Search Results (2,606)

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

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology, extensive intratumoral heterogeneity, and profound resistance to standard therapies. While recurrent genetic alterations such as KRAS mutations are central to PDAC initiation, growing evidence demonstrates that epigenetic dysregulation is a critical determinant of disease progression, cellular plasticity, immune evasion, and therapeutic failure. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, shape transcriptional programs without altering the underlying DNA sequence, rendering them dynamic and potentially reversible therapeutic targets. This review provides a comprehensive overview of key epigenetic proteins implicated in PDAC, encompassing writers, readers, and erasers of chromatin marks. Aberrant activity of histone methyltransferases and acetyltransferases, bromodomain-containing proteins, histone deacetylases, and demethylases orchestrates transcriptional reprogramming that promotes epithelial–mesenchymal transition, stem-like phenotypes, metabolic adaptation, and resistance to chemotherapy and radiotherapy. In parallel, epigenetic alterations within the tumor microenvironment contribute to stromal activation and immune suppression, further limiting therapeutic efficacy. We summarize recent advances in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies integrating epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. Emphasis is placed on emerging experimental platforms—including patient-derived organoids, co-culture systems, and in vivo models—combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimize therapeutic design. Collectively, this review highlights epigenetic regulation as a central and actionable vulnerability in PDAC and outlines future directions toward biomarker-guided, personalized epigenetic therapies aimed at overcoming resistance and improving clinical outcomes. Full article

Honey bees are exposed to a wide range of environmental and ecological stressors that threaten individual health and colony sustainability. Growing evidence suggests that many of these stressors converge on a common target: the gut microbiome and its metabolic functions. The honey bee microbiome–metabolome axis represents a central regulatory system linking microbial symbionts with host nutrition, detoxification, immune competence, neural signaling, and social behavior. This review synthesizes current knowledge on how major stressors—including pesticides, antibiotics, pathogens, nutritional imbalance, thermal stress, habitat change, and environmental contaminants—reprogram honey bee chemistry by disrupting microbial community structure and, importantly, microbial and host metabolic pathways. We highlight recurring patterns consistent with functional dysbiosis, characterized by impaired energy metabolism, reduced production of short-chain fatty acids, altered amino acid and lipid metabolism, compromised antioxidant and detoxification capacity, and weakened immune regulation. However, much of the current evidence is correlative and derived from short-term or laboratory-focused studies; longitudinal and multi-site field validation of causal links remains limited. Importantly, emerging multi-omics studies suggest that profound metabolic disturbances can occur even when taxonomic changes in the microbiome are modest, emphasizing the need to move beyond descriptive community profiling toward functional and mechanistic assessments. We further discuss how stress-induced metabolic reprogramming at the individual level scales up to influence behavior, division of labor, and colony-level resilience. Finally, we propose a conceptual model illustrating how diverse stressors converge to disrupt the microbiome–metabolome axis, potentially leading to functional dysbiosis and host impairment. Full article

Background/Objectives: Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to sustain proliferation, survive under metabolic stress, and develop therapeutic resistance. While oncogenic signaling pathways regulating cancer metabolism have been extensively studied, increasing evidence indicates that non-coding RNAs (ncRNAs) play essential roles in coordinating metabolic adaptation. This review aims to synthesize current knowledge on long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) as important but relatively less characterized regulators of cancer metabolic adaptation and discuss their potential as biomarkers and therapeutic targets. Methods: We analyzed their roles across multiple types of cancer, prioritizing studies that integrate ncRNA profiling with metabolomics and mechanistic investigations, with particular attention to their diagnostic, prognostic, and predictive value. Results: LncRNAs and circRNAs regulate major metabolic pathways, including glycolysis, mitochondrial function, glutaminolysis, lipid metabolism, and redox balance. They act through transcriptional and epigenetic mechanisms, protein scaffolding, peptide encoding, and miRNA sponging, frequently converging on key regulators such as HIF-1α, c-Myc, p53, AMPK, and mTOR. However, many reported associations remain largely correlative, with limited integration of quantitative metabolic flux analyses and insufficient validation in physiologically relevant models. Conclusions: Although lncRNAs and circRNAs constitute an important context-dependent regulatory layer linking oncogenic signaling to metabolic reprogramming, future studies should combine ncRNA perturbation with stable isotope tracing, fluxomics, spatial metabolomics, long-read sequencing, and single-cell approaches to define causal and spatially resolved metabolic functions. Such integrative strategies may improve biomarker development and support ncRNA-informed, metabolism-oriented therapeutic interventions. Full article

