Search Results (176)

Anaplastic thyroid carcinoma (ATC) represents the most aggressive thyroid malignancy, characterized by rapid progression, therapeutic resistance, and poor prognosis. Conventional treatments remain largely ineffective, highlighting the need for novel therapies. Metabolic reprogramming, particularly the Warburg effect (WE), has emerged as a promising area of investigation. This review synthesizes current evidence on the role of WE in ATC and PDTC, integrating data from molecular profiling, preclinical studies, and emerging therapeutic strategies. Oncogenic alterations frequently observed in ATC, including mutations in BRAF, RAS, TP53, and activation of PI3K/AKT/mTOR and HIF-1α signaling, converge to promote glycolytic reprogramming. This metabolic shift supports tumor proliferation, immune evasion, and metastasis through increased glucose uptake, lactate production, and microenvironmental remodeling. Key metabolic nodes, including glucose transporters, hexokinase, and monocarboxylate transporters, are regarded as promising targets. Preclinical studies suggest that pharmacological inhibition of these pathways reduces tumor growth, enhances radiosensitivity, and improves response to targeted therapies. Future efforts should focus on combination therapies, biomarker-driven patient stratification, and the development of targeted delivery systems to overcome toxicity and resistance. A deeper understanding of tumor metabolic heterogeneity will be essential for translating these approaches into clinical practice. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global metabolic disorder. As a non-pharmacological intervention, the effects of high-intensity interval training (HIIT) on MASLD and its molecular mechanisms remain poorly understood. This study aimed to investigate whether HIIT could ameliorate high-fat diet (HFD)-induced liver fibrosis by recalibrating the intrahepatic lactate metabolic axis. Methods: An HFD-induced murine MASLD model combined with HIIT intervention was utilized to evaluate the therapeutic efficacy and underlying mechanisms. Hepatosomatic indices, histological architecture and fibrosis severity were examined. Lactate concentrations within the systemic circulation and hepatic parenchyma, alongside comprehensive lipid profiles, were measured. The expressions of genes and proteins involved in hepatic lactate metabolism were delineated via qPCR and Western blotting. Results: The 8-week HIIT intervention effectively improved liver lipid accumulation, hepatocellular injury, and oxidative stress caused by a high-fat diet. Fibrotic expansion and suppressed hepatic stellate cell activation were restricted markedly, as evidenced by the downregulation of collagen type I alpha 1 chain and alpha-smooth muscle actin(α-SMA). HIIT reversed the HFD-induced accumulation of lactate in both systemic circulation and liver tissues, which was found to positively correlate with hepatic α-SMA. Mechanistically, HIIT regulated the expression of the lactate metabolism-related proteins lactate dehydrogenase A and monocarboxylate transporter 1, while selectively enhancing the expression of the gluconeogenic enzymes. Conclusions: Our findings indicate that HIIT effectively ameliorated MASLD and associated hepatic fibrosis by remodeling the hepatic lactate metabolic axis, specifically through the suppression of lactate production and the enhancement of its clearance. These results indicate that targeting lactate homeostasis might be a promising therapeutic strategy for MASLD. Full article

High lactate concentration is a hallmark of the tumor microenvironment (TME). Regulatory T cells (Tregs) exhibit unique metabolic adaptability to this lactate-rich environment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that the monocarboxylate transporter MCT4 is upregulated in tumor-infiltrating Tregs and mediates direct lactate uptake. Using Treg-specific conditional knockout (cKO) mice, we show that MCT4 deficiency does not affect basal Treg development but abrogates lactate-induced Foxp3 stabilization and impairs Treg suppressive function. Mechanistically, MCT4-mediated lactate uptake promotes the lactylation of Foxp3 at lysine 277 (K277), which competitively inhibits its ubiquitination, thereby enhancing Foxp3 protein stability and nuclear localization. Nuclear Foxp3 subsequently interacts with IRF3 to promote IL-10 transcription and secretion. In the B16 melanoma model, MCT4-deficient Tregs display compromised stability and reduced tumor infiltration, leading to enhanced CD8⁺ T cell effector function and attenuated tumor growth. Collectively, our findings reveal that MCT4-mediated lactate uptake sustains Treg stability and function through Foxp3 lactylation, identifying MCT4 as a potential therapeutic target for modulating Treg activity in cancer. Full article

