła Barańska, Katarzyna Matera, Aleksandra Palatyńska-Ulatowska, Wojciech Młynarski, Agnieszka Zmysłowska and Michal Ciborowski

Metabolites 2026, 16(4), 281; https://doi.org/10.3390/metabo16040281 - 20 Apr 2026

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Abstract

Background: Wolfram syndrome (WFS) is a rare neurodegenerative disease that is genetically determined and inherited in an autosomal recessive manner. Although the first clinical symptom appearing in early childhood is diabetes mellitus, subsequent symptoms are associated with optic nerve atrophy, followed by [...] Read more.

Background: Wolfram syndrome (WFS) is a rare neurodegenerative disease that is genetically determined and inherited in an autosomal recessive manner. Although the first clinical symptom appearing in early childhood is diabetes mellitus, subsequent symptoms are associated with optic nerve atrophy, followed by central nervous system atrophy. Methods: The aim of the study was to analyse magnetic resonance images (MRI) of the brain in combination with single-voxel magnetic resonance spectroscopy (MRS) and to assess the copy number of mitochondrial DNA (mtDNA-CN) in 10 patients with WFS compared with a control group of 17 healthy individuals. Results: A significant decrease in the amount of selected metabolites was observed in WFS patients compared to controls in all assessed brain regions (pons, cerebellum, white matter, thalamus, and hippocampus). For three metabolites, Glutamate (Glu), Glutamate + Glutamine (Glx) and total N-acetylaspartate (TNAA), significant differences in concentrations were found between the study groups in almost all matrices evaluating specific areas of the brain (p < 0.011), with the exception of a trend toward reduced TNAA in the hippocampus (p = 0.065). In addition, patients with WFS had a significant decrease in the mitochondrial-to-nuclear DNA ratio compared to controls (p < 0.0003). Some metabolites, such as N-acetylaspartate and total N-acetylaspartate, showed strong correlations with specific regions of the visual pathway on MRI scans in patients with WFS. Conclusions: Selected brain metabolites and mtDNA-CN may become potential markers of WFS, and the results of this study may be used to define indicators for future therapeutic strategies. Full article

(This article belongs to the Special Issue Brain Metabolic Alterations in Neurodegenerative Diseases)

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19 pages, 714 KB

Open AccessArticle

Red Blood Cell Distribution Width and Neutrophil-to-Lymphocyte Ratio as Markers of Cardiovascular Disease and Vascular Calcification in Chronic Kidney Disease: A Large Cohort Study

by Anastasios Zagaliotis, Athanasios Roumeliotis, Stefanos Roumeliotis, Ioannis E. Neofytou, Garyfallia Varouktsi, Eirini Leptokaridou-Mourtzila, Aikaterini Stamou, Vasiliki Sgouropoulou, Gordana Kocic, Andrej Veljkovic, Rudolf Bittner, Willi Jahnen-Dechent, Leon J. Schurgers and Vassilios Liakopoulos

Metabolites 2026, 16(4), 280; https://doi.org/10.3390/metabo16040280 - 20 Apr 2026

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Abstract

Background/Objectives: Cardiovascular disease (CVD) in chronic kidney disease (CKD) arises from a multifaceted interplay of pathophysiological processes, including chronic inflammation, oxidative stress (OS), and accelerated vascular calcification (VC). Red blood cell distribution width (RDW) and the neutrophil-to-lymphocyte ratio (NLR) have emerged as simple, [...] Read more.

Background/Objectives: Cardiovascular disease (CVD) in chronic kidney disease (CKD) arises from a multifaceted interplay of pathophysiological processes, including chronic inflammation, oxidative stress (OS), and accelerated vascular calcification (VC). Red blood cell distribution width (RDW) and the neutrophil-to-lymphocyte ratio (NLR) have emerged as simple, inexpensive, and readily available hematological indices that may capture these underlying disturbances. As such, they hold promise as accessible biomarkers for stratifying cardiovascular risk in patients with CKD. Methods: This cross-sectional study enrolled 497 patients, comprising 477 with CKD across all stages and 20 controls. We evaluated the associations of RDW and NLR with both traditional and non-traditional cardiovascular risk factors, as well as with serum calcification propensity (T50). Spearman’s correlation and multivariable regression analysis were used to assess these relationships. Results: Both RDW and NLR were significantly elevated in patients with established CVD (p < 0.001 for both) and demonstrated a progressive increase across advancing CKD stages (p < 0.001). RDW and NLR showed positive correlations with age, CVD duration, urea, phosphorus, parathormone, CRP, FG23, and mean carotid intima–media thickness (cIMT), while exhibiting inverse correlations with eGFR, serum albumin, hemoglobin, lipids, antioxidants such as superoxide dismutase, fetuin-A, and T50. Additionally, NLR correlated positively with the duration of hypertension and diabetes, as well as with albuminuria. Quartile analysis revealed a stepwise decline in T50 across increasing categories of RDW and NLR, supporting the link with impaired calcification defense. In multivariable analysis, T50 independently predicted NLR (β = −0.013; p = 0.018), whereas total cholesterol (β = −0.011; p = 0.019) and cIMT (β = 0.38; p = 0.018) emerged as independent determinants of RDW. Conclusions: RDW and NLR strongly reflect the burden of inflammation, metabolic disturbance, and vascular dysfunction in patients across the CKD spectrum. The consistent associations with impaired calcification defense and with established cardiovascular risk markers underscore the potential value as accessible indicators of cardiovascular vulnerability in CKD. These findings support incorporating RDW and NLR into routine risk assessment and highlight T50 as a mechanistically relevant determinant of hematologic inflammation profiles. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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16 pages, 15310 KB

Open AccessArticle

Metabolomic Profiling Reveals Geographical Origin, Tissue-Specific Specialization, and Environmental Plasticity in Secondary Metabolism of Dendrobium officinale

by Zhiyong Li, Jian Li, Yue Hu, Xinyi Wu, Xiaojuan Duan, Demin Kong, Xiaowen Li, Jin Cheng and Meina Wang

Metabolites 2026, 16(4), 279; https://doi.org/10.3390/metabo16040279 - 20 Apr 2026

Cited by 1 | Viewed by 665

Abstract

Background/Objectives: Dendrobium officinale (D. officinale), an endangered ornamental and medicinal orchid, displays significant variability in its bioactive compounds depending on geographical and environmental factors. To decipher these influences, we investigated metabolic divergence across three cultivars (GN, LS, DX) cultivated in [...] Read more.

Background/Objectives: Dendrobium officinale (D. officinale), an endangered ornamental and medicinal orchid, displays significant variability in its bioactive compounds depending on geographical and environmental factors. To decipher these influences, we investigated metabolic divergence across three cultivars (GN, LS, DX) cultivated in greenhouse and outdoor conditions using untargeted metabolomics. Methods: Metabolites extracted from stem and leaf tissues were analyzed via UHPLC-Q Exactive Orbitrap MS, and the raw data were processed using XCMS for peak alignment and quantification. Differentially abundant metabolites (DAMs) were identified by multivariate statistical analyses including PCA and OPLS-DA. Metabolic pathways were annotated using KEGG, HMDB, and LIPID Maps databases, with enrichment analysis and visualization performed via TBtools II and Hiplot. Results: Metabolite profiling and multivariate analysis revealed distinct chemotypes. The DX cultivar exhibited anthocyanin enrichment in its stems, correlating with a red pigmentation, while GN accumulated specific amino acid derivatives. Tissue-specific metabolic specialization was evident, with leaves displaying greater flavonoid diversity and stems prioritizing lipid and amino acid metabolism. Outdoor cultivation enhanced flavonoid biosynthesis, whereas greenhouse conditions favored alkaloid accumulation. Functional analysis identified both conserved pathways, like phenylpropanoid biosynthesis, and varietal-specific adaptations in amino acid and secondary metabolism. Notably, alkaloid levels declined sharply during plant defoliation. Conclusions: Our findings demonstrate that environmental factors and geographical origin synergistically shape the metabolic profiles of D. officinale. This provides a scientific basis for optimizing cultivation strategies—through targeted environmental adjustments and varietal selection—to enhance the yield of desired bioactive compounds. Full article

(This article belongs to the Special Issue Metabolomics and Plant Defence, 2nd Edition)

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9 pages, 1443 KB

Open AccessCommunication

Identification of Primary Hyperoxaluria Type III by Gas Chromatography/Mass Spectrometry-Based Urine Metabolomics

by Tomiko Kuhara, Morimasa Ohse, Tatsuya Fukasawa, Koichi Maruyama and James Pitt

Metabolites 2026, 16(4), 278; https://doi.org/10.3390/metabo16040278 - 19 Apr 2026

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Abstract

Objectives: Primary hyperoxaluria type III (PH3) causes kidney stones in children and adults. Gas chromatography/mass spectrometry (GC/MS)-based metabolomics has been applied to study patients with primary hyperoxaluria types I and II, 2,8-dihydroxyadenine lithiasis, and xanthinuria types I to III. This study was performed [...] Read more.