Ultra-processed foods (UPFs) represent a distinct dietary paradigm characterized by structurally simplified food matrices and chronic exposure to multiple additives, including emulsifiers, artificial sweeteners, and preservatives. Rather than acting in isolation, these compounds operate within a multi-additive environment that reshapes the gut ecosystem through convergent mechanisms. Emerging evidence suggests that additive-rich ultra-processed dietary environments may disrupt the gut ecosystem through three interconnected layers: (1) structural impairment of the intestinal barrier, including mucus erosion and tight-junction destabilization; (2) microbial metabolic shifts marked by short-chain fatty acid depletion, altered bile acid signaling, and enrichment of lipopolysaccharide-producing taxa; and (3) immune and inflammatory reprogramming promoting low-grade systemic inflammation. These processes collectively reduce ecosystem resilience—the capacity of the gut microbiota to resist and recover from perturbation. Vulnerability to additive-driven dysbiosis varies across the life course. During infancy, incomplete ecosystem stabilization may increase susceptibility to long-term ecological imprinting, whereas in older age, reduced microbial diversity and immune remodeling may impair recovery capacity following dietary stressors. In contrast, fiber-rich, minimally processed dietary patterns appear to enhance microbial resilience by reinforcing functional redundancy, metabolic buffering, and barrier integrity. Although much mechanistic evidence has been derived from experimental models, accumulating human data support the biological plausibility of additive-associated microbiota alterations. By integrating multi-additive exposure, ecosystem disruption, life-course modulation, and resilience within a unified framework, this review provides a mechanistically coherent model linking ultra-processed dietary environments to microbiota-mediated chronic disease risk. Here, we formalize this integrative perspective as the Three-Layer Ecosystem Disruption (TLED) Model. Full article

Calcific aortic valve disease (CAVD) is an active pathological process driven by complex cellular and molecular mechanisms rather than passive aging. The disease is characterized by endothelial dysfunction, lipid infiltration, inflammation, extracellular matrix remodeling, and osteogenic differentiation of valvular interstitial cells, ultimately leading to hydroxyapatite deposition and progressive valve calcification. Key signaling pathways, including Notch, Wnt/β-catenin, BMP2, and TGF-β, play critical roles in osteogenic reprogramming, while inflammatory cytokines such as IL-6, IL-1β, and TNF-α contribute to a pro-calcific microenvironment. To summarize current knowledge on CAVD pathophysiology and emerging therapeutic strategies, relevant preclinical studies were identified through searches of PubMed, and clinical trials were identified through ClinicalTrials.gov. Evidence indicates that extracellular matrix remodeling, fibrosis, and dysregulated phosphate metabolism, particularly involving TNAP and DPP-4, further accelerate disease progression. Despite advances in understanding disease mechanisms, effective pharmacological therapies remain limited, with the current treatment largely restricted to valve replacement. Emerging therapeutic approaches targeting molecular pathways, including enzyme inhibition, RNA-based therapeutics, and advanced drug delivery systems, may offer promising strategies for disease modification. A deeper understanding of CAVD pathophysiology may facilitate the development of targeted therapies to delay or prevent disease progression. Full article

