Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach—including metabolomics, proteomics, and lipidomics—was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.

Dysregulation of alternative splicing is increasingly associated with cancer development and tumor progression. BCL2-associated transcription factor 1 (BCLAF1) is involved in a wide range of biological processes and it is continuously being investigated due to its intricate function in tumorigenesis and drug resistance. In acute myeloid leukemia (AML) cell lines, we identified two distinct, unbalanced isoforms of BCLAF1: the full-length isoform, which exhibits oncogenic properties, and the short-length isoform, which seems to act as a tumor suppressor. Treatment with specific epidrugs can re-establish the physiological balance of full- and short-length isoforms, restoring their correct equilibrium. Our results suggest the existence of a newly identified mechanism underlying the regulation of BCLAF1 splicing orchestrated, at least in part, by the interplay between HDAC1 and DNMT3A, and directly correlated with the healthy or cancerous state of hematopoietic cells. Our findings shed light on a novel regulatory axis in AML and highlight the potential of epidrugs to restore normal splicing patterns, paving the way for innovative therapies.

CBX7, a member of the Chromobox protein family and a core subunit of Polycomb Repressive Complex 1 (PRC1), has recently gained attention as an important regulator of chromatin organization and gene expression. In tumorigenesis, CBX7 can act as an oncogene or tumor suppressor highlighting a complex role to be investigated. In glioblastoma multiforme (GBM), CBX7 acts primarily as a tumor suppressor. Reduced CBX7 activity is related to poor patient survival by inducing glioblastoma cell hyperproliferation and invasiveness. Several molecular studies have highlighted the direct involvement of CBX7 in fundamental processes such as cell cycle regulation and the maintenance of stem-like characteristics. In GBM, epigenetic phenomena (such as hypermethylation of the CBX7 promoter region), regulation mediated by specific miRNAs, and protein-protein interactions are responsible for CBX7 downregulation. Restoring CBX7 expression in GBM reduced cell invasiveness and migration, highlighting its importance as a prognostic indicator and potential therapeutic target. Overall, current data support a model in which CBX7 operates as a crucial epigenetic regulator in glioblastoma, and its modulation may offer new opportunities for the development of targeted treatment strategies.

Although cancer treatment strategies have made considerable progress in recent decades, the challenge of selectively killing tumor cells while minimizing damage to healthy tissue remains. Radiotherapy (RT) continues to be crucial for tumor growth control when combined with surgery, chemotherapy, and immunotherapy. RT effectiveness depends on factors such as cancer type, tumor features, and the choice of external or internal treatment. Given its non-invasive nature and low systemic toxicity, RT is a suitable strategy for elderly patients. However, despite its efficacy, variations in cell sensitivity to radiation influence treatment outcomes, and normal cells surrounding the tumor can also be affected. Radiation-induced DNA damage can trigger cellular senescence, a permanent cell cycle arrest with a pro-inflammatory secretory phenotype, contributing to tissue damage in healthy cells and radio-resistance in tumor cells. RT causes not only DNA breakage but also epigenetic remodeling. Epigenetic pathways are involved in RT response, and the radiosensitivity of tumor cells can be modulated using epigenetic compounds. Emerging treatments based on more precise forms of RT, such as boron neutron capture therapy (BNCT), offer promising results by selectively targeting tumors while potentially preserving healthy tissues. BNCT has shown efficacy in glioblastoma, recurrent head and neck carcinoma, and melanoma. This review i) examines the mechanisms and challenges of conventional RT, focusing on aging and its role in treatment efficacy and tolerability, ii) describes the impact of senescence and epigenetic factors on resistance, iii) explores advances in BNCT, and iv) considers the potential of epigenetic drugs to optimize RT outcomes.

INTRODUCTION:Lysine demethylases (KDMs) are crucial epigenetic regulators that modulate gene expression via demethylation of histone and non-histone proteins, playing a pivotal role in cancer progression. Dysregulation of KDM activity, particularly in KDM1A, KDM4, KDM5, and KDM6, has been linked to several cancers, including leukemia and breast, lung, and prostate cancers, leading to the emergence of KDM inhibitors (KDMi) as promising therapeutic agents. These inhibitors target KDMs by mimicking cofactors, chelating metal ions, or competing with histone substrates to disrupt demethylation. Some of the most studied KDMi are those targeting KDM1A. AREAS COVERED:In this review, we critically explore the complex roles of KDMs in cancer, provide a detailed overview of patents describing KDMi published from 2015 to the present, and assess European clinical trials investigating KDMi developed for cancer therapy. EXPERT OPINION:Despite the promising potential of KDMi, their clinical development is hampered by significant challenges including safety concerns, suboptimal patient enrollment, and difficulties in optimizing dosing regimens and identifying reliable biomarkers. Future research must focus on refining dosing protocols, discovering predictive biomarkers, and developing effective combination therapies to maximize patient outcomes, ultimately realizing the full promise of KDMi in cancer treatment.

