Search Results (1,135)

Oxidative stress is a central driver of atherosclerosis progression, promoting lipid peroxidation, vascular inflammation, and hepatic metabolic dysfunction. Forchlorfenuron (KT-30), a cytokinin-like plant growth regulator widely used on fruits such as kiwifruit, grapes, and watermelon, has been reported to elevate serum cholesterol levels, suggesting potential atherogenic effects. However, whether KT-30 induces oxidative stress and accelerates atherosclerosis remains unknown. Here, apolipoprotein E-deficient (apoE^−/−) mice were orally administered KT-30 (5 mg/kg/day) for four weeks. KT-30 significantly accelerated atherosclerotic lesion formation, elevated plasma cholesterol levels, upregulated scavenger receptors SR-A and CD36, and downregulated ABCA1 and LXRα, indicating impaired reverse cholesterol transport and enhanced foam cell formation. KT-30 also increased pro-inflammatory cytokines (IL-1β, IL-6, MIP-2) and aortic expression of F4/80 and VCAM-1. Critically, KT-30 exposure was associated with elevated oxidative stress markers, as evidenced by elevated plasma MDA levels, increased aortic 4-HNE immunostaining, and upregulation of NOX-1/4. In the liver, KT-30 induced lipid accumulation, characterized by elevated cholesterol and free fatty acids, accompanied by SREBP-1/2-driven de novo lipogenesis and impaired lipoprotein uptake. Proteomic analysis revealed significant alterations in mitochondrial oxidative phosphorylation- and sirtuin signaling-related protein expression. Taken together, KT-30-associated oxidative stress, accompanied by upregulation of NOX-1/4 and alterations in mitochondrial pathway-related protein expression, may represent an important mechanistic link between lipid homeostasis disruption and accelerated atherosclerosis in apoE^−/− mice, highlighting the potential pro-atherogenic effects of KT-30 in a susceptible experimental model and providing mechanistic evidence that warrants further investigation of its possible cardiovascular implications. Full article

Fructooligosaccharides (FOSs) are a class of functional prebiotics that effectively modulate the composition of the intestinal microbiota and regulate metabolic processes in animals. This study aimed to determine how early FOS supplementation affects jejunal development, which is vital for the rapid growth of suckling piglets. Sixty newborn piglets (Duroc × Landrace × Large White) from six litters were randomly assigned to either a control (CON) or an FOS group (n = 5 per litter per group). From days 2 to 21, piglets in the FOS group received 5 mL of an FOS solution orally (3 g/day/piglet), while those in the CON group received an equal volume of saline. Piglets were weighed on days 1, 7, 14, and 21, and samples were collected on days 7, 14, and 21. Early FOS intervention can enhance the growth performance of suckling piglets (p < 0.01), which is related to the development of the jejunum. Specifically, it improved intestinal morphology, stem cell function, and nutrient transport by increasing mRNA and protein expression of key genes in the Wnt/β-catenin signaling pathway. This may be related to increased abundance of jejunal Lactobacillus and the concentrations of metabolites such as lactate and short-chain fatty acids (SCFAs). Early FOS intervention drove jejunal development through Wnt/β-catenin activation, a process mediated by microbiota-metabolite shifts that augmented intestinal stem cell renewal. Full article