Drought is one of the main stress factors significantly affecting the growth, development and yield of agricultural crops. This study investigated the impact of drought stress on the grapevine. The 30 cultivars were classified as drought-tolerant, intermediately tolerant or sensitive. The phenotypic characteristics the number of new leaves, the number of second-order roots and the length of second-order roots (NL, NR2 and LR2 respectively) were identified as the most sensitive biometric characteristics. These parameters can be used to determine the optimal level of stress exposure for plants. Using transcriptomic data from five cultivars with different levels of tolerance, differentially expressed genes (DEGs) were identified in control plants and in plants under stress, as well as DEGs between different varieties when exposed to 2% mannitol. General patterns of gene expression under drought stress were subsequently identified, including the activation of antioxidant defense systems and changes in the metabolism and biosynthesis of glucan, cellulose, polysaccharides, monocarboxylic acids, fatty acids and metal transport and splicing processes. It is hypothesized that drought tolerance is determined by the increased expression of genes associated with glutathione metabolism and methylation processes. Full article

Background: The monocarboxylate transporter 1 (MCT1) plays a central role in myocardial lactate handling and metabolic adaptation. The functional rs1049434 polymorphism (T1470A; Asp490Glu) affects MCT1-mediated lactate transport and substrate utilization, but its clinical relevance in sarcomere-related hypertrophic cardiomyopathy (HCM) remains poorly defined. Methods: We studied 56 carriers of pathogenic or likely pathogenic sarcomeric variants examined in a familial HCM program. All participants underwent standardized clinical phenotyping, including electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging. Genotyping of MCT1 rs1049434 was performed on genomic DNA. Analyses focused on sex-stratified genotype distribution, phenotypic expression among the 26 individuals who fulfilled diagnostic criteria for HCM, and the influence of habitual vigorous exercise. Septal wall thickness was the primary structural endpoint. Results: Among the 26 patients with established HCM (10 women, 16 men), a marked sex-specific effect emerged. Female carriers of the T-allele (TT/TA) exhibited significantly greater interventricular septal thickness compared with AA homozygotes (23.2 vs. 14.2 mm; p = 0.037). In men, septal thickness did not differ by genotype. However, male patients engaged in vigorous physical activity showed a consistently milder structural phenotype, including lower septal thickness (18.3 vs. 19.9 mm; p = 0.585) and directionally favorable markers of mechanical severity. Phenotypic distribution was predominantly asymmetric septal hypertrophy in both sexes, without genotype-dependent differences. Conclusions: The phenotypic impact of MCT1 rs1049434 in sarcomere-positive HCM is context-dependent. In women, impaired monocarboxylate handling is associated with greater hypertrophic remodeling, whereas in men, exercise-related metabolic conditioning appears to attenuate disease severity. These findings support a genotype–sex–environment interaction relevant to precision medicine approaches in HCM. Full article

Transmembrane facilitation of substrates by channels and secondary active transporters results in a defined steady-state concentration ratio across the membrane. Evidence is accumulating that asymmetry in the structural build of the transporters, or interaction with asymmetric partner proteins, can shift the position of the transmembrane equilibrium by biased transport directionality. For instance, the bacterial lactose transporter, LacY, and two amino acid transporters, i.e., the human excitatory amino acid carrier, EAAC1, and the yeast lysine permease, Lyp1, were reported to exhibit distinct transport kinetics in the inward and outward direction by protein-intrinsic properties. A recent example is transport modulation of human monocarboxylate transporters, MCT, by shedding of the extracellular domain of an ancillary protein, basigin. Loss of the domain selectively increases export of lactate from lung cancer cells by a factor of four, contributing to the Warburg effect and malignancy. Further, intrinsic properties of monocarboxylate transporters involving asymmetric affinities of substrate binding, or biased open probabilities were shown to generate preference for one transport direction. Here, we discuss molecular mechanisms and physiological contexts of asymmetric secondary active transmembrane transport. Focus is laid on experimentally established cases, and examples are given in which putative bias in transport directionality may have been overlooked. Full article