Chromobox (CBX) proteins play a crucial role in regulating epigenetic processes. They are extensively involved in various biological processes, including embryonic development, stem cell maintenance, cell proliferation and apoptosis control. The disruption and malfunction of CBXs in cancer typically results in the interference or abnormal activation of developmental pathways, which facilitate the onset, growth, and advancement of cancer. This review initially introduces the physiological properties and functions of the CBXs. Subsequently, it examines the involvement of CBXs in different cancer types. Cancer hallmarks driven by CBXs are mediated through multiple mechanisms, including changes in gene expression patterns, epigenetic dysregulation of chromatin control, disruption of intracellular signaling and alterations in cell metabolism. The study also highlights novel potential anticancer therapeutics targeting CBXs in cancer. In this review we provide novel perspectives and a solid foundation for future investigations on CBXs as promising therapeutic targets for cancer treatment.

Background: Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and are strongly influenced by dietary habits. Beyond caloric intake, nutrients act as molecular signals that regulate cardiac metabolism, mitochondrial function, inflammation, and epigenetic remodeling. Objectives: This review aims to synthesize current evidence on how dietary patterns and specific nutritional interventions regulate cardiac metabolism and function through interconnected molecular and epigenetic mechanisms, highlighting their relevance for cardiovascular disease prevention. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2006 and 2025. Experimental, translational, and clinical studies addressing diet-induced modulation of cardiac metabolic pathways, oxidative and inflammatory signaling, epigenetic regulation, and gut microbiota-derived metabolites were included. Results: The analyzed literature consistently shows that unbalanced diets rich in saturated fats and refined carbohydrates impair cardiac metabolic flexibility by disrupting key nutrient-sensing pathways, including AMP-activated protein kinase (AMPK), proliferator-activated receptor alpha (PPARα), mammalian target of rapamycin (mTOR), and sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (SIRT1/PGC-1α), leading to mitochondrial dysfunction, oxidative stress, chronic inflammation, and maladaptive remodeling. In contrast, cardioprotective dietary patterns, such as caloric restriction (CR), intermittent fasting (IF), and Mediterranean and plant-based diets, enhance mitochondrial efficiency, redox balance, and metabolic adaptability. These effects are mediated by coordinated activation of AMPK-SIRT1 signaling, suppression of mTOR over-activation, modulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, and favorable epigenetic remodeling involving DNA methylation, histone modifications, and non-coding RNAs. Emerging evidence also highlights the central role of gut microbiota-derived metabolites, particularly short-chain fatty acids, in linking diet to epigenetic and metabolic regulation of cardiac function. Conclusions: Diet quality emerges as a key determinant of cardiac metabolic health, acting through integrated molecular, epigenetic, and microbiota-mediated mechanisms. Targeted nutritional strategies can induce long-lasting cardioprotective metabolic and epigenetic adaptations, supporting the concept of diet as a modifiable molecular intervention. These findings provide a mechanistic rationale for integrating personalized nutrition into cardiovascular prevention and precision cardiology, complementing standard pharmacological therapies.

N6-methyladenosine (m6A) is an RNA modification that governs multiple aspects of RNA metabolism, including splicing, translation, stability, decay, and the processing of marked transcripts. Although accumulating evidence suggests that the m6A writer METTL16 is involved in leukemia, the molecular pathway(s) by which it contributes to leukemogenesis remain unexplored. In this study, we shed light on a novel molecular mechanism whereby METTL16 plays a role in acute myeloid leukemia (AML) progression through an m6A-dependent manner. Our investigations revealed that METTL16 is overexpressed in primary AML cells. Genetic depletion of METTL16 or its pharmacological inhibition strongly affected the proliferation of AML cells, eventually triggering apoptosis. Transcriptome-wide analysis identified mRNA of MAX Dimerization Protein 4 (MXD4), a MYC pathway regulator, as a downstream target of METTL16. Mechanistically, we showed that METTL16 controls the stability of MXD4 mRNA, resulting in a reduction in MXD4 protein levels that indirectly activates the MYC-MAX axis, essential for leukemogenesis. Strikingly, the suppression of MXD4 rescued the expression levels of MYC target genes, restoring AML cell survival. Our findings unveil a novel METTL16-MXD4 oncogenic axis crucial for AML progression, establishing small-molecule inhibition of METTL16 as a potential therapeutic approach in leukemia and providing a new strategy to target MYC activity in cancer.

Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N-6-methyladenosine (m(6)A) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the m(6)A system, has shown a dramatic impact on cancer development. However, the cellular localization of m(6)A proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that m(6)A methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond m(6)A that still represent an unexplored field. To date novel epigenetic drugs targeting m(6)A modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco-properties of m(6)A effectors beyond m(6)A is required. Here we will provide an overview of methylation-independent functions of the m(6)A players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics.

