Search Results (506)

While metabolomics has emerged as a powerful tool for discovering disease biomarkers, the clinical utility of plasma or tissue metabolite profiles remains limited due to metabolic heterogeneity and flexibility across cell types. Traditional bulk metabolomics fails to capture the distinct metabolic programs operating within rare cell populations that often drive disease pathogenesis. This review examines cutting-edge approaches that overcome these limitations by characterizing metabolism at single-cell and cell-type-specific resolution, with particular emphasis on rare immune cell populations as a proof of concept. We discuss how the integration of flow cytometric metabolic profiling, molecular techniques, advanced metabolomics platforms, and computational modeling enables unprecedented insight into cell-intrinsic metabolic states within physiological contexts. We critically evaluate how these technologies reveal metabolic plasticity that confounds bulk measurements while identifying cell-type-specific metabolic vulnerabilities. Finally, we address the crucial challenge of establishing causality in metabolic pathways, a prerequisite for translating metabolomic discoveries into clinically actionable interventions. By moving beyond descriptive metabolomics toward a mechanistic understanding of cell-type-specific metabolism, these approaches promise to deliver the precision required for effective metabolic targeting in disease. Full article

Breast cancer (BC) is a heterogeneous disease with distinct molecular subtypes that exhibit variable immune responses and metabolic profiles. Recent studies have suggested that immunometabolic pathways play a role in tumor progression and treatment resistance. This study investigates the expression patterns of ALKBH7 and NLRP3 across BC molecular subtypes and explores their relationships with clinicopathological parameters and potential immunometabolic profiles. A total of 118 BC patients were classified into HER2+, TNBC, Luminal A, and Luminal B subtypes. Gene expression levels of ALKBH7 and NLRP3 were analyzed using quantitative real-time PCR (qRT-PCR), and correlations with clinical markers were assessed. ALKBH7 and NLRP3 expression levels varied significantly between subtypes, with the highest expression observed in HER2+ tumors. Strong positive correlations were found between ALKBH7 and NLRP3 in all subtypes, particularly in HER2+ (r = 0.812, p < 0.001). Additionally, NLRP3 correlated with Ki-67 in Luminal B tumors, indicating a link between inflammation and proliferative capacity. These findings suggest that ALKBH7 may function as a dual-role biomarker involved in metabolic adaptation and immune signaling in BC. The strong co-expression of ALKBH7 and NLRP3 suggests a functional association between these molecules that may be critical in shaping the tumor microenvironment. This co-expression set, particularly in aggressive subtypes (HER2+ and TNBC), warrants further mechanistic validation as a potential prognostic marker and a novel therapeutic vulnerability. Full article

Background: Diabetic nephropathy (DN) accelerates renal aging through chronic inflammation and metabolic dysregulation; however, the role of metformin in this process remains incompletely understood. This study investigated whether metformin attenuates diabetes-driven renal senescence through the modulation of the fatty acid-binding protein 4 (FABP4)/forkhead box protein O1 (FOXO1) axis and key immunometabolic enzymes. Methods: Thirty-two male Wistar rats were divided into healthy and diabetic groups and treated with either saline or metformin (200 mg/kg) for 10 weeks. Type 2 diabetes was induced by multiple low doses of streptozotocin (30 mg/kg, intraperitoneally) and high-fat diet. Renal function indices, lipid profile, inflammatory cytokines, succinate dehydrogenase (SDH), ATP-citrate lyase (ACLY), and senescence markers were measured, while FABP4 and FOXO1 expression, macrophage infiltration, and kidney histology were assessed using immunoassays and microscopy. Results: Metformin considerably reduced serum creatinine, urea, and blood urea nitrogen; normalized the lipid profile; suppressed interleukin (IL)-6 and tumor necrosis factor-α; and increased IL-10 levels. Additionally, it reversed DN-associated alterations in SDH and ACLY; downregulated FABP4, FOXO1, and P16^INK4a; decreased macrophage infiltration; promoted M2 polarization; and improved renal architecture. Conclusions: This study is the first to demonstrate that metformin mitigates diabetic renal senescence by simultaneously targeting the FABP4/FOXO1 axis and immunometabolic enzymes SDH and ACLY. These findings highlight the translational significance of metformin as a prototype for immunometabolic and immunosenescence-directed therapies in DN. Full article