Objectives: Primary hyperoxaluria type III (PH3) causes kidney stones in children and adults. Gas chromatography/mass spectrometry (GC/MS)-based metabolomics has been applied to study patients with primary hyperoxaluria types I and II, 2,8-dihydroxyadenine lithiasis, and xanthinuria types I to III. This study was performed to verify the usefulness of this technique for the diagnosis of PH3. Specifically, we evaluated an 8-month-old infant with recurrent kidney stones. Methods: GC/MS-based metabolomics was performed on spot urine samples using initial urease pretreatment without fractionation. Results: Metabolomics revealed increased levels of 2,4-dihydroxyglutarate and 4-hydroxyglutamate. No simultaneous elevations of these two critical biomarkers were observed in other patients, except for one case of PH3 confirmed by the identification of HOGA1 mutations. A moderate increase in 4-hydroxyglutamate has been observed only in cases of primary hyperammonemia, in which analytes such as orotate, uridine, glutamine, or proline, but not 2,4-dihydroxyglutarate, are biomarkers, thus distinguishing PH3 from primary hyperammonemia. Conclusions: GC/MS-based urine metabolomics enables the rapid screening and chemical diagnosis of PH3 and other congenital anomalies that cause urolithiasis. This technique can also be used to monitor disease progression, as patients with PH3 benefit from long-term follow-up, particularly when transitioning from childhood to adulthood. The timely identification of patients with hereditary urolithiasis is crucial. To address this, a discussion was had about the current diagnostic criteria. Full article

(This article belongs to the Special Issue Mass Spectrometry-Based Metabolomics in Disease Biomarker Discovery)

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24 pages, 937 KB

Open AccessReview

Diagnostic Criteria and Genetic Basis of Polycystic Ovary Syndrome: A Narrative Review

by María de los Angeles Cepero-González, Adriana Aguilar-Galarza, Víctor Manuel Rodríguez-García, Teresa García-Gasca and Ulisses Moreno Celis

Metabolites 2026, 16(4), 277; https://doi.org/10.3390/metabo16040277 - 19 Apr 2026

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Abstract

This study reviews the main candidate genes involved in the pathophysiology of Polycystic Ovary Syndrome (PCOS). PCOS is a common endocrine–metabolic disorder in women of reproductive age, characterized by menstrual irregularity, hyperandrogenism, and polycystic ovarian morphology. It is associated with increased metabolic and [...] Read more.

This study reviews the main candidate genes involved in the pathophysiology of Polycystic Ovary Syndrome (PCOS). PCOS is a common endocrine–metabolic disorder in women of reproductive age, characterized by menstrual irregularity, hyperandrogenism, and polycystic ovarian morphology. It is associated with increased metabolic and cardiovascular risk and is a leading cause of infertility. Although its pathophysiology is not fully understood, alterations in the hypothalamic–pituitary–ovarian axis, insulin metabolism, and steroidogenesis have been described. Polymorphisms in genes encoding hormones, enzymes, and receptors in these pathways contribute to clinical variability and ethnic differences, offering potential for early diagnosis and personalized medicine. This review summarizes key candidate genes related to insulin metabolism (INS, INSR, IRS-1), the hypothalamic–pituitary–ovarian axis (LHβ, LHCGR, FSHR, GnRHR, AMH, AMHR2, KISS1, CAPN10), steroidogenesis (CYP11A, CYP17A1, CYP19A1, CYP21, 17β-HSD, SHBG, AR, STAR), and other clinically relevant mechanisms such as obesity, lipid metabolism (PPARG, VDR, FTO), and follicular development (ACE). Full article

(This article belongs to the Special Issue Endocrine Disruptors, Nutritional Modulators and Metabolic Pathways in PCOS: From Exposure to Intervention)

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18 pages, 13187 KB

Open AccessArticle

Unveiling the Fragrant Secrets of Dendrobium devonianum: Terpenoid Pathways and Floral Scent Dynamics

by Shichao Wang, Shu He, Congjun Yuan, Xingliang Chen, Hoang Van Sam, Wei Chen Lum, Yaquan Dou and Rui Shi

Metabolites 2026, 16(4), 276; https://doi.org/10.3390/metabo16040276 - 18 Apr 2026

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Abstract

Background/Objectives: The orchid Dendrobium devonianum Paxt., valued for its ornamental and medicinal properties, is widely used in horticulture, medicine, and food industries. Methods: This study investigated dynamic changes in aroma-active volatile organic compounds (VOCs) and associated gene expression in D. devonianum flowers across [...] Read more.

Background/Objectives: The orchid Dendrobium devonianum Paxt., valued for its ornamental and medicinal properties, is widely used in horticulture, medicine, and food industries. Methods: This study investigated dynamic changes in aroma-active volatile organic compounds (VOCs) and associated gene expression in D. devonianum flowers across four developmental stages (bud, half bloom, full bloom, and aging) using headspace solid-phase microextraction, gas chromatography–mass spectrometry, and transcriptome analysis. Results: Floral VOCs, particularly volatile terpenoids and esters, were most abundant at full bloom. Among the 664 VOCs identified, α-hemelene, β-bisabolene, δ-naphthalene, perillyl alcohol, L-perillyl alcohol, terpinen-4-ol, 2-(4-methylphenyl)propan-2-ol, cis-3-hexenyl butyrate, and α-pinene were likely to contribute to floral scent. Terpene biosynthesis pathways played a pivotal role in floral fragrance formation. A comprehensive terpenoid biosynthesis pathway for D. devonianum floral scent was proposed, and eight genes encoding key regulatory enzymes were identified. Conclusions: These results provide new insights into terpenoid metabolism in Dendrobium and may guide future research on the utilization of floral scent. Full article

(This article belongs to the Section Plant Metabolism)

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20 pages, 5525 KB

Open AccessArticle

Parishin B Attenuates PTZ-Induced Seizures in Zebrafish and Is Associated with Neurotransmitter Balance and ACLY-Related Metabolic Pathways

by Meng Sun, Haida Liu, Zhiying Hou, Qiong Wang and Wu Zhong

Metabolites 2026, 16(4), 275; https://doi.org/10.3390/metabo16040275 - 18 Apr 2026

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Abstract

Background: Epilepsy is a chronic neurological disorder characterized by recurrent seizures, complex neurochemical, and metabolic disturbances. Parishin B, a major bioactive component of Gastrodia elata, has shown neuroprotective potential, but its systemic mechanisms remain unclear. Methods: A pentylenetetrazol (PTZ)-induced seizure model in zebrafish [...] Read more.

