Search Results (389)

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

Cancer cells, like yeast, use fermentation despite the presence of oxygen, a phenomenon called aerobic glycolysis. The advantage is that it maintains many C-C bonds of glucose, allowing highly proliferating cells to produce the biomolecules that are necessary for cytokinesis. However, aerobic glycolysis is less energy-efficient than respiration, and it must operate at high frequency and produces large amounts of lactate, which modifies and stimulates DNA repair enzymes via lysine lactylation. This makes cancer cells resistant to radiotherapy, which requires a combination with chemotherapy using drugs that inhibit DNA repair. However, this converts healthy cells to cancer cells, indicating that research is still required regarding the relationship between glycolysis and cancer. Using yeast as a model, we discovered that the glycolytic enzymes TPI and GAPDH (Tpi1p and Tdh1-3p in yeast) interact with the DNA damage-dependent Checkpoint Rad9p (53BP1/BRCA1/MDC1 in humans). We propose that Tpi1p and Tdh1-3p override Rad9p, allowing cells with damaged DNA to proliferate. We isolated tpi and gapdh mutant strains that are deficient in DNA repair. While the tpi mutant strain has lower enzymatic activity, the gapdh mutant strains have normal enzymatic activity, confirming previous reports that GAPDH moonlights in the DNA damage response. Full article

The family of Nek kinases has 11 human members that are conserved in their kinase domains but diverse in their regulatory domains. Functionally, they can be associated with diverse aspects of cell cycle regulation, from mitosis and primary cilia function to centrosome disjunction in the G2 phase and checkpoints of the DNA damage response. However, novel functional contexts have emerged in recent years, including regulatory roles of Neks 1, 4, 5, and 10 in mitochondrial metabolic and morphological homeostasis. We recently generated, by CRISPR-Cas9 technology, a DU-145 prostate cancer cell line, with an NEK6 gene knockout. Here, we focus on a detailed characterization of changes in this cell line, in mitochondrial respiration function and morphology. DU-145 NEK6 knockout cells exhibited reduced mitochondrial respiration and a fragmented phenotype in electron microscopy, with reduced mitochondrial cristae numbers. Alterations in mitochondrial architecture and respiration were correlated with increased expression of anaerobic glycolytic proteins (HK2, PFKP, and LDHA) and decreased expression of PDH, an enzyme of aerobic glycolysis. Molecular analysis by Western blot revealed decreased levels of mitochondrial mass and biogenesis protein markers (TOM20, TFAM), without alterations in other markers such as VDAC1/3 or mtDNA copy number in the NEK6 knockout cells. Furthermore, the regulators of mitochondrial fusion/fission are altered in the knockout cells (decrease in the Long-OPA1:Short-OPA1 ratio and DRP1 total level), which is associated with an increase in endoplasmic reticulum–mitochondria contact at ≤20 nm observed in transmission electron microscopy (TEM) image analysis. Using analysis of TEM micrographs, we found an increase in the autophagic structures (autophagosome, amphisome, and autolysosome), with mitochondria as cargo in some structures, which was correlated with a decrease in LC3A/B and an increase in the BECLIN1 total level, and with an increase in acidic vesicles approximation, suggesting that reduction in TOM20 and TFAM without alterations in VDAC1/3 and mtDNA copy number might be related to mitochondrial degradation through autophagy. Together, our data suggest a new role for NEK6 in regulating mitochondrial homeostasis, where its loss alters mitochondrial morphology and respiration, and could be associated with an increase in the degradation of the dysfunctional mitochondria through autophagy. Full article