Bacterial metabolites play a dual role in hepatocellular carcinoma (HCC), exhibiting both tumor-promoting and tumor-suppressing activities dictated by their structural diversity. This review synthesizes recent advances in understanding how key microbial metabolites—such as bile acids, short-chain fatty acids, and polyamines—remodel the tumor immune microenvironment through mechanisms including immunometabolic reprogramming, epigenetic modification, and regulation of signaling pathways (e.g., FXR, TLR, and mTOR). We highlight their roles in modulating the function of T cells, NK cells, and tumor-associated macrophages and discuss emerging strategies that target these metabolites—including probiotic interventions, fecal microbiota transplantation, and metabolite-based adjuvants—to enhance immunotherapy efficacy and overcome resistance. By integrating mechanistic insight into translational potential, this work outlines a metabolite–immunometabolism–hepatocarcinogenesis framework and proposes novel combinatorial approaches for HCC treatment. Full article

Ferroptosis is a novel iron-sensitive subtype of regulated cell death (RCD), persisting under extreme lipid peroxidation and iron/redox imbalances. Unlike apoptosis, necroptosis, and pyroptosis, ferroptosis is a signaling-driven process mediated through iron metabolism imbalance, polyunsaturated fatty acid (PUFA) exceeding oxidation, and defects in its protective systems like Xc-/GSH/GPx4. Specifically, this review establishes that iron-driven ferroptosis is a central underlying pathomechanistic factor in a broad range of human diseases. Significantly, whether its modulation is therapeutic, it is entirely conditional on the specific disease context. Thus, its induction can provide a promising antidote for destructive cancer cells when conjoined with immuno-therapies to boost anticancer immunity. Conversely, iron-mediated ferroptosis suppression is a key factor in countering destructive changes in a whole range of degenerative and acute injuries. Current therapeutic approaches include iron chelators, lipid oxidation inhibitors, GPx4 activators, natural and active compounds, and novel drug delivery systems. However, against all odds and despite its intense therapeutic promise, its translation into a practical medicinal strategy faces many difficulties. Thus, a therapeutic agent specifically focused on its modulation is still lacking. The availability of selective biologic markers is a concern. The challenges in the direct pathologic identification of ferroptosis in a complex in vivo systemic scenario remain. Current avenues for its future development are pathogen infections, the discovery of novel regulating factors, and novel approaches to personalized medicine centered on its organ-level in vivo signatures. Full article

Major depressive disorder arises from complex interactions between genetic variation, environmental influences, and receptor-mediated signaling that regulate mood, cognition, and stress resilience. This review synthesizes recent empirical evidence examining how genetic and epigenetic variation intersect with receptor function, binding, and expression to shape depressive phenotypes and treatment outcomes. Findings are organized into ten interconnected biochemical domains: monoaminergic, glutamatergic, GABAergic, neuropeptidergic, hormonal-metabolic, immuno-inflammatory, neurotrophic-plasticity, epigenetic/gene–environment, opioidergic and emerging therapeutics, with summary tables included for most domains to aid cross-system interpretation. Across these pathways, convergent receptor–gene relationships highlight integrative themes such as multi-omics approaches, in vivo receptor imaging, single-cell resolution mapping, and circuit-level analyses. Collectively, these findings position receptor systems as central hubs linking genetic risk and environmental modulation, providing a translational framework for receptor-centric, precision-psychiatry interventions. Full article