Background: Mitochondria are multifunctional organelles that play a central role in maintaining cellular homeostasis by regulating energy metabolism, reactive oxygen species (ROS) generation, ion homeostasis, and apoptotic signaling. Dynamic processes such as mitochondrial fission, fusion, and intracellular trafficking enable cells to adapt to metabolic and environmental stress. Growing evidence indicates that dysregulation of these processes is a hallmark of cancer, contributing to metabolic reprogramming, redox imbalance, evasion of apoptosis, and disease progression. This narrative review aims to discuss the role of mitochondrial alterations in the pathophysiology of chronic myeloid leukemia (CML) and their potential therapeutic implications. Methods: Original research articles published between 2010 and 2025 were considered in this narrative review. The selected studies were critically discussed and categorized into three principal thematic domains: mitochondrial regulation of redox homeostasis, metabolic rewiring, and control of cell death pathways. Evidence was synthesized to elucidate the contribution of mitochondrial dysfunction to CML initiation, progression, and therapeutic resistance. Results: The reviewed studies highlight how mitochondrial abnormalities play a pivotal role in BCR-ABL1-driven leukemogenesis. Alterations in mitochondrial metabolism and ROS signaling support sustained proliferative signaling, promote genomic instability, and facilitate resistance to apoptosis. In addition, mitochondrial adaptations contribute to resistance to tyrosine kinase inhibitors (TKIs) and are essential for the persistence and survival of leukemic stem cells. Conclusions: Mitochondria emerge as central regulators of CML pathobiology. Therapeutic strategies targeting mitochondrial metabolism, redox homeostasis, and apoptotic signaling pathways represent promising approaches to overcoming TKI resistance and may improve clinical outcomes for patients with CML. Full article

Hypocrellin A (HA) represents a pharmaceutically important perylenequinone photosensitizer produced by Shiraia bambusicola. However, submerged fermentation remains constrained by filamentous morphological characteristics and inherent mass transfer limitations. Although microparticle-enhanced cultivation (MPEC) has demonstrated efficacy in filamentous fungal systems, the molecular mechanisms by which physical cues, such as microparticle-induced shear stress, reprogram fungal metabolism remain largely unexplored. This work systematically optimizes SiO₂-based MPEC parameters for S. bambusicola GDMCC 60438, including particle dimensions, temporal addition protocols, and solid loading. Mechanistic investigations integrated pellet morphology analysis, membrane lipid composition, intracellular redox status, energy/precursor markers, and RNA-seq transcriptomic profiling with qRT-PCR validation. Under optimized conditions (10% w/v SiO₂, 30 mesh, added at 6 h), HA yield reached 41.76 ± 5.02 mg/L, representing a 3.65-fold increase over controls. MPEC shifted morphology toward smaller, more porous pellets with denser internal structure, accompanied by increased membrane fluidity (unsaturated/saturated fatty acid ratio from 1.54 to 2.63), elevated ROS levels with antioxidant enzyme activation, and enhanced acetyl-CoA and ATP accumulation. Transcriptomic analysis identified 206 differentially expressed genes enriched in oxidative phosphorylation, carbon metabolism, and stress responses, with upregulation of PKS-related biosynthetic genes and major facilitator superfamily transporters. This work establishes an integrated mechanistic framework linking particle-induced morphological changes to metabolic reprogramming through oxidative stress and subsequent transcriptional activation of the HA biosynthetic pathway, providing rational design principles for MPEC strategies in filamentous fungi. Full article

Hypoxic pulmonary hypertension (HPH), classified as Group 3 pulmonary hypertension in the current clinical classification system, represents a complex and progressive cardiopulmonary disorder characterized by elevated pulmonary arterial pressure due to chronic alveolar hypoxia. This condition significantly contributes to morbidity and mortality in patients with chronic lung diseases and individuals residing at high altitudes. The pathogenesis of HPH involves a multifactorial interplay between sustained hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, endothelial dysfunction, and inflammatory responses. This review provides a comprehensive synthesis of recent advances in HPH pathophysiology and their clinical translation, with a focus on integrating molecular mechanisms with emerging therapeutic strategies. The pathogenesis of HPH involves a complex interplay of hypoxia-inducible factor (HIF) signaling, mechanosensitive ion channel dysregulation (particularly TRPC channels), metabolic reprogramming featuring glycolytic shift and mitochondrial dysfunction, immune–inflammatory mechanisms including macrophage-centered immunopathology, and dysregulation of the nitroxidergic system. Recent clinical advances include refined risk stratification using advanced echocardiographic techniques, identification of novel biomarkers such as lactylation-associated proteins, and development of targeted therapies including immunomodulatory approaches, metabolic modulators, and epigenetic interventions. Ongoing clinical trials are investigating innovative strategies ranging from iron supplementation to nanoparticle-based drug delivery systems. Despite these advances, significant translational challenges remain, including limitations of preclinical models, patient heterogeneity, and the need for HPH-specific outcome measures. This review bridges the gap between mechanistic insights and clinical applications, offering an integrated framework that highlights precision medicine approaches, emerging therapeutic targets, and priority research directions for improving outcomes in this challenging condition. Full article