BackgroundBreast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear.MethodsIn this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes.ResultsCollectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions.ConclusionsThese observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

Aging is a pathophysiological process that causes a gradual and permanent reduction in all biological system functions. The phenomenon is caused by the accumulation of endogenous and exogenous damage as a result of several stressors, resulting in significantly increased risks of various age-related diseases such as neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, and immune system diseases. In addition, aging appears to be connected with mis-regulation of programmed cell death (PCD), which is required for regular cell turnover in many tissues sustained by cell division. According to the recent nomenclature, PCDs are physiological forms of regulated cell death (RCD) useful for normal tissue development and turnover. To some extent, some cell types are connected with a decrease in RCD throughout aging, whereas others are related with an increase in RCD. Perhaps the widespread decline in RCD markers with age is due to a slowdown of the normal rate of homeostatic cell turnover in various adult tissues. As a result, proper RCD regulation requires a careful balance of many pro-RCD and anti-RCD components, which may render cell death signaling pathways more sensitive to maladaptive signals during aging. Current research, on the other hand, tries to further dive into the pathophysiology of aging in order to develop therapies that improve health and longevity. In this scenario, RCD handling might be a helpful strategy for human health since it could reduce the occurrence and development of age-related disorders, promoting healthy aging and lifespan. In this review we propose a general overview of the most recent RCD mechanisms and their connection with the pathophysiology of aging in order to promote targeted therapeutic strategies.

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation.

Cell homeostasis results from a proper balance between the generation of new cells and the removal of old ones. Cells have a well-defined life cycle, after which they naturally die by activating various internal processes. An alteration of these processes causes the interruption of the homeostatic balance leading to the origin of many diseases, including cancer. Altered death patterns are often associated with a low response rate to standard chemotherapy and poor patient survival, highlighting the idea that targeting the mechanisms of cell death in tumourigenesis could represent a strategic tool in oncology. Several types of cancer are still difficult to treat and are known as "poor prognosis cancers"; leukemia is among these and, in particular, some forms are resistant to the current therapies. The correlation between tumourigenesis and cell death alteration is well defined, but the characterization of the molecular pathways involved is still poorly understood. To date, autophagy and apoptosis represent the two best known and characterized forms of cell death, the alteration of which is documented in various tumors including leukemias. The link between apoptosis (self-destruction) and autophagy (self-eating) is still complicated since they can both be activated by same upstream signals, resulting in a combined form of cell death. In this chapter we are reporting a crucial focus on the pathophysiological relevance of apoptosis and autophagy in leukemia with particular attention to drug classes aimed at overcoming resistance mechanisms.

Diabetes mellitus, a metabolic condition affecting around 537 million individuals worldwide, poses significant challenges, particularly among the elderly population. The etiopathogenesis of type 2 diabetes (T2D) depends on a combination of the effects driven by advancing age, genetic background, and lifestyle habits, e.g. overnutrition. These factors influence the development of T2D differently in men and women, with an obvious sexual dimorphism possibly underlying the diverse clinical features of the disease in different sexes. More recently, environmental pollution, estimated to cause 9 million deaths every year, is emerging as a novel risk factor for the development of T2D. Indeed, exposure to atmospheric pollutants such as PM2.5, O3, NO2, and Persistent Organic Pollutants (POP)s, along with their combination and bioaccumulation, is associated with the development of T2D and obesity, with a 15 % excess risk in case of exposure to very high levels of PM2.5. Similar data are available for plasticizer molecules, e.g. bisphenol A and phthalates, emerging endocrine-disrupting chemicals. Even though causality is still debated at this stage, preclinical evidence sustains the ability of multiple pollutants to affect pancreatic function, promote insulin resistance, and alter lipid metabolism, possibly contributing to T2D onset and progression. In addition, preclinical findings suggest a possible role also for plastic itself in the development of T2D. Indeed, pioneeristic studies evidenced that micro- or nanoplastics (MNP)s, particles in the micro- or nano- range, promote cellular damage, senescence, inflammation, and metabolic disturbances, leading to insulin resistance and impaired glucose metabolism in animal and/or in vitro models. Here we synthesize recent knowledge relative to the association between air-related or plastic-derived pollutants and the incidence of T2D, discussing also the possible mechanistic links suggested by the available literature. We then anticipate the need for future studies in the field of candidate therapeutic strategies limiting pollution-induced damage in preclinical models, such as SGLT-2 inhibitors. We finally postulate that future guidelines for T2D prevention should consider pollution and sex an additional risk factors to limit the diabetes pandemic.

Polycomb group proteins, known for their role in epigenetic gene silencing, are critical regulators of cell fate and tissue development across species. These highly conserved proteins are assembled into two multi-protein complexes: Polycomb Repressive Complex 1 and Polycomb Repressive Complex 2. In zebrafish, a prominent vertebrate model, the roles of PRC1 and PRC2 have been extensively studied, particularly in the context of organogenesis. This review focuses on the emerging functions of PcG proteins in zebrafish development, with an emphasis on the involvement of PRC1 and PRC2 in the formation and differentiation of the heart and pectoral fins. By integrating findings from recent studies, we aim to provide a comprehensive overview of how PcG function contributes to the intricate processes underlying zebrafish heart and pectoral fin development. This review highlights the zebrafish model as a powerful system for unravelling the complex roles of PcG proteins in vertebrate development.