Depression and obesity are amongst the most serious global health challenges. Each of them is associated with high morbidity, chronicity, and socioeconomic burden. Increasing evidence suggests that these conditions are not merely comorbid but share convergent biological pathways (e.g., hypothalamic–pituitary–adrenal axis dysregulation, chronic inflammation, gut dysbiosis, and mitochondrial dysfunction). All these components contribute together to the development and persistence of depressive symptoms as well as to an increase in adiposity. Within this framework, adipose tissue has emerged as an essential endocrine organ that has a deep impact on neuroimmune signalling and mood regulation through its secreted molecules, such as leptin, adiponectin, resistin, omentin, apelin, chemerin, and visfatin. The current management of depression involves a comprehensive, multidisciplinary approach that includes pharmacological treatment and psychotherapeutic support, alongside lifestyle changes. Here we highlight the molecular crosstalk between adipose tissue and the brain, summarising the evidence of adipokines’ dysregulation role in connecting metabolic dysfunction to depressive neurobiology. By integrating metabolic, immunological, and neuroendocrine perspectives, this narrative review underscores the need to reconceptualise depression as an immunometabolic disorder. Understanding adipokine-mediated pathways may reveal new biomarkers and therapeutic targets, fostering interdisciplinary approaches. This would allow for the development of new treatment strategies, which include recombinant adipokines, anti-inflammatory agents, and microbial modulation. These new strategies might provide a significant benefit in selected patients, in addition to conventional antidepressants. Full article

Semaphorin3A (Sema3A) is a regulatory protein found to be expressed on regulatory T and B cells and also secreted into peripheral blood. It has been identified as a potent immune regulator; however, not all its regulatory mechanisms have been evaluated. In this respect, we aim to investigate how Sema3A affects key metabolic pathways in T cells during homeostasis and rheumatoid arthritis (RA), and on the AKT/mTORC1 signaling axis. In this study, peripheral blood samples were collected from 119 healthy donors and 32 rheumatoid arthritis patients. T cells were subjected to Seahorse analysis to evaluate OXPHOS and glycolysis, live cell TMRE staining to evaluate mitochondrial activity, mass spectrometry for metabolite profiling, ATP determination to study ATP production, and Western blot analysis to investigate the signaling pathway activity. This study presents evidence showing that Sema3A inhibits the AKT/mTORC1 pathway, leading to a decreased glucose uptake and glycolysis disruption. Furthermore, we show that Sema3A reduces mitochondrial capacity and OXPHOS in activated T cells of healthy and RA donors, leading to a decreased ATP production. In contrast, Sema3A upregulates fatty acid oxidation (FA), probably as a backup pathway to ensure cell survival. Results with p values of <0.05 were considered significant. Our data may point to Sema3A’s ability to convert activated T cells’ metabolic profile back to its non-activated state. This may suggest that Sema3A might be a beneficial treatment for immune-mediated diseases by metabolically reprogramming activated T cells. Full article

Background/objectives: Sjögren’s disease (SjD) is an autoimmune disorder characterized by lymphocytic infiltration and inflammation leading to exocrine gland dysfunction. Th17 cells play a central role in autoimmune pathology and are defined by markers such as IL-23R, CCR6, and IL-17. However, the combined characterization of these markers and their relevance in SjD remain poorly understood. Methods: Forty-one participants were enrolled, including twenty-two patients with SjD and nineteen control subjects (CS). Peripheral blood immunophenotyping was performed using multicolor flow cytometry, and serum cytokine concentrations were quantified within a multiplex assay. Non-parametric analyses were conducted using the Mann–Whitney U test and Spearman’s rank correlation. Results: Compared with CS, patients with SjD exhibited higher frequencies of CD3⁺CD4⁺IL-23R⁺ T cells and elevated IL-23 levels. The proportion of CCR6⁺IL-23R⁺ T helper cells tended to be higher in SjD than in controls, although this difference did not reach statistical significance (8.8% vs. 5.3%, p = 0.056). Within clinical subgroups, anti-Ro-negative patients showed increased frequencies of CD3⁺CD4⁺IL-23R⁺ cells. Patients with hypertriglyceridemia displayed reduced frequencies of CCR6⁺IL-23R⁺IFN-γ⁺ cells, whereas normal HDL levels were associated with CCR6 expression and IL-17A production. Conclusions: These findings highlight the heterogeneity of Th17 cells in Sjögren’s disease and reinforce the involvement of the IL-23/IL-23R axis in disease pathogenesis. Exploratory associations between Th17 subsets and lipid parameters suggest a potential immunometabolic interplay that warrants further investigation. Together, these data provide a more comprehensive view of Th17 dynamics in SjD and establish a foundation for future mechanistic studies in larger cohorts and tissue-specific contexts. Full article