Metabolic reprogramming is a core hallmark of malignancy, enabling tumor cells to sustain rapid proliferation, evade immune elimination, and develop resistance to therapy. Although a wide range of plant-derived phytochemicals exhibit anticancer activity with comparatively low toxicity, their capacity to disrupt specific metabolic dependencies exploited by tumors has not been comprehensively synthesized. This review brings together current mechanistic evidence showing how major phytochemical classes, including polyphenols, terpenes and terpenoids, glucosinolates, and alkaloids, interfere with pathways central to tumor metabolic fitness, such as aerobic glycolysis, pentose phosphate pathway flux, mitochondrial substrate oxidation, glutamine dependence, and redox homeostasis. It further introduces a pathway-focused framework that links phytochemical mechanisms to quantifiable metabolic outcomes and highlights their potential to remodel the tumor microenvironment by altering nutrient competition, oxidative stress responses, and hypoxia-driven signaling. Key barriers such as poor systemic bioavailability, rapid metabolic degradation, and limited tissue penetration are assessed alongside emerging formulation and delivery strategies designed to enhance therapeutic exposure while preserving low-toxicity profiles. Mapping these mechanistic insights onto clinical development needs allows prioritization of specific phytochemical-metabolic pathway pairs with the strongest potential for translation. This positions plant-derived metabolic disruptors as promising candidates for next-generation, low-toxicity anticancer therapies that strategically exploit defined metabolic vulnerabilities. Full article

In 1988, two seminal studies were published almost simultaneously in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in a long-lasting debate that appeared to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are fueling the active brain with adenosine triphosphate (ATP). The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by respective oxygen consumption, but a non-oxidative glucose utilization or what has become known as “aerobic glycolysis”. Consequently, for almost four decades, researchers in this field have been divided between those who profess that brain activity is supported by oxidative lactate metabolism and those who insist that non-oxidative glucose metabolism supports it. Hypotheses for both concepts were offered, “The Astrocyte Neuron Lactate Shuttle Hypothesis” and “The Efficiency Tradeoff Hypothesis,” respectively. To bridge the gap between the two groups, a recent editorial, authored by over twenty leading investigators, was published. The editorial received two separate responses from investigators who supported the non-oxidative glucose consumption as the main process supporting neural activity, signaling that the gap between the two groups remained. The present perspective highlights the principal disagreements that divide this utmost important field of research. It argues that the main reason for these disagreements is rooted in the assumption that pyruvate is the end-product of aerobic glycolysis, even when many among those who adhere to this assumption accept that in the active brain glycolysis is the main provider of the necessary ATP and the end-product is lactate under aerobic conditions. The consideration of a paradigm shift, according to which lactate is the real end-product of glycolysis, independent of the presence or absence of oxygen, could bridge the great divide between those who separate glycolysis into two outcomes and those who profess that there is only one, prefix-less glycolytic pathway that always ends with the production of lactate. Full article

Background/Objectives: Lung cancer (LC) remains the leading cause of cancer-related death worldwide, despite advances in systemic and targeted therapies. A mechanism of survival of tumor cells is metabolic reprogramming, characterized by increased glucose uptake, aerobic glycolysis, and alterations in mitochondrial function. These adaptations seem to support tumor growth, immune evasion, and therapeutic resistance. In parallel, supportive care and specifically nutritional interventions have become essential components of modern oncology. The interplay between metabolic reprogramming and targeted nutritional strategies represents a promising area of investigation that bridges tumor biology with supportive care, aiming to enhance both therapeutic efficacy and patient quality of life. Methods: This narrative review explores the biological and pathophysiological rationale for the ketogenic diet (KD) as a possible complementary intervention in LC management and summarizes the published preclinical and clinical data supporting this rationale. Results: We discuss key aspects of tumor metabolism, including the Warburg effect, glucose dependency, oxidative stress regulation, fatty acid metabolism, lactate cycling and tumor microenvironment interactions, with particular emphasis on how carbohydrate restriction and ketosis may exacerbate mitochondrial dysfunction in cancer cells and modulate inflammatory pathways. Furthermore, we summarize available preclinical and clinical evidence evaluating the KD in oncology and, more specifically, in LC, focusing on feasibility, safety, metabolic effects, and potential synergy with chemotherapy, radiotherapy, and immunotherapy. Conclusions: While preclinical models suggest enhanced treatment efficacy, clinical data remain limited and heterogeneous, with patient adherence representing a major challenge. Further well-designed longitudinal studies are required to clarify the therapeutic role of the ketogenic diet in lung cancer. Full article