Background: Epilepsy is a chronic neurological disorder characterized by recurrent seizures, complex neurochemical, and metabolic disturbances. Parishin B, a major bioactive component of Gastrodia elata, has shown neuroprotective potential, but its systemic mechanisms remain unclear. Methods: A pentylenetetrazol (PTZ)-induced seizure model in zebrafish larvae was developed and used to evaluate the anti-seizure effects of Parishin B. Behavioral analysis, ELISA-based biochemical assays, integrated untargeted metabolomics with DIA-based proteomics, and qPCR were performed to decipher underlying molecular mechanisms. Results: Parishin B (0.0625–0.25 mg/mL) significantly alleviated PTZ-induced hyperactivity without developmental toxicity. Parishin B restored neurotransmitter balance by increasing GABA, dopamine, and norepinephrine levels while reducing 5-HT. In addition, it suppressed neuroinflammation and enhanced antioxidant capacity. Integrated multi-omics analysis revealed that Parishin B modulated key metabolic pathways, particularly the TCA cycle and lipid metabolism, and reversed the downregulation of ATP-citrate lyase (ACLY). Parishin B was also associated with the regulation of ferroptosis-related pathways, supported by changes in acsl4a and fth1a expression. qPCR results further confirmed the regulation of aclya, unc13c, and GABAergic signaling genes. Conclusions: Parishin B exerts anti-seizure effects through coordinated regulation of neurotransmitter homeostasis, neuroinflammation, and ACLY-associated energy–lipid metabolism, with potential involvement in ferroptosis-related processes. These findings provide molecular insights supporting Parishin B as a promising candidate for epilepsy therapy. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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15 pages, 5939 KB

Open AccessArticle

Deep Learning-Based and Python-Driven Construction and Application of a Mass Spectrometry Data Analysis Workflow: Taking Glucosinolates as an Example

by Shangshen Yang, Siyu Jia, Peiyu Jia, Wenyu Xie and Xiaoming Wang

Metabolites 2026, 16(4), 274; https://doi.org/10.3390/metabo16040274 - 17 Apr 2026

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Abstract

Background: Radish seeds are our model on glucosinolates (GSLs), which is a class of secondary metabolites in medicinal plants of the Brassicaceae family. Multilayer perceptron (MLP) network is highly effective in the study of complex plants. This study came up with a smart [...] Read more.

Background: Radish seeds are our model on glucosinolates (GSLs), which is a class of secondary metabolites in medicinal plants of the Brassicaceae family. Multilayer perceptron (MLP) network is highly effective in the study of complex plants. This study came up with a smart plan through the Python language. Methods: First, we used the MLP network to pick out GSL precursor ions, running them through a deep learning filter. Next, we set up an automated screening system and looked at how standard chemicals break down. To speed things up, we created a scoring system that flagged promising compounds. After that, we built a tracer molecular network, basically connecting compounds according to how the plant makes them, which helped us label everything accurately. Finally, we brought in a math-based tool that pieces together different chemical parts to predict new GSL structures. Results: With this workflow, we annotated 195 glucosinolate-related compounds in radish seeds. That includes 86 regular GSLs, 34 malonyl products, 40 sinapoyl compounds, and 35 diglycosides. Among them, eight compounds were confirmed by comparison with authentic standards (retention time and MS/MS data), whereas the remaining compounds were tentatively annotated based on accurate mass measurements, diagnostic fragment ions, Tracer Molecular Nnetworking, and literature/database matching. In addition, 36 compounds were considered putatively novel derivatives pending further structural confirmation. Conclusions: This new approach reduces the time spent on determining chemicals in complicated samples. This can be done with other vegetables and medicinal herbs by researchers. It assists us in knowing the chemistry of plants in a deeper manner. Full article

(This article belongs to the Special Issue LC-MS/MS Analysis for Plant Secondary Metabolites, 2nd Edition)

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17 pages, 5410 KB

Open AccessArticle

Bile and Serum Metabolomics in Living Donor Liver Transplantation: Exploratory Insights into Acute Rejection Biomarkers

by Yuta Hirata, Yasunaru Sakuma, Hideo Ogiso, Taiichi Wakiya, Takahiko Omameuda, Toshio Horiuchi, Noriki Okada, Yukihiro Sanada, Yasuharu Onishi, Hironori Yamaguchi, Ryozo Nagai and Kenichi Aizawa

Metabolites 2026, 16(4), 273; https://doi.org/10.3390/metabo16040273 - 17 Apr 2026

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Abstract

Background: Acute rejection remains a major complication following liver transplantation, yet reliable noninvasive biomarkers for its early prediction and diagnosis remain unidentified. This exploratory study characterized bile and serum metabolites associated with acute rejection in living donor liver transplantation using comprehensive metabolomic profiling [...] Read more.

Background: Acute rejection remains a major complication following liver transplantation, yet reliable noninvasive biomarkers for its early prediction and diagnosis remain unidentified. This exploratory study characterized bile and serum metabolites associated with acute rejection in living donor liver transplantation using comprehensive metabolomic profiling combined with machine learning. Methods: Non-targeted metabolomics were performed on bile samples collected on post-operative day (POD) 1 (n = 38) and serum on POD 14 (n = 45) from liver transplant recipients. Partial least squares discriminant analysis-based variable selection was followed by logistic regression and least absolute shrinkage and selection operator models, which were evaluated via cross-validation in the discovery cohort to explore potential biomarkers for acute rejection. Results: A three-variable, bile-based model for predicting acute rejection achieved a mean cross-validated AUC of 0.872 (95% confidence interval: 0.814–0.930). Glycohyocholic acid and sulfolithocholylglycine were the main contributors. A nine-variable serum model for the Rejection Activity Index, including the change in γ-glutamyl transferase, showed a mean cross-validated R² of 0.728 (95% confidence interval: 0.609–0.846), with methionine, creatine, and oxidized fatty acids contributing prominently. Conclusions: These findings suggest that metabolomic profiling combined with machine learning may provide candidate biomarkers for acute rejection after liver transplantation. However, given the exploratory nature of the study and the lack of external validation, the clinical utility of these metabolite signatures remains to be determined. Therefore, external validation in larger, independent cohorts will be required. Full article

(This article belongs to the Special Issue Proteomics and Metabolomics in Human Health and Disease)

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17 pages, 2939 KB

Open AccessArticle

Untargeted GC-IMS Metabolomics of Wound Headspace for Bacterial Infection Biomarker Discovery

by Yanyi Lu, Bowen Yan, Lin Zeng, Bangfu Zhou, Ruoyu Wu, Xiaozheng Zhong and Qinghua He

Metabolites 2026, 16(4), 272; https://doi.org/10.3390/metabo16040272 - 17 Apr 2026

Viewed by 647

Abstract

Background/Objectives: Wound infections cause significant morbidity, yet current diagnostics rely on time-consuming microbial culture. Volatile organic compounds (VOCs) from bacterial metabolism offer potential for early diagnosis. This study aimed to validate the volatile metabolites profiled by gas chromatography–ion mobility spectrometry (GC-IMS) combined with [...] Read more.

Background/Objectives: Wound infections cause significant morbidity, yet current diagnostics rely on time-consuming microbial culture. Volatile organic compounds (VOCs) from bacterial metabolism offer potential for early diagnosis. This study aimed to validate the volatile metabolites profiled by gas chromatography–ion mobility spectrometry (GC-IMS) combined with machine learning for rapid identification of wound infections and certain bacterial infections. Methods: Headspace of clinical wound samples were analyzed using GC-IMS. Volatile metabolite profiles were compared between infected and non-infected groups and between Escherichia coli (E. coli)-positive and negative samples. Partial least squares discriminant analysis (PLS-DA) and Mann–Whitney U test were used for preliminary screening with variable importance in projection (VIP) > 1 and p-value < 0.05. Three machine learning algorithms, namely support vector machine (SVM), logistic regression (LR), and random forest (RF), were trained on the selected features for classification, using 5-fold cross-validation with 10 repeated runs. Model performance was assessed using key evaluation metrics, including accuracy, sensitivity, specificity, the area under the curve (AUC) and feature importance ranking to identify the most relevant biomarkers. Results: A total of 19 volatile metabolites associated with clinical wound samples were identified. The RF model achieved 90.15% sensitivity and 0.91 AUC for bacterial infection detection. For E. coli identification, LR reached 85.35% sensitivity and 0.89 AUC. Potential volatile metabolic biomarkers including elevated 3-methyl-1-butanol, 2-methyl-1-butanol, and ethyl hexanoate for identifying bacterial infection were selected through the cross-validation results of the three algorithms. Conclusions: Untargeted metabolomics by GC-IMS effectively captures infection-specific volatile metabolic signatures in complex wound samples. Integration with machine learning enables rapid, high-accuracy diagnosis of bacterial infections and E. coli identification at point of care. This approach addresses clinical metabolomics translational challenges by providing a portable and cost-effective method, potentially reducing antibiotic misuse through more timely and targeted therapy. Full article

(This article belongs to the Special Issue New Findings on Microbial Metabolism and Its Effects on Human Health)

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23 pages, 3083 KB

Open AccessArticle

Dynamic Role of Omega-3/Omega-6 Polyunsaturated Fatty Acid Ratio in Modulation of Adipogenicity, Lipid Metabolites, and Adipokines Associated with Platelet Hyperactivity

by Sultanah Turki Almolafikh, Pandurangan Subash-Babu, Tlili Barhoumi and Ali A Alshatwi

Metabolites 2026, 16(4), 271; https://doi.org/10.3390/metabo16040271 - 17 Apr 2026

Viewed by 1154

Abstract

Background: Unhealthy expansion of adipose tissue (AT) due to excessive dietary intake of omega-6 or overnutrition stimulates the overaccumulation of the extracellular matrix (ECM), resulting in AT metabolic dysregulation. Hypertrophic conditions, excessive adipose depots, and hypoxia stimulate the overproduction of collagenous and non-collagenous [...] Read more.