Background: Myeloid-derived suppressor cells (MDSCs) drive immunosuppression in the hepatocellular carcinoma (HCC) tumor microenvironment (TME), contributing to immune checkpoint blockade (ICB) resistance. This review explores underlying mechanisms and therapeutic strategies. Methods: We synthesize the recent literature on MDSC biology in HCC, focusing on signaling pathways, metabolic/epigenetic reprogramming, and novel interventions, including AI-driven analyses. Results: Key mechanisms include JAK–STAT3 activation for MDSC expansion, CXCL12-CXCR4 for recruitment, enhanced glycolysis/lipid metabolism for suppressive function, and epigenetic changes sustaining immunosuppression. Therapeutic approaches encompass inhibitors, differentiation promoters, metabolic modulators, transcriptional reprogramming, microbiome modulation, and combinations with ICB/locoregional therapies or standard chemoimmunotherapy, yielding improved outcomes in trials. Conclusions: Targeting MDSC redundancies via multi-modal strategies offers a roadmap for overcoming resistance, with AI enhancing biomarker-guided precision immunotherapy in HCC. Full article

Hypoxia is a common feature of many physiological and pathological conditions, including inflammation, ischemia, and chronic lung disease, where limited oxygen availability disrupts mitochondrial metabolism and promotes excessive reactive oxygen species (ROS) generation. Hypoxia-inducible factor-1α (HIF-1α) is the central transcriptional regulator that enables cellular adaptation to low-oxygen environments by coordinating metabolic reprogramming, mitochondrial remodeling, and redox control. While HIF-1α is widely recognized for its role in promoting glycolysis, evidence indicates that it also suppresses mitochondrial ROS production through coordinated regulation of mitochondrial metabolism, biogenesis, and quality control. This review examines how HIF-1α integrates these mitochondrial and redox-adaptive mechanisms and highlights its bidirectional interactions with key stress-responsive signaling pathways, including PI3K/Akt, MAPK, Nrf2, and NF-κB, that together shape metabolic adaptation, inflammatory responses, and cell survival under hypoxic stress. By integrating these diverse mechanisms, this review provides a comprehensive understanding of the pathophysiology of hypoxia-associated diseases and underscores the therapeutic potential of targeting HIF-1α-regulated metabolic and inflammatory pathways to mitigate oxidative damage induced by hypoxia and environmental stressors. Full article

The etiology of gastric cancer (GC) is increasingly defined by the complex interplay within the oral-gastric microbial axis. This conceptual shift extends beyond the classical Helicobacter pylori (H. pylori) model. Instead, it encompasses a broader polymicrobial network. Mechanisms underlying ectopic colonization of oral pathobionts are examined alongside their synergistic contributions to mucosal dysbiosis. Remodeling of the tumor microenvironment is discussed through the analysis of critical functional modules, including biofilm formation, metabolic reprogramming, and immune dysregulation. Carcinogenesis is reportedly promoted by specific genotoxic metabolites and perpetuation of chronic inflammation. Diagnostic capabilities are evaluated with a focus on noninvasive biomarkers, where integration of artificial intelligence for risk stratification is identified as a transformative tool for early detection. Furthermore, therapeutic perspectives are expanded by evidence linking microbial composition to the efficacy of immune checkpoint inhibitors and chemotherapy. Strategies for prevention and treatment are proposed based on restoration of microbial homeostasis. Collectively, a roadmap for translating microbiome research into personalized clinical practice for gastrointestinal malignancies is provided by this review. Full article