Median overall survival remains a central endpoint in oncology, but it can obscure a clinically meaningful long tail of patients with advanced solid tumors who survive well beyond the median. One biological context in which this pattern may be relevant is tumor microenvironment (TME) acidosis. Driven by aerobic glycolysis, hypoxia, impaired perfusion, and proton-export programs, acidic TME is increasingly implicated in invasion, therapeutic resistance, and immune suppression. This narrative review examines TME acidosis as the primary biological framework and considers long-tail survival as a clinical lens through which its implications may be interpreted. We summarize the biological basis and heterogeneity of acidic TME, review current approaches to clinical and translational assessment of tumor acidity, including acidoCEST magnetic resonance imaging (MRI) and positron emission tomography (PET)-based approaches, and discuss the potential and limitations of alkalization-oriented interventions such as buffering and diet-based strategies. Particular attention is given to the distinction between direct measurements of tumor acidity and clinically feasible but indirect markers such as urinary pH, which should not be interpreted as a direct surrogate for local tumor extracellular pH. From a science-based medicine perspective, long-tail survival is treated here as a hypothesis-generating clinical signal rather than proof of causality. Overall, alkalization-oriented interventions appear biologically plausible and clinically testable, but current clinical evidence remains limited and context-dependent. Future progress will require mechanistically informed biomarkers, careful safety evaluation, and trial designs capable of detecting delayed separation of survival curves and tail-oriented patterns of benefit. Full article

Vascular remodeling driven by the phenotypic switching of vascular smooth muscle cells (VSMCs) poses a significant health risk to astronauts during long-duration spaceflight. While the morphological and molecular changes are well recognized, the underlying metabolic drivers and potential translational countermeasures remain elusive. To investigate the metabolic determinants of VSMCs phenotypic switching, human aortic smooth muscle cells (HASMCs) were subjected to cyclic mechanical stretch, an in vitro model offering indirect mechanistic insights into mechanical loading conditions relevant to spaceflight-associated hemodynamic alterations. An integrated approach combining quantitative proteomics, flux analysis (Seahorse), and functional assays (cell cycle, wound healing, transwell) was used to characterize the accompanying metabolic and phenotypic alterations. Molecular mechanisms were assessed using immunoprecipitation, protein crosslinking, and immunofluorescence. Mechanical stretch triggered a contractile-to-synthetic phenotypic switch in HASMCs, accompanied by a shift from oxidative phosphorylation to aerobic glycolysis. Pyruvate kinase M2 (PKM2) was identified as a central metabolic regulator of this process, its silencing reversed the pro-synthetic phenotype. Notably, lactate, a glycolytic product, was found to exert a self-limiting feedback signal. Exogenous lactate suppressed the synthetic switch in associated with increased PKM2 lactylation. Further analysis indicated that PKM2 lactylation was associated with enhanced stability of its active tetrameric conformation, which was associated with a metabolic shift toward oxidative phosphorylation and restored expression of contractile markers. Although specific lactylation sites on PKM2 were not identified in this study, and direct causality between lactylation and tetramerization remains to be established, these findings identify a previously unrecognized association. This study reveals a novel metabolic regulatory mechanism in which lactate correlates with the suppression of synthetic switching of VSMCs, linked to PKM2 lactylation and tetramer stabilization. The observed lactate-PKM2 axis represents a candidate metabolic node associated with VSMCs phenotype regulation and offers a potential therapeutic target for modulating vascular remodeling. Upon direct validation under relevant conditions in future studies, this mechanism may inform the development of novel therapeutic strategies for managing vascular adaptation during long-duration spaceflight and other aerospace-related physiological challenges. Full article