Background: Unhealthy expansion of adipose tissue (AT) due to excessive dietary intake of omega-6 or overnutrition stimulates the overaccumulation of the extracellular matrix (ECM), resulting in AT metabolic dysregulation. Hypertrophic conditions, excessive adipose depots, and hypoxia stimulate the overproduction of collagenous and non-collagenous proteins, which pathophysiologically initiate the pro-fibrotic signaling pathway associated with fibrosis progression, resulting in atherosclerosis and cardiovascular diseases. Methods: We aimed to investigate adipocyte plasticity in response to a varying ratio of omega-3 (ω3) to omega-6 (ω6) supplementation during the chemically induced adipogenic differentiation of human mesenchymal stem cells. Additionally, changes in lipid accumulation, adipocyte hypertrophy and hyperplasia, active lipid metabolites, and inflammatory cytokine profiles were evaluated. Furthermore, conditioned media from adipocytes treated with different ω3/ω6 ratios were applied to platelets to assess inflammatory responses through prostaglandin and thromboxane measurements. Results: A 1:3 ratio of ω3/ω6 (20:60 µM) significantly reduced lipid accumulation, promoted brown-like adipocyte morphology, and decreased apoptosis and reactive oxygen species (ROS) generation, as confirmed via FACS analysis. Transcriptional control of adipose tissue expansion was confirmed by the downregulation of LIPIN1 and COL1A1 mRNA expression and p-prostaglandin12-R protein levels in a 1:3 ratio when compared with 1:1, 1:2, 1:4, or 2:6 ratios of ω3/ω6. Notably, a 1:3 ratio of fatty-acid-treated adipocyte-conditioned media-treated platelets significantly reduced platelet activation and aggregation, as evidenced by lower p-thromboxane A2 protein levels. Conclusions: Supplementation with a 1:3 (20:60 µM) ω3/ω6 ratio favored the development of lean adipocytes, evidenced by the decreased lipid storage achieved by mitochondrial thermogenesis, which attenuated minimal adipocyte expansion and metabolic inflammation. Full article

(This article belongs to the Section Advances in Metabolomics)

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12 pages, 231 KB

Open AccessArticle

Association Between Vitamin D Deficiency and Glycemic, Lipid, and Adiposity Markers in Older Adults: A Nationally Representative Study

by Yong-Joon Kim and Kyeongmin Jang

Metabolites 2026, 16(4), 270; https://doi.org/10.3390/metabo16040270 - 16 Apr 2026

Viewed by 620

Abstract

Background/Objectives: Vitamin D plays an important role in glucose metabolism, lipid regulation, and inflammatory processes, and has been implicated in cardiometabolic health. However, its associations with specific metabolic biomarkers remain inconsistent, particularly in older adults. This study aimed to examine whether vitamin D [...] Read more.

Background/Objectives: Vitamin D plays an important role in glucose metabolism, lipid regulation, and inflammatory processes, and has been implicated in cardiometabolic health. However, its associations with specific metabolic biomarkers remain inconsistent, particularly in older adults. This study aimed to examine whether vitamin D deficiency is differentially associated with multiple metabolic biomarkers in a nationally representative sample of older adults. Methods: This cross-sectional study used data from the 2024 Korea National Health and Nutrition Examination Survey, including 1806 adults aged ≥65 years. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D levels < 20 ng/mL. Metabolic biomarkers included fasting glucose, glycated hemoglobin (HbA1c), triglycerides, C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-C), waist circumference, and body mass index (BMI). Complex sample linear regression analyses were performed with sequential adjustment for sociodemographic factors, health behaviors, and comorbidities. Results: In unadjusted analyses, vitamin D deficiency was associated with adverse metabolic profiles, including higher fasting glucose, HbA1c, triglycerides, waist circumference, and CRP levels, and lower HDL-C levels. After adjustment for sociodemographic factors, health behaviors, and comorbidities, significant associations remained for HbA1c (β = 0.10, p = 0.034), triglycerides (β = 0.10, p = 0.003), and waist circumference (β = 1.21, p = 0.040). No significant associations were observed for fasting glucose, HDL-C, CRP, or BMI. Conclusions: Vitamin D deficiency was independently associated with poorer long-term glycemic status, hypertriglyceridemia, and central adiposity in older adults, but not with other metabolic markers after adjustment. These findings suggest that the metabolic correlates of vitamin D deficiency may be domain-specific rather than generalized. Longitudinal and interventional studies are needed to clarify causality and underlying mechanisms. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

16 pages, 2010 KB

Open AccessReview

Precision Exercise in Type 2 Diabetes Mellitus: Targeting Signaling Networks for Lipid Homeostasis

by Tan Tian, Feiyang Yu, Xingran Liu, Xuelin Zeng, Jianjun Yue and Shanjun Bao

Metabolites 2026, 16(4), 269; https://doi.org/10.3390/metabo16040269 - 16 Apr 2026

Viewed by 738

Abstract

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article [...] Read more.

Type 2 diabetes mellitus (T2DM) is frequently complicated by dyslipidemia, which accelerates insulin resistance and the progression of cardiovascular and hepatic diseases. While exercise intervention is a cornerstone of T2DM management, a systems-level understanding of its underlying molecular mechanisms remains incomplete. This article summarizes current evidence to propose that exercise functions as a signaling network regulator, concurrently modulating critical lipid metabolism-related signaling pathways: cyclic adenosine monophosphate (cAMP), phosphatidylinositol 3-kinase–protein kinase B (PI3K–AKT), forkhead box O (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways. We delineate how dysregulation of these signaling pathways contributes to lipid disorders in T2DM, highlighting their tissue-specific and often bidirectional roles. Subsequently, we detail the molecular adaptations induced by various exercise modalities—from aerobic training to high-intensity intervals—that restore homeostasis of this signaling network. By integrating these findings, we present a novel framework for precision exercise—defined as the tailoring of exercise modality, intensity, and volume based on an individual’s predominant signaling pathway disturbance, assessed via circulating or tissue-specific biomarkers. This framework advocates for future exercise prescriptions to be guided by molecular profiling alongside traditional physiological indicators. This mechanistic insight not only deepens our comprehension of exercise physiology but also paves the way for more effective, personalized strategies to combat T2DM and its metabolic complications. Full article

(This article belongs to the Special Issue Lipid Metabolism Dysregulation in Metabolic Disorders: Unraveling the Molecular Complexity)

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21 pages, 4648 KB

Open AccessArticle

M-GNN: A Topology-Enhanced Multi-Modal Graph Neural Network for Cancer Driver Gene Prediction

by Lu Qin, Wen Zhu, Xinyi Liao and Yujing Zhang

Metabolites 2026, 16(4), 268; https://doi.org/10.3390/metabo16040268 - 16 Apr 2026

Viewed by 751

Abstract

Background: Accurate identification of cancer driver genes is essential for understanding tumorigenesis and developing targeted therapies. Although graph neural networks (GNNs) have advanced multi-omics integration, existing methods often simply concatenate omics features and underutilize the topological information of biological networks. Methods: We propose [...] Read more.

