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Scafoglio, C.

Publications and source records attributed to Scafoglio, C..

3 recordsLinked to original sources
bioRxiv2025

Dietary α-Ketoglutarate delays lung adenocarcinoma in females and modulates TBX5-associated transcriptional programs and the immune microenvironment

Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. -Ketoglutarate (-KG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we show that dietary -KG remodels LUAD in a sex-dependent manner. In female mice, -KG reduced tumor area, decreased repressive histone marks (H3K27me3, H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, -KG-treated male mice exhibited increased tumor area, elevated H3K27me3, and immune remodeling characterized by CD8 T cell expansion and transcriptomic signatures of T cell exhaustion. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support -KG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies. SummaryOral -Ketoglutarate (-KG) has a known anti-aging effect and has been suggested to inhibit cancer development. However, the role of -KG in lung cancer is not known. Here, we investigated the effect of oral -KG on the development of lung adenocarcinoma in a KrasG12D-driven murine model. In females, -KG reduced lung tumor growth, accompanied by TBX5 induction, activation of a myogenesis transcriptional program, and loss of repressive histone methylation. In males, -KG increased tumor growth, coinciding with TBX5 repression, suppression of myogenesis programs, and accumulation of repressive histone methylation. -Ketoglutarate also remodeled the tumor immune microenvironment in a sex-dependent manner, with divergent effects on T cell infiltration. HIGHLIGHTSO_LIOral -Ketoglutarate reduces lung adenocarcinoma development in a genetically engineered murine model in a sex-dependent manner C_LIO_LIIn females, -Ketoglutarate reduces repressive histone marks and induces TBX5/myogenesis C_LIO_LIIn males, -Ketoglutarate increases repressive histone marks and suppresses TBX5/myogenesis C_LIO_LI-Ketoglutarate remodels the tumor immune microenvironment with sex-specific effects C_LIO_LITBX5 is enriched in female LUAD patients and predicts improved survival in human datasets C_LI CONTEXT AND SIGNIFICANCELung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer mortality worldwide. Preventive strategies are limited, highlighting the need for safe approaches that can intercept tumor progression. Metabolic cofactors are increasingly recognized as modulators of the cancer epigenome. Among these, -Ketoglutarate (-KG), a central metabolite of the tricarboxylic acid cycle, functions as a cofactor for chromatin-modifying enzymes. Here, we demonstrate that dietary -KG supplementation limits LUAD progression in female mice, reduces repressive histone methylation, and activates TBX5-associated transcriptional programs. These effects are sex dependent, underscoring the importance of biological context in shaping metabolic responses. In human LUAD, TBX5 is enriched in females and predicts improved survival, suggesting that it may serve as a marker of favorable outcome and help guide future studies of -KG. Together, this work identifies -KG as an epigenetically active metabolite with translational promise for lung cancer chemoprevention. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/677388v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1615a31org.highwire.dtl.DTLVardef@68884corg.highwire.dtl.DTLVardef@cc5ed1org.highwire.dtl.DTLVardef@1652c60_HPS_FORMAT_FIGEXP M_FIG C_FIG One-sentence summary-Ketoglutarate remodels lung adenocarcinoma through sex-dependent epigenetic, transcriptional, and immune reprogramming.

cancer biology↗
bioRxiv2023

Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma

Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction by glucose transporter blockade or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are unknown. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) induces cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (KG), leading to attenuated activity of KG-dependent histone demethylases and histone hypermethylation. We further show that this de-differentiated phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1 (HIF1), triggering epithelial to mesenchymal transition. Finally, we identified an HIF1-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to therapies targeting glucose metabolism.

cancer biology↗
bioRxiv2022

Mitoquinone mesylate targets SARS-CoV-2 and associated lung inflammation through host pathways

To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern in vitro and in vivo. Mito-MES had nanomolar in vitro antiviral potency against the Beta and Delta SARS-CoV-2 variants as well as the murine hepatitis virus (MHV-A59). Mito-MES given in SARS-CoV-2 infected K18-hACE2 mice through oral gavage reduced viral titer by nearly 4 log units relative to the vehicle group. We found in vitro that the antiviral effect of Mito-MES is attributable to its hydrophobic dTPP+ moiety and its combined effects scavenging reactive oxygen species (ROS), activating Nrf2 and increasing the host defense proteins TOM70 and MX1. Mito-MES was efficacious reducing increase in cleaved caspase-3 and inflammation induced by SARS-CoV2 infection both in lung epithelial cells and a transgenic mouse model of COVID-19. Mito-MES reduced production of IL-6 by SARS-CoV-2 infected epithelial cells through its antioxidant properties (Nrf2 agonist, coenzyme Q10 moiety) and the dTPP moiety. Given established safety of Mito-MES in humans, our results suggest that Mito-MES may represent a rapidly applicable therapeutic strategy that can be added in the therapeutic arsenal against COVID-19. Its potential long-term use by humans as diet supplement could help control the SARS-CoV-2 pandemic, especially in the setting of rapidly emerging SARS-CoV-2 variants that may compromise vaccine efficacy. One-Sentence SummaryMitoquinone/mitoquinol mesylate has potent antiviral and anti-inflammatory activity in preclinical models of SARS-CoV-2 infection.

microbiology↗