Per- and polyfluoroalkyl substances (PFAS) continue to be one of the most persistent global contaminants and are increasingly recognized as leading metabolic- and hepatic-dysfunction mediators. Despite extensive investigation of PFAS toxicity, a critical gap in the identification and integration of toxicokinetic drivers of hepatic bioaccumulation with mechanistic pathways driving mitochondrial and nuclear receptor-related injury, more specifically, with respect to alternative PFAS strategies, still remains. Legacy PFAS, including PFOA and PFOS, accumulate in the liver and disturb mitochondrial homeostasis as they disrupt β-oxidation, induce oxidative stress, and alter lipid and bile acid metabolism. Meanwhile, the next-generation PFAS variants (including short-chain and polymeric substitutes) are rapidly increasing in environmental concentrations, but remain insufficiently characterized and poorly regulated, raising concerns that substitution-based strategies may maintain their toxicological risk. We summarize the evidence of the association between PFAS bioaccumulation and mitochondrial dysfunction, metabolic reprogramming, and inflammatory signaling, and illustrate mechanistic convergence across legacy and emerging PFAS. We also review insights from recent experimental models, such as 3D hepatocyte systems and human-relevant receptor platforms that more closely mimic chronic exposure states. This review emphasizes mechanistic convergence across legacy and emerging PFAS, highlighting shared pathways that may persist despite chemical substitution. Thus, we discuss key gaps in monitoring, toxicity assessment, and policy, including the requirement of regulatory paradigms that treat PFAS as a class rather than individual compounds. Full article

Primary biliary cholangitis (PBC) is an autoimmune-mediated disease characterized by chronic, non-suppurative, small-duct lymphocytic cholangitis. The prognosis largely depends on early disease recognition and treatment. Suboptimal response to first-line therapy (ursodeoxycholic acid) is associated with risk for disease progression. Reliable biomarkers are also required to enhance risk stratification. The traditional gold standard for assessing fibrosis is liver biopsy, but it is invasive and unsuitable for serial evaluations. Hence, trends are towards non-invasive surrogate biomarkers (blood-based and imaging biomarkers respectively) which have a much better safety profile. Blood-based biomarkers include: (i) Fibrosis-4 [Fib-4], (ii) Aspartate Aminotransferase to Platelet Ratio Index [APRI], (iii) Enhanced Liver Fibrosis score [ELF], and (iv) total bile acid to platelet ratio [TPR]. They show much potential but are not particularly sensitive tests. Ultrasound-based imaging biomarkers are increasingly being utilized for liver stiffness measurement (LSM), with vibration-controlled transient elastography (VCTE) emerging as the preferred technique. However, despite its growing popularity, VCTE is limited by technical issues. Hence, currently, none of the non-invasive tests fulfill the prerequisites to be the new gold standard as defined by the FDA. Nonetheless, there may be value to combining LSM with various serum biomarkers such as Fib-4, APRI, as aforementioned. The hope is to create nomograms for predicting liver-related events and decision tree algorithms. Newer studies are investigating microbiota in the gut-liver axis, biomolecules such as nanovesicles/nanofibers, and metabolic reprogramming as it pertains to e.g., proteomics and lipidomics. These approaches hold much promise, and if validated, could significantly change the management of PBC. Full article

Trained immunity confers protection against subsequent unrelated infections through metabolic and epigenetic reprogramming. Unlike adaptive immunity, trained innate immunity provides broad, non-specific protection against diverse heterologous pathogens. In addition to potentiating inflammatory responses upon secondary challenge, trained innate immune cells can also acquire anti-inflammatory and tolerogenic phenotypes, a property with important implications for chronic inflammatory diseases such as allergic disorders. Trained immunity-based vaccines (TIbVs) have emerged as promising immunomodulatory strategies capable of attenuating allergic inflammation by inducing immune tolerance. Similarly, allergen-specific immunotherapy (AIT) promotes long-term tolerance to allergens through metabolic and epigenetic reprogramming of innate immune cells. AIT drives the differentiation of monocytes into tolerogenic dendritic cells, thereby reshaping downstream adaptive immune responses. This review summarizes the current understanding of trained immunity and its role in protection against the same and heterologous infections. We discuss the molecular mechanisms underlying trained immunity, with an emphasis on metabolic and epigenetic reprogramming. Furthermore, we highlight the therapeutic potential of TIbVs and AIT as next-generation vaccines for allergic diseases. A deeper understanding of AIT-induced immune tolerance, the identification of predictive biomarkers, and the optimization of delivery platforms—such as lipid nanoparticle-based systems—will be critical for improving the safety and efficacy of future anti-allergy vaccines. Full article