Background: Accurate identification of cancer driver genes is essential for understanding tumorigenesis and developing targeted therapies. Although graph neural networks (GNNs) have advanced multi-omics integration, existing methods often simply concatenate omics features and underutilize the topological information of biological networks. Methods: We propose M-GNN, a multi-modal GNN framework for cancer driver gene prediction. It employs separate Graph Convolutional Network (GCN) encoders to process four types of omics data (mutation, expression, methylation, copy number variation (CNV)), each represented as a 16-dimensional vector. We incorporate knowledge distillation by using soft labels from a pre-trained teacher model to enhance feature representation. An attention mechanism adaptively fuses the encoded omics features, and a dual-path classifier combining a GCN and a Multilayer Perceptron (MLP) preserves both intrinsic gene properties and network topology. Results: Experiments on three public protein–protein interaction (PPI) networks show that M-GNN consistently achieves the highest or second-highest AUPRC compared to five state-of-the-art methods. Ablation studies confirm the contribution of each module, and biological interpretability analysis—including analysis of GO enrichment and drug sensitivity—validates the reliability of the predicted genes. Conclusions: M-GNN provides a robust and interpretable computational tool for systematic cancer driver gene identification, effectively integrating multi-omics and network data. Full article

(This article belongs to the Special Issue Machine Learning in Metabolomics: Unlocking the Future of Data Analysis)

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14 pages, 680 KB

Open AccessReview

The Thyroid–Metabolism Axis: Pathways of Dysregulation and the Effects of Treatment

by Martina Curcio and Royce P. Vincent

Metabolites 2026, 16(4), 267; https://doi.org/10.3390/metabo16040267 - 16 Apr 2026

Viewed by 1000

Abstract

Thyroid hormones regulate a complex and interconnected network of metabolic signaling. Thyroid dysfunction is, at present, defined and monitored through circulating thyroid-stimulating hormone (TSH) and free thyroid hormones. However, biochemical normalization does not entirely indicate restoration of metabolic homeostasis. This discrepancy highlights a [...] Read more.

Thyroid hormones regulate a complex and interconnected network of metabolic signaling. Thyroid dysfunction is, at present, defined and monitored through circulating thyroid-stimulating hormone (TSH) and free thyroid hormones. However, biochemical normalization does not entirely indicate restoration of metabolic homeostasis. This discrepancy highlights a critical limitation of the current TSH-centric paradigm, which also fails to explain the heterogeneity in cardiometabolic outcomes observed among patients with similar biochemical profiles. Metabolomics, through the analysis of tissue-specific biofluids, could aid in capturing the complex metabolic perturbations that characterize this disease. In this review, we summarize metabolomic signatures typical of thyroid dysfunction, perform a critical evaluation of limitations and variability across studies, and explore the clinical and translational implications of metabolomics in thyroid pathology. In addition, five metabolic hubs influenced by thyroid hormone activity are summarized: (i) lipid and lipoprotein remodeling; (ii) mitochondrial energetics and redox balance; (iii) amino acid metabolism and protein turnover; (iv) gut–liver–thyroid axis and (v) biological impact of subclinical thyroid diseases. Taken together, these findings challenge the sufficiency of a diagnostic model based on TSH measurement and pose metabolomics as a promising tool to refine risk stratification, uncover subclinical vulnerability and guide patient-centered management of thyroid disease. Despite its promise, clinical adoption of metabolomics is hindered by a lack of standardization and complex data interpretation. To overcome these limitations, coupling metabolomics with genomics and transcriptomics may allow its translation into practical application. Full article

(This article belongs to the Special Issue Exploring Metabolomic Signatures and the Metabolic Impact of Thyroid Dysfunction)

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15 pages, 6244 KB

Open AccessArticle

Temporal Metabolic Reprogramming Reveals Stage-Specific Adaptations in Proso Millet Resistance Against Head Smut

by Wenqi Fan, Mingyu Qi, Zhiguang Li, Yanyan Zuo, Min Zhao, Hanyu Liu, Yahui Wen, Xinxin Wang, Limei Bian and Liyuan Zhang

Metabolites 2026, 16(4), 266; https://doi.org/10.3390/metabo16040266 - 16 Apr 2026

Viewed by 474

Abstract

Background/Objectives: Proso millet (Panicum miliaceum L.), a drought-tolerant cereal vital to semi-arid agriculture, faces severe yield losses from head smut disease caused by the pathogen Sporisorium destruens. Although partial resistance exists, the dynamic molecular mechanisms governing its defense response across developmental [...] Read more.

Background/Objectives: Proso millet (Panicum miliaceum L.), a drought-tolerant cereal vital to semi-arid agriculture, faces severe yield losses from head smut disease caused by the pathogen Sporisorium destruens. Although partial resistance exists, the dynamic molecular mechanisms governing its defense response across developmental stages remain poorly understood. Methods: Here, we performed untargeted metabolomics on leaf samples from Inoculated Asymptomatic (IA) and Inoculated Symptomatic (IS) plants of the partially resistant cultivar ‘Chishu 13’ at four key growth stages following pathogen inoculation, with group classification validated by qPCR. Using weighted metabolite co-expression network analysis (WGCNA) combined with differential metabolite screening, we identified 18 metabolites markedly enriched in the tricarboxylic acid (TCA) cycle, metabolite transport-related processes, and phenylpropanoid biosynthesis pathways. Results: Notably, L-phenylalanine accumulated substantially in IA plants relative to IS plants and correlated closely with biosynthesis of key defensive phenylpropanoids, including cinnamic acid and p-coumaric acid. Our results reveal distinct temporal patterns in metabolic reprogramming that correlate with resistance outcomes in Inoculated Asymptomatic plants: early stages are characterized by differential regulation of energy metabolism, while later stages show enhanced phenylpropanoid biosynthesis. These stage-specific metabolic adaptations are strongly associated with successful defense outcomes. Conclusions: These findings elucidate stage-specific metabolic adaptations that distinguish successful defense in IA plants from susceptibility in IS plants, providing robust biomarkers and stage-targeted strategies for breeding smut-resistant millet varieties. Full article

(This article belongs to the Section Plant Metabolism)

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18 pages, 607 KB

Open AccessReview

Ceramide in Type 2 Diabetes and Obesity: Modulation by Nutrients and Dietary Patterns and Opportunities to Prevent and/or Manage Metabolic-Related Conditions

by Melania Gaggini, Adrian Florentin Suman and Cristina Vassalle

Metabolites 2026, 16(4), 265; https://doi.org/10.3390/metabo16040265 - 14 Apr 2026

Viewed by 854

Abstract

Ceramides, sphingolipids produced from fatty acids linked to sphingosine and an amide, are structural elements of cellular membranes and lipoproteins. These molecules also retain biological effects in key cellular pathways such as oxidative stress and inflammation, apoptosis, and fibrosis, with a role in [...] Read more.

Ceramides, sphingolipids produced from fatty acids linked to sphingosine and an amide, are structural elements of cellular membranes and lipoproteins. These molecules also retain biological effects in key cellular pathways such as oxidative stress and inflammation, apoptosis, and fibrosis, with a role in the onset and development of many pathophysiological conditions, including obesity, diabetes, and insulin resistance. Increasing evidence suggests that different nutrients and dietary patterns may affect ceramide levels, both negatively (e.g., fructose and the Western diet), whereas others improve the ceramide profile (e.g., ω-3 PUFAs, resveratrol, vitamin D, and the Mediterranean and the Nordic diets). Thus, ceramide nutritional modulation could represent a simple, additive, and reliable tool to improve metabolic health. This review focused on the role of ceramides in the pathophysiology of diabetes and obesity, as well as their pathogenetic mechanisms of action. Ceramides are increasingly recognized as “dynamic metabolic interfaces” linking nutrition and disease. This review aims to address a critical gap by synthesizing recent evidence on how dietary interventions, in addition to pharmacological approaches, can specifically target the enzymatic pathways involved in ceramide synthesis to enhance metabolic health. Thus, this review offers a concentrated analysis of the response of specific ceramide species, such as Cer16:0 and Cer18:0, to distinct dietary factors. Additionally, it incorporates emerging evidence on the role of gut microbiota in the biotransformation of sphingolipids, thereby adding a contemporary dimension to the established nutritional perspective. Full article

(This article belongs to the Special Issue Role of Lipid Metabolism in Cardiovascular Health)

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17 pages, 1674 KB

Open AccessArticle

Evidence That Oscillations in Glucose Metabolism Promote Optimal Islet Function

by Brian P. List, Nicholas B. Whitticar, Kathryn L. Corbin and Craig S. Nunemaker

Metabolites 2026, 16(4), 264; https://doi.org/10.3390/metabo16040264 - 14 Apr 2026

Viewed by 785

Abstract

Background/Objectives: Impairment in pulsatile insulin release contributes to insulin resistance and is one of the earliest markers of developing type 2 diabetes. Insulin delivered to the liver in pulses has a stronger glucose-lowering effect than continuous insulin delivery. Whether pulsatility benefits the islet [...] Read more.