Aim: To establish and validate a quantitative transporter-mediated imaging framework based on gadoxetic acid-enhanced T1 mapping for assessing liver functional reserve (LFR) and to investigate the physiological significance of the relative change in longitudinal relaxation rate (ΔR1%) as a quantitative imaging biomarker. Methods: Female C57BL/6J mice (6–8 weeks old) representing five experimental liver conditions (control, transporter-deficient Slco1b2/Slco1a5 double-knockout, carbon tetrachloride-induced fibrosis, methionine–choline-deficient diet-induced steatohepatitis, and alcohol-associated fatty liver disease; n = 6 per group) underwent serial Gd-EOB-DTPA-enhanced T1 mapping. Quantitative ΔR1% was calculated to characterize hepatobiliary enhancement kinetics. Liver functional reserve was independently evaluated using multispectral optoacoustic tomography of indocyanine green (ICG) pharmacokinetics and serum ICG retention assays, with histopathological and hepatocellular transporter analyses performed for mechanistic validation. Longitudinal data were analyzed using restricted maximum likelihood (REML)-based mixed-effects models. Intergroup comparisons were performed using one-way ANOVA or Kruskal–Wallis tests with appropriate post hoc analyses, and associations between imaging and functional parameters were evaluated using Spearman rank correlation analysis. A two-sided p < 0.05 was considered statistically significant. Results: Five experimental liver models exhibited distinct transporter-dependent hepatobiliary enhancement patterns. The transporter-deficient knockout mice showed minimal enhancement, whereas fibrosis and steatotic liver injury models demonstrated intermediate but clearly distinguishable functional profiles. Longitudinal mixed-effects analysis identified significant effects of time, experimental group, and time-by-group interaction on ΔR1% dynamics (all p < 0.0001). Although MRI-derived ΔR1% parameters were not significantly correlated with regional optoacoustic ICG kinetics, ΔR1% area under the curve showed a strong inverse correlation with serum ICG retention at 600 s (r = −0.729, p < 0.0001), indicating that MRI-derived ΔR1% and ICG-based measurements provide complementary rather than interchangeable assessments of liver function. Histological and molecular analyses further demonstrated marked heterogeneity in fibrosis, steatosis, and hepatobiliary transporter expression across models, whereas transporter abundance alone did not consistently predict imaging-derived functional performance. Conclusions: Quantitative Gd-EOB-DTPA-enhanced T1 mapping provides a transporter-mediated imaging framework for evaluating hepatic functional reserve across mechanistically distinct liver injury models. As a normalized quantitative imaging biomarker, ΔR1% captures the integrated functional consequences of hepatobiliary transport dysfunction and complements established liver function tests. These findings support the translational potential of quantitative T1 mapping as a standardized, noninvasive approach for assessing liver functional reserve. Full article

Background: Hepatic lipid metabolism disorder has been linked to a wide range of diseases. Aspalathin is a flavonoid enriched in rooibos tea and has shown capacity to protect against hyperlipidemia, oxidative stress and inflammation. In the current study, we investigated the functional role of aspalathin in regulating liver metabolism and gut microbiota in the context of a high-fat diet (HFD). Methods: Male mice were fed a control diet or HFD, then HFD-fed animals were treated with or without aspalathin-rich extract (ASE). Hepatic neutral lipids were detected using oil red O staining and a colorimetric assay. Expression of cholesterol metabolism-, lipogenesis- and fatty acid β-oxidation-associated genes was measured. Gut microbiota was analyzed using 16S rRNA sequencing and bioinformatic approaches. Results: HFD-fed mice had markedly higher levels of triglycerides and cholesteryl esters and downregulated expression of cholesterol metabolism-, transport- and lipogenesis-related genes in the liver. ASE administration counteracted HFD-induced effects. In addition, HFD altered the composition, diversity and metabolic pathways of the gut microbiota. The richness of beneficial bacteria, particularly the butyrate-producing bacteria, was significantly decreased. The altered metabolic pathways are involved in the metabolism of carbohydrates, lipids, amino acids and nucleotides, as well as mitochondrial function. ASE treatment reversed most of the alterations back to the characteristics of the control group. Conclusions: Our results demonstrated the potential of ASE improving liver lipid metabolism and gut microbiota in the scenario of a high-fat diet, providing insights into future studies on the mechanism of ASE regulating lipid metabolism disorder. Full article