Osteosarcoma (OS) is an aggressive bone malignancy with poor prognosis, characterized by high metastasis rates. Kinesin family member 18B (KIF18B), a key protein in cell division and mitosis, has emerged as a potential diagnostic and therapeutic target in various cancers, including OS. This study investigates the role of KIF18B in OS progression and its underlying mechanisms. We found that KIF18B expression is significantly upregulated in OS tissues and correlates with lymph node metastasis (N-stage) and clinical stage. Knockdown of KIF18B inhibited OS cell migration, invasion, proliferation, and tumorigenesis. Mechanistically, KIF18B promotes OS survival through the ubiquitin–proteasome system (UPS) by regulating Skp2 protein degradation. KIF18B knockdown accelerated Skp2 ubiquitination, leading to reduced Skp2 levels and inhibited OS cell viability and glycolytic metabolism. Overexpression of KIF18B enhanced OS cell viability and glycolysis in an Skp2-dependent manner. These findings suggest that the KIF18B-Skp2 axis plays a critical role in the metabolic reprogramming of OS cells and serves as a novel prognostic biomarker and therapeutic target in OS. Full article

Oral squamous cell carcinoma (OSCC) remains a major global health burden due to aggressive invasion, early metastasis, therapeutic resistance, and poor long-term survival. Beyond tumor-intrinsic genetic and epigenetic alterations, accumulating evidence highlights the critical role of the tumor microenvironment in shaping OSCC progression and clinical outcomes. Cancer-associated fibroblasts (CAFs) and immune cells orchestrate tumor initiation, immune evasion, and recurrence through extracellular matrix remodeling, cytokine signaling, angiogenesis, and metabolic and redox regulation. Key oncogenic pathways, including EGFR/PI3K/AKT/mTOR, TGF-β, Wnt, and Notch, integrate with non-coding RNA networks to reinforce stemness, epithelial–mesenchymal transition, and therapy resistance. Moreover, PD-1/PD-L1-mediated immune escape, CAF-driven biomechanical remodeling, and metabolic reprogramming such as aerobic glycolysis and lipid metabolism contribute to OSCC heterogeneity. This review synthesizes current insights into OSCC across genomic, epigenetic, metabolic, and microenvironmental dimensions, emphasizing CAF biology, immune landscape reprogramming, and non-coding RNA regulation. We further discuss emerging biomarkers, liquid biopsy approaches, and targeted therapeutic strategies, providing a system-level framework for biomarker-guided stratification and precision combination therapies in OSCC. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, arising from profound metabolic reprogramming and widespread epigenetic dysregulation. However, the role of epigenetic aberrations in modulating metabolic reprogramming and the interplay between cis-regulatory elements (CREs), such as promoters, enhancers and super-enhancers, and metabolic adaptation have not been systematically summarized. Therefore, this review aims to integrate current evidence to elucidate the mechanisms of how cis-regulatory elements (CREs) drive oncogenic and metabolic signals in HCC progression. For instance, enhancers and super-enhancers transcriptionally activate key metabolic genes involved in aerobic glycolysis (GLUT1, HK2, PKM2, LDHA), de novo lipogenesis (ACLY, FASN, ACC), glutaminolysis (SLC1A5, GLS), and nucleotide synthesis. Meanwhile, many metabolic intermediates, including acetyl-CoA, succinyl-CoA and lactate, act as cofactors or substrates for epigenetic modifiers, creating bidirectional feedback loops that reinforce CRE-driven malignant phenotypes. Therefore, aberrant CREs acts as “metabolic switches” that sense and respond to various metabolic conditions to sustain HCC growth. Consequently, targeted intervention against oncogenic CREs, such as super-enhancers or their co-activators, to disrupt CRE-mediated metabolic vulnerabilities, has emerged as a highly promising new paradigm for precision therapy in HCC. Full article

Psoriasis, a chronic inflammatory skin disease, is driven by immune dysregulation and keratinocyte hyperproliferation, with current biologics facing limitations. Emerging evidence points to mitochondrial dysfunction and a pathological shift to aerobic glycolysis as core disease drivers. Here, we report that MitoFu-O, a novel mitochondria-targeting TPP-thiazole derivative, effectively ameliorates psoriasiform inflammation in imiquimod-induced mice and cytokine-stimulated keratinocytes. Mechanistically, MitoFu-O acts by inhibiting pathological glycolysis, downregulating key glycolytic enzymes (HK1, GAPDH, LDHA), and subsequently suppressing the activation of pivotal pro-inflammatory signaling pathways (MAPK, NF-κB, and STAT3). Our findings establish targeted mitochondrial modulation as a potent therapeutic strategy, positioning MitoFu-O as a promising lead compound that acts upstream of cytokine signaling by normalizing the metabolic reprogramming fundamental to psoriatic pathogenesis. Full article