Background: Epicardial adipose tissue (EAT) is a visceral fat depot surrounding the myocardium. It contributes to coronary artery disease (CAD) through local inflammation, while its metabolic activity, including the expression of uncoupling protein-1 (UCP-1) and incretin receptors (GLP-1R, GIPR), may exert protective effects. The relationship between EAT immunohistochemical features and imaging-derived volume remains unclear. Methods: We prospectively studied 50 patients undergoing cardiac surgery: 25 with CAD undergoing coronary artery bypass grafting and 25 without CAD undergoing valve replacement. EAT samples were immunohistochemically stained for CD3, CD68, MPO, UCP-1, GLP-1R, and GIPR. Preoperative CT was used to quantify EAT volume. Results: Patients with CAD more frequently had higher CD3 immunopositivity compared to the control group (84.0 vs. 58.3%, p = 0.047), with no difference in MPO and CD68 immunoexpression. UCP-1 expression was elevated in CAD patients (p = 0.004), whereas GLP-1R and GIPR immunopositivity were similar. EAT volume did not differ between CAD and non-CAD patients (102.87 cm³ vs. 99.38 cm³, p = 0.964) but correlated modestly with BMI (r_s = 0.325, p = 0.021). UCP-1 and GLP-1R immunopositivity, as well as larger LVEDD (left ventricular end-diastolic diameter), were positively associated with greater EAT volume. Conclusions: EAT in CAD exhibits increased T-cell infiltration and elevated UCP-1 expression, indicating an inflammatory yet metabolically active profile. Larger EAT volume was associated with UCP-1 and GLP-1R expression, underscoring the immunometabolic role of EAT in CAD. Full article

Viruses account for the most abundant biological entities in the biosphere and can be either symbiotic or pathogenic. While pathogenic viruses have developed strategies to evade immunity, the host immune system has evolved overlapping and redundant defenses to sense and fight viral infections. Nutrition and metabolic needs sculpt viral–host interactions and determine the course and outcomes of the infection. In this review, we focus on the hexosamine biosynthesis pathway (HBP), a nutrient-sensing pathway that controls immune responses and host–viral interactions. The HBP converges on O-GlcNAcylation, a dynamic post-translational modification of cellular proteins, that emerged as a critical effector of immune cell development, differentiation, and effector functions. We present a broad overview of uncovered O-GlcNAc substrates identified in the context of viral infections and with a functional impact on antiviral immunity and viral restriction, or conversely on exacerbating viral-induced pathologic inflammation or viral oncogenesis. We discuss the clinical implications of these findings, current limitations, and future perspectives to harness this pathway for therapeutic purposes. Full article

Atopic dermatitis (AD) is a multifactorial skin disorder characterized by immune and barrier dysfunction. The gut–skin axis is a bidirectional pathway through which gut and skin influence each other via microbial metabolites. Bioactive metabolites produced by microbial transformation of phytochemicals show potential for AD prevention. This study developed a computational systems biology pipeline that prioritized gut-derived metabolites from Philippine medicinal plants by integrating metabolite prediction, pharmacokinetics, network analysis, and molecular simulations. From 2231 predicted metabolites, 31 satisfied pharmacological criteria and were mapped to 199 AD-associated targets, with ALB, CASP3, and PPARG identified as hub genes. Two metabolites, THPOC and PM38, exhibited complementary target affinities and strong binding stability. THPOC stabilized ALB and CASP3, supporting barrier integrity and apoptosis regulation, while PM38 strongly engaged PPARG, modulating lipid metabolism and anti-inflammatory transcription. They exhibited comparable or superior docking scores, stable MD interactions, and favorable binding free energies, compared to abrocitinib, an approved AD treatment. DFT analysis confirmed electronic stability and donor–acceptor properties linked to target selectivity. These findings highlight THPOC and PM38 as promising immunometabolic modulators acting on key AD-related pathways. Collectively, this study introduces a reproducible systems-based computational discovery framework, offering a novel preventive strategy for AD. Full article