The heart is a highly energy-demanding organ that depends on metabolic flexibility to adjust substrate utilization in response to changes in nutrient availability, endocrine signals, and energetic demands. Accumulating evidence demonstrates that dietary patterns are key determinants of myocardial metabolic homeostasis, affecting substrate selection, mitochondrial function, nutrient-sensing pathways, and long-term transcriptional and epigenetic regulation. This review analyzes the molecular mechanisms through which diet regulates cardiac metabolism and explores how chronic nutritional exposures influence the myocardial energetic phenotype. The physiological regulation of cardiac substrate utilization is described, with emphasis on fatty acids, glucose, ketone bodies, and branched-chain amino acids, underscoring the importance of metabolic flexibility in sustaining cardiac efficiency. The regulation of substrate transport and oxidation is examined, including the roles of the carnitine shuttle, insulin signaling, AMPK, mTOR, PPARα–PGC-1α, SIRT3, and other nutrient-sensing networks that coordinate mitochondrial ATP production. The effects of dietary composition and meal timing, such as caloric restriction and intermittent fasting, are discussed as modulators of myocardial metabolism. The adverse effects of chronic nutrient excess are reviewed, including lipotoxicity, glucotoxicity, insulin resistance, mitochondrial dysfunction, oxidative stress, pseudo-hypoxia, fetal metabolic reprogramming, and maladaptive cardiac remodeling. Recent findings on the gut–heart axis, microbiota-derived metabolites, circadian regulation, and metabolic–epigenetic interactions are also considered. Overall, current evidence supports the view that diet is an important and potentially modifiable regulator of the cardiac metabolic phenotype. Advancing the understanding of diet–metabolism interactions may enable the development of targeted nutritional strategies to maintain metabolic flexibility, enhance cardiac bioenergetics, and prevent the progression of heart failure and other cardiometabolic diseases. Full article

Wheat Fusarium head blight (FHB) is a globally prevalent and destructive fungal disease predominantly caused by Fusarium graminearum. Pydiflumetofen, a novel succinate dehydrogenase inhibitor (SDHI) fungicide, exhibits strong inhibitory activity against F. graminearum; however, the molecular regulatory mechanisms underlying the field-developed resistance in this pathogen remain poorly defined. In the present study, a field-evolved resistant isolate W24-039 and a sensitive isolate W24-016 were subjected to multi-omics analysis. The sequencing results identified compound mutations C89S/A93V in SdhC2, and A21T/S30F in SdhD of the resistant strain, which confer stable fungicide resistance without any detectable fitness costs. Physiological tests revealed that these target mutations sustain the homeostasis of succinate dehydrogenase (SDH) activity and intracellular ATP production. Following pydiflumetofen treatment, the sensitive isolate displayed remarkable declines in SDH activity, intracellular ATP content and deoxynivalenol (DON) biosynthesis, accompanied by markedly elevated cell membrane permeability. Transcriptomic sequencing uncovered 2221 differentially expressed genes (DEGs) in the sensitive strain under fungicide stress, and 2566 DEGs in the resistant isolate under the same conditions. The genes associated with detoxification and drug efflux, including cytochrome P450, glutathione S-transferase (GST), ABC and MFS transporters, were significantly upregulated in the resistant isolate. Metabolomic analysis indicated that differential metabolites were mainly enriched in the tricarboxylic acid (TCA) cycle, amino acid metabolism and membrane lipid biosynthesis pathways. The resistant strain maintained intact TCA cycle operation and accumulated high levels of pivotal metabolites such as phosphatidylcholine, unsaturated fatty acids and reduced glutathione. Integrated multi-omics analysis verified that the ABC transporter and glutathione metabolism pathways serve as core regulatory modules governing fungicide resistance. Collectively, F. graminearum develops resistance via the synergistic effects of SDH compound mutations, enhanced detoxification and efflux, and global metabolic remodeling, demonstrating that target-site mutation alone is not the sole driver of resistance, which is instead controlled by an intricate regulatory network involving multiple coordinated pathways. This study systematically characterizes the resistance regulatory network of F. graminearum against pydiflumetofen, and provides theoretical guidance for the rational application and sustainable field resistance management of this fungicide. Full article

Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid with important health benefits. However, DHA enrichment in ruminant milk is limited by inefficient post-absorptive transport. This study evaluated whether combined supplementation of rumen-protected algae powder (RPA) and rumen-protected choline (RPC) enhances DHA enrichment in goat milk. Nine lactating dairy goats were assigned to three groups (n = 3/group) for 28 days: RPA alone, RPA + low-dose RPC (5 g/d), and RPA + high-dose RPC (10 g/d). Milk DHA content, bioconversion efficiency, serum biochemical parameters, and lipid profiles were analyzed. Compared with RPA alone, low- and high-dose RPC increased milk DHA content to 27.98 and 33.50 mg/100 mL, respectively, representing increases of 23.0% and 47.3%, and enhanced DHA bioconversion efficiency to 20.66% and 24.29% compared with 16.86% in the RPA group. RPC supplementation increased serum VLDL and triglyceride concentrations, and lipidomics revealed increased DHA-containing triglycerides (TG-DHA). These findings suggest that RPC may enhance DHA enrichment in goat milk by promoting VLDL-mediated DHA transport. Further studies with larger animal populations are required to confirm these effects. These findings contribute to a better understanding of nutritional regulation of DHA transfer and provide insights into strategies for developing DHA-enriched dairy products. Full article

Large-scale mining of rare earth resources has caused a series of ecological and environmental problems in mining areas, including soil structural degradation, nutrient depletion, acidification, and rare earth element (REE) accumulation. Conventional physicochemical remediation technologies are often limited by high costs, strong disturbance, and insufficient long-term stability. To compare the effects of different vegetation types on ecological restoration of ion-adsorption REE tailing soils, this study was conducted in an abandoned REE tailing area in Changfeng’ao, Ganxian District, Ganzhou City, Jiangxi Province. A small-scale field restoration experiment was established with three treatments: unrestored tailings (CK), slash pine (PE), and broadleaf paspalum (CS). Soil physicochemical properties, REE concentrations, bacterial and fungal community structures, and untargeted metabolomic profiles were comprehensively analyzed. Compared with CK, both PE and CS increased soil organic matter, alkali-hydrolyzable nitrogen, and available potassium and were associated with lower concentrations of several REEs, including Dy, Nd, Er, Y, and Yb, whereas the response of Ce differed between vegetation types. The two vegetation treatments exerted inconsistent effects on microbial communities: PE significantly increased bacterial richness and Shannon index and increased fungal richness, but decreased fungal Pielou evenness and Shannon index; in contrast, CS did not markedly enhance bacterial alpha diversity. Community composition analysis showed that vegetation treatments altered the relative abundances of dominant bacterial and fungal taxa, which were closely associated with changes in pH, soil organic matter, nitrogen, phosphorus and potassium nutrients, and REEs. Metabolomic analysis indicated that fatty acyls, organooxygen compounds, and carboxylic acids and derivatives were the major classes of differential metabolites. Pathways such as ABC transporters, nicotinate and nicotinamide metabolism, purine metabolism, and secondary metabolite biosynthesis may participate in soil metabolic reshaping under vegetation restoration. Overall, this study indicates that broadleaf paspalum and slash pine have differentiated ecological effects in REE tailing restoration and provides preliminary field evidence for vegetation recovery and soil microecological reconstruction in REE mining areas of southern Jiangxi. Full article