Beneficial effects of the microbiota-derived metabolite butyrate at the colonic level are well established, particularly through its relevance in colorectal cancer (CRC) and inflammatory bowel disease (IBD), two major intestinal pathologies. Therefore, the mechanisms involved in butyrate transport across colonic epithelial cell membranes (uptake transporters: monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter 1 (SMCT1); efflux transporters: breast cancer resistance protein (BCRP) and MCT1/monocarboxylate transporter 4 (MCT4)), which are determinant for its intracellular levels, are of primary importance for its beneficial effects at the colonic level. The available data suggest that all these butyrate transporters can be modulated by redox and inflammatory status, but the evidence is scarce and rather inconsistent. Nevertheless, a role of nuclear factor erythroid 2-related factor 2 (Nrf2) and of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in mediating the effect of oxidative stress and inflammation, respectively, on MCT1 and SMCT1 is suggested. So, more investigation on this subject is needed, given the fact that increased oxidative stress levels and inflammatory status are present in a series of intestinal conditions and pathologies, including CRC and IBD, which could help to establish these transporters as potential cellular targets in these diseases. Full article

Lactate, as a pivotal metabolite generated by the body, has attracted considerable attention in numerous biological disciplines in recent years. In addition to its role in supplying energy, lactate also functions as a signaling molecule, with the capacity to mediate a diverse array of physiological effects. Within the central nervous system, lactate is involved in the regulation of critical physiological processes, including neurogenesis, synaptic plasticity, mitochondrial biogenesis, neuroinflammation, and cerebral angiogenesis. Furthermore, lactate has been implicated in the pathogenesis of several central nervous system diseases, such as Alzheimer’s disease, stroke, and spinal cord injury, among others. Physical exercise is recognized as a significant neuroprotective strategy; however, further research is required to elucidate the underlying biological mechanisms. In essence, the role of lactate as a metabolic-epigenetic core is gradually becoming a subject of increasing academic interest. The regulatory function of lactate is thought to involve its production (via lactate dehydrogenase), shuttle (via monocarboxylate transporters), sensing (via G protein-coupled receptor 81), and lactylation modifications, among others. This review synthesizes current evidence to elucidate the multifaceted roles of lactate in central nervous system physiology and pathology under exercise regulation, with a view to bridging the gap between molecular mechanisms and therapeutic potential, thereby paving the way for novel strategies in central nervous system disease intervention. Full article

Bladder cancer (BC), particularly muscle-invasive urothelial bladder carcinoma (UBC), remains a clinical challenge due to frequent recurrence, chemoresistance, and limited treatment options. This study investigates the functional and mechanistic insights of 3-hydroxybutyrate (3-OBA), a ketone body with known metabolic and epigenetic roles, in muscle-invasive UBC models. 3-OBA significantly inhibited cell viability, proliferation, migration, and invasion in T24 and HT1376 cell lines in a dose-dependent manner. In vivo, 3-OBA impaired tumor growth and angiogenesis in the chick chorioallantoic membrane model. Mechanistically, 3-OBA did not alter the expression of the G-protein-coupled lactate receptor GPR81 or associated markers (phospho-ERK1/2, LDHA, MCT1/4, CD147), indicating its antitumor effects are GPR81-independent. Moreover, extracellular lactate modulation upon 3-OBA treatment varied between cell lines, with HT1376 cells showing reduced lactate production under nutrient deprivation, suggesting cell-specific metabolic responses to 3-OBA. These findings highlight 3-OBA’s potential as a metabolic modulator with antitumor efficacy in UBC, particularly in metabolically constrained tumors. However, its dual role—as both a potential energy source and therapeutic agent—demands context-specific investigation. Future studies should focus on patient stratification and preclinical validation to clarify 3-OBA’s therapeutic window and mechanism of action in bladder cancer. Full article

Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with high CAIX expression exhibited significantly reduced median survival (p < 0.001). Moreover, CAIX correlated with HIF-1α, PD-L1, and immunosuppressant molecules, linking hypoxia-driven metabolic alterations with immune dysfunction. Here, we evaluated the capacity of 4-methylumbelliferone (4Mu) to counteract these effects and enhance antitumor immunity. In vitro, hypoxia increased CAIX and monocarboxylate transporter -4 (MCT4) expression in lung carcinoma cells, elevated lactate release, and reduced extracellular pH while promoting an M2-like macrophage profile and impairing antigen-specific splenocyte proliferation (p < 0.01). Treatment with 4Mu downregulated CAIX expression, restored extracellular pH, decreased lactate secretion, and rescued lymphocyte proliferation (p < 0.01). In vivo, 4Mu reduced CAIX expression, shifted macrophage polarization toward a pro-inflammatory phenotype, and enhanced CD8+ T cell infiltration. 4Mu was safe and well tolerated, and notably, combined with anti-PD-1 therapy, it synergistically inhibited tumor growth and increased both CD4+ and CD8+ T cell infiltration. These findings support 4Mu as a metabolic modulator capable of mitigating CAIX-driven acidosis and improving the efficacy of immunotherapy in lung cancer. Full article