Background/Objectives: The association between plasma metabolites derived from dietary substrates and inflammatory processes remains underexplored, despite its potential relevance in the prevention of non-communicable diseases. This systematic review aimed to examine the relationship between blood metabolites and the modulation of inflammatory biomarkers. Methods: A total of 25 randomized controlled trials, published between 2019 and 2024, were included from an initial pool of 111 records. These studies investigated the effects of dietary patterns, specific food groups, or nutritional supplements on the human metabolome and their potential links to inflammation. Results: Metabolomic analyses were predominantly performed using mass spectrometry (MS)-based platforms (17 out of 25), with liquid chromatography–mass spectrometry as the most frequently employed method. Both targeted (n = 14) and untargeted (n = 11) approaches were represented, and samples were drawn from plasma, urine, and feces. Across the interventions, 64 metabolites were modulated, including fatty acyls, glycerolipids, benzenoids, and organic acids, reflecting potential changes in pathways related to oxidative stress, lipid and carbohydrate metabolism, and inflammatory signaling. Several studies also assessed classical inflammatory biomarkers such as C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Interventions involving healthy traditional dietary patterns, improvements in dietary fat quality, or the use of specific probiotic strains were often associated with favorable immunometabolic outcomes. In contrast, some interventions, such as Mohana Choorna, elicited upregulation of immune-related gene expression in adipose tissue without improvements in glucose or lipid metabolism. Conclusions: While metabolomic responses varied across studies, the evidence highlights the value of dietary interventions in modulating systemic metabolism and inflammation. These findings support the integration of metabolomics into clinical nutrition to define more personalized and effective dietary strategies for inflammation-related chronic disease prevention. Full article

Obesity is redefined as a complex systemic disease, transcending mere caloric imbalance, driven by intricate dysregulation across metabolic, neuroendocrine, immunological, and epigenetic axes. Central to its pathology is adipose tissue, which is considered a dynamic endocrine and immune organ. Its dysfunctional expansion fuels chronic, low-grade systemic inflammation, termed “metaflammation”, characterised by pathways such as NF-kB and NLRP3 inflammasome activation, as well as pervasive immune cell infiltration. This inflammatory state could profoundly impair insulin signalling and contribute to major complications, including insulin resistance, type 2 diabetes, and cardiovascular disease. Further exacerbating this systemic dysfunction is gut microbiota dysbiosis, which promotes metabolic endotoxemia and neuroendocrine dysregulation, impacting hypothalamic function, central hormone resistance, and reproductive health. Epigenetic modifications also serve as crucial mediators, translating environmental exposures into altered gene expression that perpetuates susceptibility across generations. This review summarises the current understanding of obesity by integrating molecular, neuroendocrine, and immunometabolic underpinnings, reinterpreting it as a comprehensive expression of systemic dysfunction. Through this integrated perspective our hope is to highlight the necessity of a paradigm shift towards personalised, multi-targeted interventions that extend beyond conventional weight management. An integrative, translational approach modulating the immunometabolic network, microbiota, and epigenetics is essential to effectively address the global obesity epidemic and its far-reaching health implications. Full article

Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. In recent years, mortality rates have declined due to antismoking policies, earlier detection, and the advent of targeted therapies and immunotherapy, particularly for non-small cell lung cancer (NSCLC), which accounts for 85% of all cases. With improved survival, however, LC patients are increasingly exposed to competing causes of mortality, among which cardiovascular disease (CVD) is highly prevalent, affecting 30–50% of patients and contributing to nearly 30% of deaths. This burden reflects both shared risk factors and the cardiotoxic potential of radiotherapy, chemotherapy, and immunotherapy. Beyond acute adverse cardiovascular events during treatment, real-world data indicate that immune checkpoint inhibitors (ICIs) may also exert chronic cardiovascular effects, significantly accelerating the atherosclerotic process in multimorbid patients. These findings underscore the importance of accurate baseline assessment and aggressive management of cardiovascular risk factors in LC patients—particularly in the adjuvant and neoadjuvant settings, where longer survival is anticipated. Moreover, long-term monitoring should be implemented through a tailored, multiparametric strategy that integrates novel biomarkers and advanced artificial intelligence–assisted imaging techniques. Achieving this ambitious goal requires the close collaboration of a multidisciplinary team, with cardiologists playing a pivotal role. This review will address the complexity of LC patients, focusing on the interplay of cardio-immuno-metabolic factors, summarizing the cardiovascular impact of immunotherapy across metastatic, locally advanced, and perioperative settings, and outlining practical strategies for the management of these vulnerable patients. Full article