Background: MASLD is a disorder linked to lipid metabolism and obesity, increasingly prevalent among sedentary people and leading to hepatic fibrosis. Cyclodipeptides (CDPs) have promising anti-obesogenic and liver-protective potential. Methods: CDP treatment was evaluated in a chronic MASLD model using female Wistar rats fed an obesogenic diet, with assessments of insulin resistance, glucose tolerance, liver damage, oxidative stress, and the expression of genes related to metabolic function. Results: MASLD CDP-treated rats showed low visceral adipose tissue (VAT) content, improved insulin responsiveness and glucose tolerance, reduced steatosis, and reversed oxidant stress and the NRF2, GPX1, and GCLC expression. Furthermore, MASLD-related dysregulation of genes involved in lipid metabolism was restored, including vLDL transport (MTTP, APOB, and RASAL2), β-oxidation (PPAR-α, ACOX1, and FOXO1), lipogenesis (ACC1 and SREBP 1C), and fatty acid transport (PSD3 and CD36). In accordance, genes of key signaling pathways were also restored, including mTOR, TSC1, and TSC2, along with fibrosis and inflammation TGF-β, Fas, NF-κB, and IL-6. In VAT of MASLD animals, crown-like structures and adiposity density were diminished by CDP treatment, with increased expression of genes associated with beige-like adipose tissue remodeling, including PGC-1α, UCP1, NRF1, ATP6v1, CEBP-α, COX4i1, PPARγ, and CS. Consistently, the UCP1 and PGC-1α protein expression was increased in the VAT of MASLD animals treated with CDPs. Conclusions: The anti-MASLD effects of CDPs were associated with reversal of key pathogenic markers in the liver and VAT, suggesting remodeling of white adipose tissue (WAT) toward a beige-like adipose tissue phenotype. The findings suggest that CDPs may modulate adipose tissue structure and adipogenesis, underscoring their therapeutic relevance for MASLD. Full article

Red blood cells (RBCs) are the most abundant cells in peripheral blood and perform critical functions including oxygen and carbon dioxide transport, acid base buffering, regulation of hemorheology, and modulation of immune signaling. Due to their high content of hemoglobin and labile iron, prolonged exposure to high oxygen tension, membrane enrichment with polyunsaturated fatty acids, and the absence of both nucleus and mitochondria, mature RBCs have limited capacity for damage repair and protein re-synthesis, making them highly susceptible to attack by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hydrogen peroxide (H₂O₂) and 2,2′-azobis(2-methylpropionamidine) dihydrochloride (AAPH) are the two most commonly used inducers in the in vitro models of RBC oxidative injury: H₂O₂ primarily generates hydroxyl radicals via hemoglobin/ferrous ion-dependent Fenton reactions, simulating acute oxidative stress. AAPH releases peroxyl radicals upon thermal decomposition, mimicking persistent lipid peroxidation in cell membranes. Curcumin, a representative polyphenolic compound derived from turmeric, exerts multiple effects including free radical scavenging, metal ion chelation, membrane stabilization, anti-inflammatory activity, and regulation of redox homeostasis. This review systematically summarizes the pathological basis of RBC oxidative damage and the protective effects of curcumin on membrane systems, antioxidant defenses, morphology, and function, based on the core evidence chain “H₂O₂/AAPH—RBCs—curcumin”, integrating recent experimental findings on H₂O₂, AAPH, blood storage-induced injury, and curcumin formulations. It emphasizes that mature RBCs lack nuclei and mitochondria, and therefore mechanisms such as Nrf2/ARE signaling, HO-1 induction, mitochondrial apoptosis, caspase cascades, and inflammasome activation should not be directly equated with transcriptional regulatory pathways within mature RBCs, but rather interpreted as indirect evidence originating from nucleated cells, erythroid progenitors, or the blood microenvironment. The article further proposes that future research should focus on standardized RBC models, physiologically relevant dosages, nanodelivery systems, and translational applications in blood storage, to facilitate the transition of curcumin’s in vitro antioxidant evidence into clinical transfusion medicine and precision nutritional interventions. Full article