Background/Objectives: Impairment in pulsatile insulin release contributes to insulin resistance and is one of the earliest markers of developing type 2 diabetes. Insulin delivered to the liver in pulses has a stronger glucose-lowering effect than continuous insulin delivery. Whether pulsatility benefits the islet itself is an open question. We previously showed that reducing glucokinase activity with the glucokinase inhibitor D-mannoheptulose (MH) improves function in islets exposed to prolonged hyperglycemic conditions. In this study, we test whether pulsatile vs. continuous delivery impacts the effectiveness of MH in islets. Methods: Islets were exposed to high-glucose conditions (20 mM glucose) for 24 or 48 h to induce early adaptations to hyperglycemia. We then used a specially designed perifusion system to impose pulsatile activity by exposing mouse islets to 3 min of MH in 20 mM glucose and 3 min of only high levels of glucose. Islets given intermittent MH for 18 h were compared with continuous delivery of MH at a full (2.5 mM) or half (1.25 mM) dose. Results: MH delivered by the forced oscillatory system reversed the effects of hyperglycemia and restored glucose sensing more effectively than continuous delivery. Specifically, fura-2AM imaging of intracellular calcium showed that islets given pulsatile MH had greater reductions in the elevated basal calcium caused by hyperglycemic conditions, improved the glucose stimulation index, and improved phase 0 response (indicating glucose-stimulated calcium uptake by the endoplasmic reticulum). Conclusions: These findings suggest that the loss of oscillatory glucose metabolism in islets contributes directly to beta-cell dysfunction. Full article

(This article belongs to the Special Issue Obesity and Metabolic Dysfunction: Disease Development and Breaking the Cycle)

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25 pages, 7408 KB

Open AccessArticle

Integrated Metabolomic and Transcriptomic Analyses Reveal Alterations in the Serotonergic Synapse Pathway and a Robust Diagnostic Model in Ulcerative Colitis

by Haiyan Wang, Hanlin Wu, Yuzhen Fu, Xuhan Lv, Chao Li, Yan Jin, Wei Ge and Zenan Wu

Metabolites 2026, 16(4), 263; https://doi.org/10.3390/metabo16040263 - 14 Apr 2026

Viewed by 759

Abstract

Objectives: To overcome the limitations of invasive diagnostic approaches for ulcerative colitis (UC) diagnosis, this study integrates liquid chromatography–mass spectrometry (LC–MS)-based serum metabolomics with mucosal transcriptomics to elucidate the interplay between systemic metabolic perturbations and neuroendocrine signaling in UC pathogenesis. Methods: Serum metabolites [...] Read more.

Objectives: To overcome the limitations of invasive diagnostic approaches for ulcerative colitis (UC) diagnosis, this study integrates liquid chromatography–mass spectrometry (LC–MS)-based serum metabolomics with mucosal transcriptomics to elucidate the interplay between systemic metabolic perturbations and neuroendocrine signaling in UC pathogenesis. Methods: Serum metabolites and mucosal differentially expressed genes (DEGs) were identified through multi-omics profiling. Key neurotransmitter receptor-related genes (NRRGs) were prioritized using three machine learning algorithms: LASSO, Random Forest, and SVM-RFE. A three-gene diagnostic nomogram was developed and rigorously validated across multiple independent cohorts (GSE48958, GSE73661) using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). Results: The integrated analysis revealed 334 dysregulated metabolites and 3093 DEGs, both converging on the serotonergic synapse pathway. Specific molecular alterations were uncovered, including tryptophan depletion linked to the downregulation of SLC6A4, concomitant with abnormal serotonin accumulation and PTGS2-mediated inflammatory responses. The three-gene signature, HTR3C, RPS6KA6, and NETO2, formed a highly robust diagnostic model, achieving an area under the ROC curve (AUC) exceeding 0.96 in both the training cohort and external validation sets. Conclusions: This multi-omics study delineates a neuroimmune mechanism in UC centered on dysregulation of the serotonergic synapse. The resulting three-gene nomogram identifies a candidate biomarker signature that demonstrates strong discriminative potential; however, given the exceptionally high performance metrics, these findings should be interpreted as a preliminary diagnostic framework rather than a clinically validated tool, and its efficacy relative to standard markers like CRP or fecal calprotectin requires further investigation in prospective real-world cohorts. Nonetheless, this study provides critical mechanistic insights into gut–brain axis dysfunction in UC. Full article

(This article belongs to the Special Issue Metabolic Disorders and Inflammatory Bowel Diseases)

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18 pages, 1044 KB

Open AccessArticle

Effects of Probiotic Supplementation on Gut Microbiota and Fecal Metabolome in Autism Spectrum Disorders: A Secondary Analysis of a Randomized Clinical Trial in Preschoolers

by Letizia Guiducci, Luca Laghi, Nicolò Dellarosa, Paola Mastromarino, Margherita Prosperi, Filippo Muratori and Sara Calderoni

Metabolites 2026, 16(4), 262; https://doi.org/10.3390/metabo16040262 - 13 Apr 2026

Viewed by 749

Abstract

Background/Objectives: Recently, a randomized clinical trial evaluated whether a six-month probiotic administration could reduce symptom severity in preschool children with Autism Spectrum Disorders (ASD), with (GI) or without (NGI) gastrointestinal symptoms. Significant positive changes were observed only in NGI children. A second explorative [...] Read more.

Background/Objectives: Recently, a randomized clinical trial evaluated whether a six-month probiotic administration could reduce symptom severity in preschool children with Autism Spectrum Disorders (ASD), with (GI) or without (NGI) gastrointestinal symptoms. Significant positive changes were observed only in NGI children. A second explorative study on children prior to intervention identified a fecal metabolome fingerprint associated with ASD severity. Building on these findings, the present study aimed to assess whether metabolomics could monitor changes in ASD severity following probiotic administration using a subset of samples from the same trial. Second, this study aimed to identify fecal metabolites to be monitored in children to predict whether their autism severity may decrease after probiotic or placebo treatment. Methods: Evaluations of the fecal metabolome and microbiota could be completed on 57 children before and after a double-blind administration of a probiotic mixture or a placebo. Results: In NGI children the probiotic was found to influence the concentration of the amino acids aspartate, leucine, tryptophan, and valine, together with nicotinate and the short chain fatty acids acetate, butyrate, isobutyrate, and propionate. Lactobacilli and Sutterella showed significant changes in response to probiotic administration (p < 0.05). Acetate, 4-hydroxyphenyl, galactose, proline, and tyramine were identified as key fecal metabolites for prediction purposes. Conclusions: The present exploratory analysis, despite the small sample size, suggests that fecal metabolomics may provide a useful approach for monitoring and potentially for predicting changes in ASD severity following probiotics administration. Full article

(This article belongs to the Special Issue Advances in Metabolomics for Precision Medicine: From Biomarker Discovery to Clinical Applications: 2nd Edition)

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18 pages, 891 KB

Open AccessArticle

Finishing Barrow Skeletal Muscle Performance and Fatigue Response to Large-Dose Nicotinamide Riboside Supplementation

by Daniela A. Alambarrio, Xiaohan Li, Siara S. Zedonek, Sophia E. Willis, Jordan N. Proctor, Faezeh Mozafari, Jarrod A. Call, Litzy E. Delgado, McKenna S. Doran and John M. Gonzalez

Metabolites 2026, 16(4), 261; https://doi.org/10.3390/metabo16040261 - 13 Apr 2026

Viewed by 680

Abstract

Background/Objective: Delaying muscle fatigue could alleviate economic and food security, and welfare concerns associated with transporting market-weight pigs to harvest. Previous research demonstrates barrow nicotinamide riboside (NR) supplementation at varying doses during the last 10 d of finishing shows to be [...] Read more.

