Gregorio Favale

Acute myeloid leukemia (AML) is a complex hematologic cancer marked by both genetic and epigenetic abnormalities that lead to the expansion of immature myeloid cells and a block in their normal differentiation. Among the various molecular mechanisms implicated in its pathogenesis, epigenetic alterations have gained increasing attention for their crucial role in initiating and sustaining leukemic transformation. Mutations in key epigenetic regulators such as DNMT3A, TET2, IDH1/2, and EZH2 have been frequently identified in AML, contributing to widespread disruptions in DNA methylation patterns, histone modification states, and chromatin structure. These changes profoundly influence gene expression programs by favoring malignant progression. Unlike permanent genetic mutations, epigenetic changes are potentially reversible, making them particularly appealing as therapeutic targets. Agents that modulate the epigenome, such as DNA hypomethylating drugs or other epi-drugs, have shown significant clinical activity, especially in older patients or those medically unsuitable for intensive chemotherapy. Additionally, novel compounds are being actively evaluated, both alone and in combination with existing therapies. Overall, the epigenetic landscape of AML offers valuable opportunities for innovative treatment approaches. Ongoing research is crucial to better understand resistance mechanisms, define predictive biomarkers, and refine therapeutic strategies aimed at improving clinical outcomes for AML patients.

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.

Radiation therapy is a cornerstone of cancer treatment, targeting tumor cells through DNA damage and subsequent induction of various forms of cell death. This chapter explores the multifaceted biological effects of Radiation therapy (RT), highlighting its ability to trigger different lethal and non-lethal death mechanisms. The mechanisms underlying these responses involve complex interactions between radiation-induced DNA damage, reactive oxygen species production, and disruption of cellular homeostasis. RT therapeutic efficacy is influenced by factors such as tumor type, microenvironment, and the balance between cell death and survival pathways. Advances in understanding how RT impacts cell death mechanisms, including the modulation of ferroptosis and pyroptosis, have unveiled new opportunities to enhance radiosensitivity and overcome tumor resistance. Furthermore, non-lethal processes, such as senescence and mitotic catastrophe, underscore the potential of RT to suppress tumor progression through mechanisms beyond direct cytotoxicity. This chapter emphasizes the need for integrating molecular insights with clinical applications to optimize the efficacy of RT while minimizing damage to healthy tissues. By examining emerging strategies, such as the exploitation of immune responses and targeting tumor microenvironmental factors, this work provides a comprehensive foundation for advancing radiotherapy in oncology.

Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, is critically implicated in the pathology of acute myeloid leukemia (AML). The dysregulation of iron metabolism and ferroptotic regulators, such as GPX4, the cystine/glutamate antiporter System Xc⁻, and several iron homeostasis proteins, contributes to leukemic cell survival and therapy resistance. These disruptions not only facilitate the survival and proliferation of leukemic cells but also enable them to evade traditional apoptotic pathways, thereby increasing resistance to standard therapeutic interventions. Recent studies have focused on identifying specific targets within the ferroptosis pathway that are aberrantly expressed in AML, highlighting potential vulnerabilities that can be exploited for therapeutic benefit. Promising compounds such as Erastin and RSL3 have emerged as effective inducers of ferroptosis in AML cells, demonstrating the capacity to circumvent resistance mechanisms. These agents function by inhibiting GPX4 and disrupting cystine uptake, which culminates in enhanced lipid peroxidation and cell death. This chapter explores the therapeutic potential of targeting ferroptosis in AML, with a particular focus on modulating iron metabolism and key regulatory pathways. By exploiting the vulnerabilities in ferroptotic processes, these strategies offer a novel approach to enhancing therapeutic efficacy and addressing the critical challenge of drug resistance in AML.

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.

Sirtuin 6 (SIRT6) is a NAD⁺-dependent nuclear deacylase and mono-ADP-ribosylase with a wide spectrum of substrates. Through its pleiotropic activities, SIRT6 modulates either directly or indirectly key processes linked to cell fate determination and oncogenesis such as DNA damage repair, metabolic homeostasis, and apoptosis. SIRT6 regulates the expression and activity of both pro-apoptotic (e.g., Bax) and anti-apoptotic factors (e.g., Bcl-2, survivin) in a context-depending manner. Mounting evidence points towards a double-faced involvement of SIRT6 in tumor onset and progression since the block or induction of apoptosis lead to opposite outcomes in cancer. Here, we discuss the features and roles of SIRT6 in the regulation of cell death and cancer, also focusing on recently discovered small molecule modulators that can be used as chemical probes to shed further light on SIRT6 cancer biology and proposed as potential new generation anticancer therapeutics.