Osteoarthritis (OA) lacks disease-modifying therapies, in part because key features of the joint microenvironment remain underappreciated. One such feature is localized acidosis, characterized by sustained reductions in extracellular pH within the cartilage, meniscus, and the osteochondral interface despite near-neutral bulk synovial fluid. We synthesize current evidence on the origins, sensing, and consequences of joint acidosis in OA. Metabolic drivers include hypoxia-biased glycolysis in avascular cartilage, cytokine-driven reprogramming in the synovium, and limits in proton/lactate extrusion (e.g., monocarboxylate transporters (MCTs)), with additional contributions from fixed-charge matrix chemistry and osteoclast-mediated acidification at the osteochondral junction. Acidic niches shift proteolysis toward cathepsins, suppress anabolic control, and trigger chondrocyte stress responses (calcium overload, autophagy, senescence, apoptosis). In the nociceptive axis, protons engage ASIC3 and sensitize TRPV1, linking acidity to pain. Joint cells detect pH through two complementary sensor classes: proton-sensing GPCRs (GPR4, GPR65/TDAG8, GPR68/OGR1, GPR132/G2A), which couple to G_s, G_q/11, and G_12/13 pathways converging on MAPK, NF-κB, CREB, and RhoA/ROCK; and proton-gated ion channels (ASIC1a/3, TRPV1), which convert acidity into electrical and Ca²⁺ signals. Therapeutic implications include inhibition of acid-enabled proteases (e.g., cathepsin K), pharmacologic modulation of pH-sensing receptors (with emerging interest in GPR68 and GPR4), ASIC/TRPV1-targeted analgesia, metabolic control of lactate generation, and pH-responsive intra-articular delivery systems. We outline research priorities for pH-aware clinical phenotyping and imaging, cell-type-resolved signaling maps, and targeted interventions in ‘acidotic OA’ endotypes. Framing acidosis as an actionable component of OA pathogenesis provides a coherent basis for mechanism-anchored, locality-specific disease modification. Full article

Background/Objectives: Lactate (LA) is a key metabolite in exercise metabolism, transported across cell membranes by monocarboxylate transporters (MCTs). Although genetic variation in MCT genes has been linked to LA kinetics, evidence in athletic populations remains limited. This study investigated nine MCT1 polymorphisms (rs4301628, rs12028967, rs10857983, rs3789592, rs10776763, rs1049434, rs6537765, rs7556664, rs7169) in relation to LA metabolism. Methods: 337 Polish and Czech males (elite athletes, sub-elite competitors, physically active controls) performed two maximal Wingate tests. Buccal swabs were collected for DNA extraction and single nucleotide polymorphism (SNP) genotyping. LA was assessed before and after the tests. Results: Five variants (rs3789592, rs7556664, rs7169, rs1049434, rs6537765) remained significantly associated with LA measured 30 min after the second Wingate (LA30′) and delta clearance capacity (DCC) in elites (codominant and recessive models: p = 0.01–0.03; false discovery rate (FDR)-adjusted p = 0.02–0.04). Rs10776763 showed the broadest associations, surviving FDR for LA30′ in all models (p = 0.003–0.03; FDR-adjusted p = 0.01–0.03) and for LA accumulation capacity (ACC) in the recessive model (p = 0.01; FDR-adjusted p = 0.03). Rs12028967 also supported a clearance role, with LA30′ significant in elites (p = 0.004; FDR-adjusted p = 0.01) and DCC in the overall cohort (p = 0.02; FDR-adjusted p = 0.03). In contrast, rs4301628 and rs10857983 demonstrated isolated LA30′ effects in elites (p = 0.004–0.01; FDR-adjusted p = 0.01), and no production-phase endpoint other than rs10776763 survived FDR; ACC remained significant in the recessive model (p = 0.01; FDR-adjusted p = 0.03). Conclusions: The results suggest that MCT1 polymorphisms contribute to differences in LA metabolism and warrant replication in larger, more diverse cohorts. Full article

