Autophagy, selective autophagy, cancer, cancer stem cells, natural products, new pharmacological target
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Scopus Publications
Scopus Publications
Uridine diphosphate drives myeloid differentiation and functional reprogramming through dynamic transcriptional network Caterina Giordano, Debora Gentile, Emilio Straface, Raffaella Gallo, Costanza Maria Cristiani, et al. Frontiers in Immunology, 2026 Background Extracellular nucleotides regulate immune responses through purinergic signaling. Uridine diphosphate (UDP), a pyrimidine-derived metabolite, has been shown to accumulate in the tumor microenvironment and modulate T cell activation. However, its effects on human myeloid cells remain poorly understood. Since monocytes represent key precursors for macrophages and dendritic cells, we investigated whether UDP could influence their proliferative and differentiation potential within peripheral blood mononuclear cells (PBMCs). Methods Freshly isolated PBMCs were stimulated with UDP, and CD14 + cell proliferation was analyzed using CFSE staining and flow cytometry. The impact of UDP on dendritic differentiation was evaluated in PBMC cultures and in purified CD14 + monocytes exposed to IL-4 and GM-CSF, in the presence or absence of UDP. Phagocytic and efferocytic activities were assessed using fluorescently labeled E. coli and apoptotic HeLa cells, respectively. Transcriptomic profiling of PBMCs stimulated with UDP for 2, 6, or 24 hours was performed using the NanoString Human Immunology Panel. Results UDP markedly suppressed CD14 + monocyte proliferation and promoted the generation of HLA-DR + CD11c + dendritic-like cells. In purified monocytes, UDP enhanced IL-4/GM-CSF-driven differentiation into CD14 - CD16 - HLA-DR + CD11c + monocyte-derived dendritic cells (moDCs). Functionally, UDP increased both bacterial phagocytosis and efferocytosis. Transcriptomic analysis revealed eight gene clusters with distinct temporal expression patterns, driven by transcription factors such as NF-κB, RUNX3, BATF, and IRF5, indicating coordinated modulation of inflammatory, antigen-presentation, and regulatory pathways. Conclusion Our findings identify UDP as a potent immunomodulatory metabolite that restricts monocyte proliferation while promoting differentiation into dendritic-like cells with enhanced phagocytic capacity. UDP engages complex transcriptional programs that integrate innate activation with adaptive immune regulation, highlighting its potential role in immune homeostasis and inflammation control.
FABP5 is a key player in metabolic modulation and NF-κB dependent inflammation driving pleural mesothelioma Eleonora Vecchio, Raffaella Gallo, Selena Mimmi, Debora Gentile, Caterina Giordano, et al. Communications Biology, 2025 Pleural mesothelioma (PM) poses a significant challenge in oncology due to its intricate molecular and metabolic landscape, chronic inflammation, and heightened oxidative stress, which contribute to its notorious resilience and clinical complexities. Despite advancements, the precise mechanisms driving PM carcinogenesis remain elusive, impeding therapeutic progress. Here, we explore the interplay between tumor growth dynamics, lipid metabolism, and NF-κB dysregulation in malignant pleural mesothelioma, shedding light on novel molecular mechanisms underlying its pathogenesis. Our study reveals distinctive growth dynamics in PM cells, characterized by heightened proliferation, altered cell cycle progression, and resistance to apoptosis. Intriguingly, PM cells exhibit increased intracellular accumulation of myristic, palmitic, and stearic acids, suggestive of augmented lipid uptake and altered biosynthesis. Notably, we identify FABP5 as a key player in driving metabolic alterations and inflammation through NF-κB dysregulation in mesothelioma cells, distinguishing them from normal mesothelial cells. Silencing of FABP5 leads to significant alterations in cell dynamics, metabolism, and NF-κB activity, highlighting its potential as a therapeutic target. Our findings unveil a reciprocal relationship between lipid metabolism and inflammation in PM, providing a foundation for targeted therapeutic strategies. Overall, this comprehensive investigation offers insights into the intricate molecular mechanisms driving PM pathogenesis and identifies potential avenues for therapeutic intervention.
Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders Anna Matveeva, Orla Watters, Ani Rukhadze, Niraj Khemka, Debora Gentile, et al. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2024 OBJECTIVE Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD. METHODS By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage. RESULTS In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology. CONCLUSIONS Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.
Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy? Debora Gentile, Marianna Esposito, Paolo Grumati Frontiers in Molecular Biosciences, 2022 Autophagy is an evolutionary conserved catabolic pathway that uses a unique double-membrane vesicle, called autophagosome, to sequester cytosolic components, deliver them to lysosomes and recycle amino-acids. Essentially, autophagy acts as a cellular cleaning system that maintains metabolic balance under basal conditions and helps to ensure nutrient viability under stress conditions. It is also an important quality control mechanism that removes misfolded or aggregated proteins and mediates the turnover of damaged and obsolete organelles. In this regard, the idea that autophagy is a non-selective bulk process is outdated. It is now widely accepted that forms of selective autophagy are responsible for metabolic rewiring in response to cellular demand. Given its importance, autophagy plays an essential role during tumorigenesis as it sustains malignant cellular growth by acting as a coping-mechanisms for intracellular and environmental stress that occurs during malignant transformation. Cancer development is accompanied by the formation of a peculiar tumor microenvironment that is mainly characterized by hypoxia (oxygen < 2%) and low nutrient availability. Such conditions challenge cancer cells that must adapt their metabolism to survive. Here we review the regulation of autophagy and selective autophagy by hypoxia and the crosstalk with other stress response mechanisms, such as UPR. Finally, we discuss the emerging role of ER-phagy in sustaining cellular remodeling and quality control during stress conditions that drive tumorigenesis.