Cervical cancer has a high incidence and mortality, and is one of the leading causes of cancer-related deaths among women worldwide. The infection with high-risk subtypes of the human papillomavirus (HPV) represents a crucial factor in the development of precancerous lesions. HPV oncoproteins target multiple host factors to promote uncontrolled cellular proliferation, genomic instability, profound metabolic reprogramming, resistance to apoptosis and immune evasion. Thus, cervical carcinogenesis involves metabolic reprogramming in patient cells, such as enhanced aerobic glycolysis, and altered glutamine, lipid and mitochondrial metabolism, which collectively support the bioenergetic and biosynthetic demands of cancer cells. Cancer cells also activate several mechanisms to adapt and survive under hypoxic/anoxic conditions. The mechanisms underlying cervical carcinogenesis often involve non-coding RNAs. This review aims at summarizing the mechanisms and factors involved in the development and progression of cervical cancer following HPV infection, and offers an overview of the available therapies that have been developed for this disease. Full article

Cancer metabolism is a cornerstone of tumor biology, characterized by profound alterations in cellular energy production and biosynthetic pathways that drive malignancy. The seminal discovery of the “Warburg effect”, the preference of cancer cells for aerobic glycolysis even under oxygen-rich conditions, provided the first major insight into this field. Historically, this observation was attributed to defective mitochondria, but modern research has revealed a far more complex picture of metabolic reprogramming that is actively driven by oncogenes, tumor suppressor genes, and the tumor microenvironment (TME). This review advances a unifying framework for understanding cancer metabolism as a dynamic ecosystem defined by three interconnected adaptations: metabolic plasticity, oncometabolite-driven epigenetic remodeling, and immune-metabolic crosstalk. These adaptations extend beyond glycolysis to encompass glutamine metabolism, lipid synthesis, amino acid utilization, and mitochondrial dynamics, all coordinated to fuel rapid proliferation, promote survival, and enable metastasis. By examining the drivers, consequences, and therapeutic barriers within this framework, we highlight emerging strategies for precision intervention. Although understanding the mechanistic basis of these pathways has unveiled new therapeutic avenues, clinical translation has been limited by metabolic redundancy, microenvironmental buffering, and patient heterogeneity. Strategies such as metabolic inhibitors, dietary interventions, and immuno-metabolic combinations offer promising prospects for disrupting tumor growth when guided by biomarker-driven patient selection and emerging technologies, including spatial metabolomics and AI-driven network modeling. Full article

Metabolic reprogramming constitutes a fundamental hallmark of malignancy, enabling cancer cells to sustain proliferation and survival under physiological stress. While aerobic glycolysis is well characterized, fatty acid oxidation (FAO) has emerged as a decisive driver of oncogenic progression and therapeutic resistance. Acylcarnitines (ACs), obligatory intermediates for the mitochondrial transport of long-chain fatty acids, have transcended their traditional categorization as passive metabolic byproducts to function as potent signaling entities and functional readouts of mitochondrial oxidative throughput. This review delineates the AC metabolic axis in oncology, examining the coordinated biochemical machinery, including the carnitine palmitoyltransferase (CPT) system, carnitine–acylcarnitine translocase (CACT; SLC25A20), and organic cation/carnitine transporter 2 (OCTN2), that governs cellular AC homeostasis. We further evaluate the clinical utility of altered AC profiles as non-invasive biomarkers for early diagnosis and risk stratification across diverse malignancies, highlighting their capacity to reflect metabolic bottlenecks and flux dynamics. Additionally, we scrutinize therapeutic strategies targeting the AC-FAO axis, demonstrating how the inhibition of key transporters and enzymes sensitizes tumors to conventional chemotherapy and immunotherapy. Ultimately, deciphering the systemic and spatial dynamics of ACs remains essential for advancing precision metabolic oncology and developing personalized therapeutic strategies based on metabolic profiling. Full article