Growing evidence links processed red meat consumption to increased diabetes risk, with oxidized proteins and/or amino acids proposed as potential mediators. We investigated whether dityrosine (Dityr), a key oxidation biomarker in high-oxidative pork (HOP) and structural analog of thyroid hormone T3, mediates HOP-induced glucose dysregulation via thyroid hormone (TH) signaling disruption. C57BL/6J mice were fed control, low-oxidative pork (LOP), HOP, LOP + Dityr, or Dityr diets for 12 weeks. HOP and Dityr impaired glucose tolerance and induced hyperglycemia and hypoinsulinemia. Both induced oxidative stress and inflammation that partly contributed to pancreatic β-cell dysfunction and reduction in insulin secretion. Crucially, they downregulated pancreatic thyroid hormone receptor β1 (TRβ1) and monocarboxylate transporter 8 (MCT-8), impairing TH signaling. This reduced TH transport in pancreatic tissue and triggered β-cell apoptosis by modulating TRβ1-mediated expression of TH-responsive genes and proteins involved in pancreatic function, ultimately leading to diminished insulin secretion and elevated blood glucose levels. Dityr alone recapitulated the metabolic and molecular disruptions of HOP. We conclude that Dityr drives HOP-induced glucose metabolism disorders primarily by disrupting TH signaling, along with promoting oxidative stress and inflammation that collectively impair β-cell function. Minimizing dietary Dityr exposure via modified cooking methods or antioxidant-rich diets may mitigate diabetes risk. Full article

Background: Monocarboxylate-transporter-8-(MCT8) deficiency, or Allan–Herndon–Dudley syndrome (AHDS), is a rare X-linked disorder caused by pathogenic variants in the SLC16A2 gene, leading to impaired transport of thyroid hormones, primarily T3 and T4, across cell membranes. The resulting central hypothyroidism and peripheral hyperthyroidism cause neurodevelopmental impairment and thyrotoxicosis. Despite the availability of therapy options, e.g., with triiodothyroacetic acid (TRIAC), diagnosis is often delayed, partly due to normal TSH levels or incomplete genetic panels. MCT8 deficiency is not yet included in newborn-screening programs worldwide. Case Description: We present a case of an infant genetically diagnosed with MCT8 deficiency at 5 months of age after presenting with muscular hypotonia, lack of head control, and developmental delay. Thyroid function testing revealed a normal TSH, low free T4, and significantly elevated free T3 and free T3/T4 ratio. Treatment with TRIAC (Emcitate^®) was initiated promptly, with close drug monitoring. Despite persistent motor deficits and dystonia, some developmental progress was observed, as well as reduction in hyperthyroidism. Discussion/Conclusions: This case underscores the importance of early free T3 and fT3/fT4 ratio testing in infants with unexplained developmental delay. Broader inclusion of SLC16A2 in genetic panels and consideration of newborn screening could improve early diagnosis and outcomes in this rare but treatable condition. Full article

Congenital hypothyroidism (CH) is a heterogeneous condition present at birth, resulting in severe-to-mild thyroid hormone deficiency. This condition is difficult to recognize shortly after birth. Therefore, many countries worldwide have implemented newborn screening (NBS) programs for CH since the 1970s. The most recent European guidelines strongly recommend screening for primary CH, as well as for central CH when financial resources are available. However, no consensus has been reached yet to screen more rare forms of CH, such as Allan–Herndon–Dudley syndrome (AHDS), an X-linked condition linked to mutations in the gene encoding a transmembrane monocarboxylate transporter (MCT8), resistance to thyroid hormone beta (RTHβ), and resistance to thyroid hormone alfa (RTHα). The combined measurement of thyroid-stimulating hormone (TSH) and total thyroxine (TT4) on DBS currently allows the recognition of central CH (TSH low/normal and low TT4 without defects in transport proteins). With the introduction of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for measurement of free triiodothyronine (FT3) and free thyroxine (FT4), it would be possible to screen for RTHβ (TSH normal/high and high FT4). More complicated would be the method to screen RTHα. It would require the combined measurement of FT4 and FT3 and the determination of FT3/FT4 ratio, while the combined measurement of FT3 and reverse T3 (rT3) to calculate FT3/rT3 ratio would be useful to screen AHDS. In this article, we provide some reflections on expanding NBS for primary CH also to other rare forms of CH. Full article