Objective: Impaired fatty acid oxidation (FAO) is considered an important metabolic mechanism underlying skeletal muscle aging and sarcopenia; however, the key regulatory molecules involved in this process remain incompletely defined. This study aimed to identify candidate biomarkers associated with impaired FAO in aged skeletal muscle, characterize their potential biological functions and regulatory features through integrated bioinformatics and machine learning analyses, and preliminarily validate their expression patterns in in vivo and in vitro aging models. Methods: Skeletal muscle aging transcriptomic datasets GSE1428 and GSE674 were obtained from the Gene Expression Omnibus database. FAO-related genes were retrieved from GeneCards. Differentially expressed FAO-related genes (DE-FAOGs) were identified through differential expression analysis and were further analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Random forest, Boruta, and protein–protein interaction (PPI) network analyses were used to screen hub genes, and an artificial neural network (ANN) model was constructed. Single-cell RNA sequencing analysis, gene set enrichment analysis, ceRNA network construction, drug prediction, molecular docking, and molecular dynamics simulation were further performed. Hub gene expression was validated by qRT-PCR in naturally aged mice and D-galactose-induced senescent C2C12 cells. Results: A total of 69 DE-FAOGs were identified and were mainly enriched in mitochondrial function, electron transport chain, and energy metabolism-related pathways. Three hub genes, creatine kinase, mitochondrial 2 (CKMT2), actin alpha cardiac muscle 1 (ACTC1), and forkhead box O3 (FOXO3), were identified by random forest, Boruta, and PPI analyses. Receiver operating characteristic (ROC) analysis showed good discriminatory performance for these genes. The three-gene ANN model achieved area under the curve (AUC) values of 0.992 and 0.964 in the training and validation datasets, respectively. Gene set enrichment analysis (GSEA) suggested that the hub genes were closely associated with mitochondrial energy metabolism, lipid metabolism, and stress regulation. qRT-PCR confirmed decreased Ckmt2 expression and increased Actc1 and Foxo3 expression under aging conditions, consistent with the bioinformatics results. Conclusions: CKMT2, ACTC1, and FOXO3 are potential biomarkers associated with impaired FAO in aged skeletal muscle. The ANN model based on these three genes showed good predictive performance and may provide new insights into the metabolic mechanisms and therapeutic targets of sarcopenia. Full article

Background/Objectives: Atherogenic dyslipidemia is a major cardiometabolic risk factor characterized by elevated circulating triglycerides (TGs), reduced HDL-C, and increased levels of atherogenic lipoproteins. Curcumin, a polyphenolic compound considered the main bioactive component of turmeric (Curcuma longa), has attracted growing interest because of its potential lipid-modifying and anti-inflammatory properties. This scoping review aimed to evaluate evidence from randomized controlled trials (RCTs) on the efficacy of curcumin supplementation in the management of atherogenic dyslipidemia and to summarize current mechanistic evidence related to curcumin absorption, metabolism, and regulation of lipid homeostasis. Methods: A PRISMA-ScR-guided scoping review was performed across five databases (PubMed, Scopus, Web of Science, Cochrane Library, and Embase). RCTs evaluating curcumin supplementation in atherogenic dyslipidemia or related cardiometabolic conditions were systematically identified and synthesized. Mechanistic and preclinical evidence was identified through separate topic-specific searches of PubMed, Scopus, and Web of Science, supplemented by citation searching, and was synthesized narratively. Results: Twenty-two RCTs published between 2008 and 2025 were included. Most studies involved patients with cardiometabolic disorders, including type 2 diabetes mellitus with hyperlipidemia, metabolic syndrome, and polycystic ovary syndrome. Curcumin supplementation, administered in various formulations and dosages, showed overall favorable effects on plasma lipid profiles, particularly TGs and LDL-C, although the magnitude of these effects varied across studies. Mechanistic and preclinical evidence suggested that curcumin may modulate multiple pathways involved in lipid homeostasis, including intestinal cholesterol uptake, hepatic lipogenesis, cholesterol synthesis, fatty acid oxidation, bile acid metabolism, and reverse cholesterol transport. Conclusions: Current evidence suggests that curcumin may improve atherogenic lipid profiles through pleiotropic effects on lipid metabolism and cholesterol homeostasis. The clinical efficacy of curcumin appears to depend substantially on formulation-related bioavailability. Despite inter-study heterogeneity, curcumin shows potential as an adjunctive strategy for the management of atherogenic dyslipidemia and associated metabolic disorders. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options. Here, we demonstrate that fucoxanthin (FUCO), a natural marine carotenoid, attenuates free fatty acid (FFA)-induced hepatocellular steatosis and inflammatory responses in vitro by targeting the EGR2-CD36 axis (EGR2, early growth response protein 2; CD36, cluster of differentiation 36). In FFA-induced hepatocyte models (HepG2, Hep3B, and AML12), FUCO significantly reduced lipid accumulation and inflammatory markers without cytotoxicity. Mechanistic studies revealed that FUCO specifically inhibited fatty acid uptake and transport by downregulating CD36, while triglyceride (TG) degradation remained unaffected. RNA sequencing identified EGR2 as a master regulator induced by FFA and suppressed by FUCO. Functional validation showed that EGR2 overexpression completely blocked FUCO’s lipid-lowering effects and restored CD36 expression, confirming that FUCO acts through EGR2-dependent CD36 inhibition. Bioinformatic analysis further supported EGR2-mediated regulation of CD36 via tumor necrosis factor (TNF) and sterol regulatory element-binding factor (SREBF) pathways. Collectively, our findings establish EGR2 as a critical molecular target for FUCO and provide mechanistic insights that may support its further evaluation in preclinical models for MASH therapy. Full article