Background/Objective: Delaying muscle fatigue could alleviate economic and food security, and welfare concerns associated with transporting market-weight pigs to harvest. Previous research demonstrates barrow nicotinamide riboside (NR) supplementation at varying doses during the last 10 d of finishing shows to be a countermeasure to muscle fatigue by reducing muscle fiber recruitment and increasing mitochondrial DNA expression in a dose-dependent manner. Therefore, this study aims to determine if a greater NR dose further enhances barrow fatigue resistance and characterize muscle mitochondria content and efficiency. Methods: Barrows (N = 87) were assigned to one of two dietary NR supplementation doses (TRT): 0 (0NR) or 150 (150NR) mg/kg body weigh NR administered during the last 14 d of finishing. Muscle (MUS) biopsies were collected on supplementation d (DAY) 0, 7 and 14 from three hind-leg muscles for NAD+ quantification and mitochondrial DNA expression and efficiency. On days 15 and 16, barrows were subjected to a performance test until they were subjectively exhausted. Electromyography data collection during the performance test were divided into five periods (PER) and included normalized root mean square (nRMS) from the same muscles. Results: There were no three-way interaction for nRMS (p > 0.83), but there were MUS × TRT and PER × TRT interactions (p < 0.05). During performance testing, 150NR had greater nRMS than 0NR in the bicep femoris (BF) and tensor fasciae latae (TFL; p < 0.01), but there were no differences in the semitendinosus (ST; p = 0.77). Treatments did not differ during PER 1 and 2 (p > 0.14) but 150NR had greater nRMS than 0NR during PER 3, 4 and 5 (p < 0.01) across all muscles. There was no three-way interaction for normalized (nNAD+; p = 0.14), but there was a DAY × TRT interaction (p < 0.05). There were no differences between 0NR and 150NR at d 0 (p = 0.95); however, by d 7 and 14, 150NR muscles had greater nNAD+ than 0NR muscles (p < 0.01). There tended to be a three-way interaction for mitochondrial DNA expression (p = 0.09). At supplementation d 14, all 150NR muscles had greater mitochondrial DNA expression and electron transport chain complex I and II activities (p < 0.01). When normalized to citrate synthase activity, electron transport chain complex I and II activity did not differ (p > 0.05). Conclusions: Large-dose NR supplementation appears to support sustained muscle fiber recruitment during prolonged activity and enhance fatigue resilience, primarily through increased NAD+ and mitochondrial biomarkers abundance and not through mitochondrial efficiency. Full article

(This article belongs to the Special Issue Muscle Metabolic Response and Adaptation to Exercise, Diet, and Environment: 2nd Edition)

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17 pages, 457 KB

Open AccessArticle

LC-MS/MS Quantification and Comparative Profiling of Stratum Corneum Ceramides in Human Normal and Dry Skin Subtypes

by Agui Xie, Yue Zhao, Yu Zhao, Xiao Zhao, Xiaoge Zhu and Jia Wang

Metabolites 2026, 16(4), 260; https://doi.org/10.3390/metabo16040260 - 13 Apr 2026

Viewed by 701

Abstract

Background: Ceramide (Cer) dysregulation in content and composition is linked to various skin conditions, particularly sensitive and dry skin. Existing ceramide quantification methods often lack efficiency, sensitivity, or comprehensive analytical capabilities. This study aimed to adopt an optimized LC-MS/MS platform to ensure [...] Read more.

Background: Ceramide (Cer) dysregulation in content and composition is linked to various skin conditions, particularly sensitive and dry skin. Existing ceramide quantification methods often lack efficiency, sensitivity, or comprehensive analytical capabilities. This study aimed to adopt an optimized LC-MS/MS platform to ensure the acquisition of reliable and accurate ceramide quantitative data, thereby providing robust methodological support for an in-depth investigation of the differences in ceramide profiles among different dry skin subtypes. Methods: Stratum corneum samples were collected via tape stripping from 93 adult female volunteers, who were stratified into sensitive dry skin, non-sensitive dry skin, and normal skin groups based on clinical assessments. Cer metabolomics was analyzed via targeted metabolomics using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Quantitative analysis of ceramide content in different groups revealed significantly elevated levels of ultra-long-chain ceramides and the atypical Cer (d17:1/24:0) in the SD group, alongside relatively lower levels of shorter-chain ceramides. The NSD group, in contrast, was predominantly enriched in shorter-chain ceramides. Statistical analysis showed statistically significant differences in the levels of Cer (d18:1/24:0), Cer (d18:1/24:1), and Cer (d17:1/24:0) between the SD group and the N group. The UPLC-MS/MS method exhibits a wide linear range and high recovery. Conclusions: This method offers a reliable tool for the quantitative analysis of ceramides in dermatological, physiological, and pathological research. The findings not only underscore the profound heterogeneity in lipid metabolism underlying different dry skin subtypes but also provide a molecular rationale linking aberrant ceramide chain lengths to compromised barrier integrity and heightened inflammatory susceptibility. The partially validated analytical platform and the specific ceramide signatures revealed herein offer valuable tools and insights for advancing the mechanistic understanding, diagnosis, and targeted intervention of sensitive dry skin. Full article

(This article belongs to the Section Metabolomic Profiling Technology)

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19 pages, 915 KB

Open AccessReview

A Dual-Target Microbial Therapeutic Strategy for Treating Metabolic Diseases: Complementary Mechanisms and Clinical Prospects of Lactiplantibacillus plantarum and Akkermansia muciniphila

by Si Liu, Mao Wang, Xiaobo Sun, Zhihao Jia and Kuilong Huang

Metabolites 2026, 16(4), 259; https://doi.org/10.3390/metabo16040259 - 13 Apr 2026

Cited by 1 | Viewed by 906

Abstract

Metabolic diseases, including obesity, type 2 diabetes, and their related complications, have emerged as major global public health challenges. Increasing evidence indicates that gut microbiota dysbiosis contributes to disrupted metabolic homeostasis, chronic low-grade inflammation, and progression of metabolic disorders. Among candidate microbiome-based interventions, [...] Read more.

Metabolic diseases, including obesity, type 2 diabetes, and their related complications, have emerged as major global public health challenges. Increasing evidence indicates that gut microbiota dysbiosis contributes to disrupted metabolic homeostasis, chronic low-grade inflammation, and progression of metabolic disorders. Among candidate microbiome-based interventions, Lactiplantibacillus plantarum (L. plantarum) and Akkermansia muciniphila (A. muciniphila) have attracted particular attention because they regulate host metabolism through partially distinct yet potentially complementary mechanisms. L. plantarum has been associated with modulation of appetite-related hormones, adipose tissue remodeling, reinforcement of intestinal barrier function, and attenuation of inflammatory signaling. A. muciniphila has been linked to strengthening of the mucus barrier, production of beneficial metabolites, and improvement in immune and metabolic homeostasis. However, current evidence remains fragmented across strain-specific studies, heterogeneous formulations, and predominantly single-strain experimental designs, and direct comparative evidence for combined administration is still limited. This review synthesizes current epidemiological, mechanistic, preclinical, and clinical evidence on L. plantarum and A. muciniphila, with emphasis on their physiological traits, gut ecological adaptability, pathway-based metabolic effects, and translational challenges in obesity, type 2 diabetes, and related complications. We further highlight the ecological rationale for their functional complementarity and discuss priorities for future combination studies and precision implementation. Overall, the available literature supports functional complementarity and possible additive metabolic benefits, but synergistic effects in humans remain unconfirmed. A clearer understanding of strain identity, active therapeutic entities, delivery strategies, and host context will be essential for advancing this dual-target microbial strategy toward clinically meaningful applications. Full article

(This article belongs to the Section Microbiology and Ecological Metabolomics)

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16 pages, 3032 KB

Open AccessArticle

A Novel Topology-Based Candidate Reaction Prediction Approach for Gap-Fillings of Genome-Scale Metabolic Models

by Jiajun Qu and Kai Wang

Metabolites 2026, 16(4), 258; https://doi.org/10.3390/metabo16040258 - 12 Apr 2026

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Abstract

Background: It is significant to predict and fill metabolic reaction gaps (gap-fillings) for reconstructions of high-quality genome-scale metabolic models (GEMs). Currently, many existing optimization-based gap-filling methods have to rely on phenotypic data, while performances of topology-based approaches by deep learning algorithms need [...] Read more.

Background: It is significant to predict and fill metabolic reaction gaps (gap-fillings) for reconstructions of high-quality genome-scale metabolic models (GEMs). Currently, many existing optimization-based gap-filling methods have to rely on phenotypic data, while performances of topology-based approaches by deep learning algorithms need to be further improved. Methods: This paper proposes a novel topology-based approach (GHCN-SE) of predicting confidence scores of candidate reactions, which can be used for gap-fillings of GEMs. The topological features of GEMs are fully extracted by simultaneously using graph and hypergraph convolutional networks, such that both associations of metabolites in the same reaction and higher-order interactions of metabolites within reactions can be captured. After the feature fusion, we further employ the squeeze-and-excitation network to enhance features. Results: The reaction prediction and reaction recovery experiments through 5-fold cross validations on 108 high-quality BiGG GEMs show that the proposed GHCN-SE is superior to other related methods. The ablation study further demonstrates the contributions of the graph convolutional network, hypergraph convolutional network, and squeeze-and-excitation network in GHCN-SE. In addition, the visualization study interprets the effectiveness of GHCN-SE. Conclusions: For potential applications in metabolic engineering, biomedicine, etc., this proposed GHCN-SE can be used to further improve the phenotypic prediction accuracy of the draft GEM generated from automated reconstruction tools. Full article

(This article belongs to the Section Bioinformatics and Data Analysis)

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16 pages, 5328 KB

Open AccessArticle

Circadian Reprogramming by Combined Time-Restricted Feeding and Exercise Improves Metabolic Homeostasis in Diabetes

by Qingxin Li, Guodong Zhang, Sugao Zhou and Yanli Xie

Metabolites 2026, 16(4), 257; https://doi.org/10.3390/metabo16040257 - 11 Apr 2026

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Abstract

Background: Circadian disruption exacerbates type 2 diabetes mellitus (T2DM). Time-restricted feeding (TRF) and exercise (EX) improve metabolic health, but their combinatory effect remains unclear. This study investigated whether combined TRF and EX additively ameliorates metabolism via circadian reprogramming in db/db mice. Methods: Eight-week-old [...] Read more.

Background: Circadian disruption exacerbates type 2 diabetes mellitus (T2DM). Time-restricted feeding (TRF) and exercise (EX) improve metabolic health, but their combinatory effect remains unclear. This study investigated whether combined TRF and EX additively ameliorates metabolism via circadian reprogramming in db/db mice. Methods: Eight-week-old male db/db mice were assigned to control (Con), diabetic model (DM), TRF (8 h feeding window), EX (treadmill, 60 min/day, 5 days/week), or combined TRF + EX groups for 8 weeks (n = 8/group). Body weight, glucose/insulin tolerance, and 24 h energy metabolism (CLAMS) were assessed. Mitochondrial function, oxidative stress, inflammation, and expression of mitophagy (Pink1, Park2, Bnip3, Fundc1) and thermogenic (Ucp1, Pgc1a, Prdm16, Cidea) genes were measured. Results: Compared with the con group, DM mice showed obesity, hyperglycemia and blunted circadian metabolic rhythm. The TRF and EX groups improved these defects. Specifically, combined TRF + EX reduced fasting blood glucose from 25.3 ± 3.1 mmol/L (DM) to 13.2 ± 1.8 mmol/L (p < 0.05), body weight from 49.8 ± 2.5 g to 39.5 ± 1.7 g (p < 0.05), and body fat percentage from 45.6 ± 3.2% to 32.1 ± 2.2% (p < 0.05). GTT area under the curve (AUC) decreased from 3711.0 ± 186.5 (DM) to 2118.0 ± 112.4 (p < 0.05), and ITT AUC decreased from 2617.5 ± 135.8 to 1260.0 ± 68.9 (p < 0.05). Notably, the combination of TRF + EX produced greater effects than either intervention alone: body weight, fasting blood glucose, and glucose/insulin tolerance were greatly improved (p < 0.05). In addition, compared with the DM group, the diurnal metabolic amplitude and phase were improved in the TRF or EX group; the combination group showed further improvements in these parameters. Furthermore, TRF and EX each resulted in significantly higher expression of key thermogenic genes (Ucp1, Pgc1a, Prdm16, Cidea) in white adipose tissue (WAT) and brown adipose tissue (BAT) (p < 0.05), and the TRF + EX group showed the highest expression levels. Combined intervention also restored skeletal muscle SOD activity (31.2 ± 2.9 U/mg prot vs. DM 20.1 ± 2.5 U/mg prot, p < 0.05) and reduced serum TNF-α (28.5 ± 4.5 pg/mL vs. DM 65.8 ± 8.5 pg/mL, p < 0.05) and IL-6 (21.6 ± 3.8 pg/mL vs. DM 50.3 ± 7.1 pg/mL, p < 0.05). Conclusions: TRF + EX additively restores metabolic homeostasis in diabetes by re-entraining circadian energy rhythms, improving mitochondrial quality, and activating adipose thermogenesis, supporting further investigation of integrated lifestyle timing as a potential therapeutic strategy. Full article

(This article belongs to the Topic Animal Models of Human Disease 3.0)

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16 pages, 470 KB

Open AccessArticle

Early Cytokine Profiles in Critically Ill Patients with COVID-19 and Their Association with Mortality

by Yenifer Gamarra-Morales, Jorge Molina-López, Juan Francisco Machado-Casas, Lourdes Herrera-Quintana, Héctor Vázquez-Lorente, José Miguel Pérez-Villares and Elena Planells

Metabolites 2026, 16(4), 256; https://doi.org/10.3390/metabo16040256 - 11 Apr 2026

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Abstract

Background/Objectives: The purpose of this study was to (i) determine the levels of interleukins in patients with COVID-19 admitted to the Intensive Care Unit (ICU) and (ii) evaluate their early dynamics, as well as (iii) assess their relationships with morbidity and mortality. Methods: [...] Read more.

Background/Objectives: The purpose of this study was to (i) determine the levels of interleukins in patients with COVID-19 admitted to the Intensive Care Unit (ICU) and (ii) evaluate their early dynamics, as well as (iii) assess their relationships with morbidity and mortality. Methods: This was a prospective analytical study of critically ill patients with COVID-19 who were monitored from admission to three days of stay in the ICU. Circulating levels of IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10, and tumour necrosis factor-alpha (TNF-α) were measured. Cytokine levels were analysed in relation to clinical severity parameters and 28-day mortality. Results: A dynamic cytokine response was observed during the first 72 h, with a significant increase in TNF-α levels and a decrease in IL-10 and IL-1β. Non-survivors showed higher TNF-α levels than survivors. In the multivariable analysis adjusted for clinical severity, TNF-α remained independently associated with 28-day mortality, whereas other cytokines did not retain statistical significance. The overall predictive performance of cytokines was moderate. Conclusions: Early cytokine dynamics reflect the evolving inflammatory response in critically ill COVID-19 patients. TNF-α emerges as an independent predictor of mortality, supporting its role as a relevant biomarker of adverse outcomes. Although its predictive capacity is moderate, TNF-α may provide clinically meaningful information for risk stratification when integrated with established clinical and laboratory parameters. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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