Emerging evidence links gut microbiota (GM) dysbiosis to hyperuricemia (HUA). The GM plays a critical role in regulating host health and homeostasis by producing a diverse array of metabolites, including short-chain fatty acids, bile acids and uremic toxins. Dysregulation of the microbial metabolite profile has been implicated in the pathogenesis of HUA. Given the urgent need for green and safe urate-lowering therapies for HUA, recent years have seen an increasing focus on interpreting the ability of natural products to modulate these microbial metabolites. Such interventions enhance beneficial metabolites and suppress uremic toxins, thereby alleviating HUA through coordinated regulation of urate transporters, restoration of intestinal barrier integrity, reprogramming of systemic metabolic disturbances, and inhibition of inflammation via Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB), Janus kinase (JAK)/ signal transducer and activator of transcription (STAT), and Phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) pathways. Furthermore, a comprehensive translational roadmap has been proposed, grounded in a critical appraisal of current trial limitations. Overall, this review consolidates evidence for the protective effects of natural products against HUA and related comorbidities, with an emphasis on GM-derived metabolites, aiming to expand clinical applications and provide insights for future studies. Full article

Background/Objectives: Dietary patterns characterized by excess saturated fat intake contribute to obesity, type 2 diabetes, and cardiac metabolic dysfunction. Ceramides, bioactive sphingolipids synthesized in response to nutrient overload, have emerged as key molecular mediators linking dietary lipid composition to alterations in cardiac metabolic signaling. This review aims to integrate current evidence on diet-induced ceramide remodeling and its impact on intracellular pathways regulating cardiac metabolism. Methods: We analyzed experimental and clinical studies investigating the effects of high-fat and Western-type diets on myocardial ceramide synthesis, lipidomic remodeling, and downstream signaling pathways. Evidence from animal models, genetic and pharmacological interventions, nutritional studies, and circulating biomarker analyses was examined to delineate mechanistic and translational insights. Results: Saturated fatty acid excess, particularly palmitate, activates the de novo ceramide synthesis pathway in the myocardium, promoting accumulation of specific ceramide species. This remodeling impairs insulin signaling through Akt inhibition, protein phosphatase 2A activation, and PKCζ-dependent mechanisms, contributing to cardiac metabolic inflexibility. Ceramides further disrupt mitochondrial function by altering electron transport chain activity, increasing reactive oxygen species production, and modulating mitophagy and apoptotic signaling. Lipidomic studies highlight species-specific effects, with C16-ceramides frequently associated with adverse metabolic and cardiovascular outcomes, whereas very-long-chain ceramides may exert distinct functional roles. Circulating ceramide profiles have also been linked to diet-associated cardiovascular risk. Conclusions: Diet-induced ceramide remodeling represents a central molecular axis connecting dietary lipid excess to altered cardiac metabolic signaling. Targeting sphingolipid metabolism through nutritional or pharmacological strategies may offer novel opportunities for preventing and managing diet-associated cardiac dysfunction. Full article