bims-medica 2025-01-12 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–01–12
fourteen papers selected by
Brett Chrest, Wake Forest University

α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
SLC7A5 is required for cancer cell growth under arginine-limited conditions.
Targeting Mitochondria in Glioma: New Hopes for a Cure.
Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.
Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.
Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP.
Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.
Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.
Formation of I2+III2 supercomplex rescues respiratory chain defects.
Glutamine metabolism is systemically different between primary and induced pluripotent stem cell-derived brain microvascular endothelial cells.
Dietary caloric input and tumor growth accelerate senescence and modulate liver and adipose tissue crosstalk.
Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study.
Increased consumption of ultra-processed foods and worse diet quality in colorectal cancer patients after colostomy: A prospective study.
HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.

Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]

α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.

DOI: https://doi.org/10.1182/blood.2024025245
Cell Rep. 2025 Jan 03. pii: S2211-1247(24)01481-5. [Epub ahead of print]44(1): 115130

SLC7A5 is required for cancer cell growth under arginine-limited conditions.

Kyle N Dunlap, Austin Bender, Alexis Bowles, Alex J Bott, Joshua Tay, Allie H Grossmann, Jared Rutter, Gregory S Ducker.

  Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.

Keywords:  CP: Cancer; CP: Metabolism; CRISPR screening; SLC7A5; amino acid transport; arginine; cancer metabolism; citrulline

DOI:  https://doi.org/10.1016/j.celrep.2024.115130
Biomedicines. 2024 Nov 28. pii: 2730. [Epub ahead of print]12(12):

Targeting Mitochondria in Glioma: New Hopes for a Cure.

Lidia Gatto, Vincenzo Di Nunno, Anna Ghelardini, Alicia Tosoni, Stefania Bartolini, Sofia Asioli, Stefano Ratti, Anna Luisa Di Stefano, Enrico Franceschi.

  Drugs targeting mitochondrial energy metabolism are emerging as promising antitumor therapeutics. Glioma treatment is extremely challenging due to the high complexity of the tumor and the high cellular heterogeneity. From a metabolic perspective, glioma cancer cells can be classified into the oxidative metabolic phenotype (mainly depending on mitochondrial respiration for energy production) and glycolytic phenotype or "Warburg effect" (mainly depending on glycolysis). Herein, we reviewed the function of novel bio-active molecules targeting oxidative phosphorylation (OXPHOS), mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising candidates to be further developed for glioma therapy. However, despite these initial encouraging results, it is imperative to rigorously assess the side effects of these metabolic drugs, which have a non-negligible toxicity profile.

Keywords:  IACS-010759; ONC201; OXPHOS; Warburg; metformin; mitochondria

DOI:  https://doi.org/10.3390/biomedicines12122730
Antioxidants (Basel). 2024 Dec 19. pii: 1563. [Epub ahead of print]13(12):

Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.

Milagros Junco, Clara Ventura, Florencia Ximena Santiago Valtierra, Eduardo Nestor Maldonado.

  Cancer metabolism is sustained both by enhanced aerobic glycolysis, characteristic of the Warburg phenotype, and oxidative metabolism. Cell survival and proliferation depends on a dynamic equilibrium between mitochondrial function and glycolysis, which is heterogeneous between tumors and even within the same tumor. During oxidative phosphorylation, electrons from NADH and FADH2 originated in the tricarboxylic acid cycle flow through complexes of the electron transport chain. Single electron leaks at specific complexes of the electron transport chain generate reactive oxygen species (ROS). ROS are a concentration-dependent double-edged sword that plays multifaceted roles in cancer metabolism. ROS serve either as signaling molecules favoring cellular homeostasis and proliferation or damage DNA, protein and lipids, causing cell death. Several aspects of ROS biology still remain unsolved. Among the unknowns are the actual levels at which ROS become cytotoxic and if toxicity depends on specific ROS species or if it is caused by a cumulative effect of all of them. In this review, we describe mechanisms of mitochondrial ROS production, detoxification, ROS-induced cytotoxicity, and the use of antioxidants in cancer treatment. We also provide updated information about critical questions on the biology of ROS on cancer metabolism and discuss dogmas that lack adequate experimental demonstration. Overall, this review brings a comprehensive perspective of ROS as drivers of cancer progression, inducers of cell death, and the potential use of antioxidants as anticancer therapy.

Keywords:  ROS; VDAC; antioxidants; cancer; lipid peroxidation; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/antiox13121563
Nat Cell Biol. 2025 Jan 06.

Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.

Anupama Hemalatha, Zongyu Li, David G Gonzalez, Catherine Matte-Martone, Karen Tai, Elizabeth Lathrop, Daniel Gil, Smirthy Ganesan, Lauren E Gonzalez, Melissa Skala, Rachel J Perry, Valentina Greco.

Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, HrasG12V cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and HrasG12V mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the HrasG12Vmodel. Using 13C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and HrasG12V mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.

DOI: https://doi.org/10.1038/s41556-024-01574-w
bioRxiv. 2024 Dec 17. pii: 2024.12.12.628246. [Epub ahead of print]

Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP.

Yunzhan Li, Zekun Li, Dongxiao Sun, Bo Ni, Mingjun Tan, Ashley E Shay, Min Wang, Chenyang Meng, Guangcong Shen, Boyang Fu, Yueying Shan, Tianxin Zhou, Yongjie Xie, Kun-Ming Chen, Bin Qiao, Yunkun Dang, Scot R Kimball, Pankaj K Singh, Xiuchao Wang, Jihui Hao, Shengyu Yang.

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the PDAC microenvironment. The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. Our data suggested that much like hypoxia, CLS in the tumor microenvironment could promote PDAC tumor growth and metastasis through upregulating anabolic metabolism of nucleotides and lipids.

DOI: https://doi.org/10.1101/2024.12.12.628246
Cancer Lett. 2025 Jan 02. pii: S0304-3835(25)00005-9. [Epub ahead of print]611 217441

Metabolic reprogramming, malignant transformation and metastasis: Lessons from chronic lymphocytic leukaemia and prostate cancer.

Madison T Hindes, Anthony M McElligott, Oliver G Best, Mark P Ward, Stavros Selemidis, Mark A Miles, Bukuru D Nturubika, Philip A Gregory, Paul H Anderson, Jessica M Logan, Lisa M Butler, David J Waugh, John J O'Leary, Shane M Hickey, Lauren A Thurgood, Douglas A Brooks.

  Metabolic reprogramming is a hallmark of cancer, crucial for malignant transformation and metastasis. Chronic lymphocytic leukaemia (CLL) and prostate cancer exhibit similar metabolic adaptations, particularly in glucose and lipid metabolism. Understanding this metabolic plasticity is crucial for identifying mechanisms contributing to metastasis. This review considers glucose and lipid metabolism in CLL and prostate cancer, exploring their roles in healthy and malignant states and during disease progression. In CLL, lipid metabolism supports cell survival and migration, with aggressive disease characterised by increased fatty acid oxidation and altered sphingolipids. Richter's transformation and aggressive lymphoma, however, exhibit a metabolic shift towards increased glycolysis. Similarly, prostate cell metabolism is unique, relying on citrate production in the healthy state and undergoing metabolic reprogramming during malignant transformation. Early-stage prostate cancer cells increase lipid synthesis and uptake, and decrease glycolysis, whereas metastatic cells re-adopt glucose metabolism, likely driven by interactions with the tumour microenvironment. Genetic drivers including TP53 and ATM mutations connect metabolic alterations to disease severity in these two malignancies. The bone microenvironment supports the metabolic demands of these malignancies, serving as an initiation niche for CLL and a homing site for prostate cancer metastases. By comparing these malignancies, this review underscores the importance of metabolic plasticity in cancer progression and highlights how CLL and prostate cancer may be models of circulating and solid tumours more broadly. The metabolic phenotypes throughout cancer cell transformation and metastasis, and the microenvironment in which these processes occur, present opportunities for interventions that could disrupt metastatic processes and improve patient outcomes.

Keywords:  Chronic lymphocytic leukaemia; Malignant transformation; Metabolic reprogramming; Metastasis; Microenvironment; Prostate cancer

DOI:  https://doi.org/10.1016/j.canlet.2025.217441
bioRxiv. 2024 Dec 20. pii: 2024.12.19.629431. [Epub ahead of print]

Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.

Sarah Ding, Anisha Banerjee, Sara N Burke, Abbi R Hernandez.

Many of the 'hallmarks of aging' involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8-25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. AKT expression was significantly reduced in kTRF fed rats within liver and muscle tissue. However, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance. Within CA3, higher levels of FOXO1 gene expression correlated with poorer cognitive performance in ad libitum fed rats. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.

DOI: https://doi.org/10.1101/2024.12.19.629431
Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]

Formation of I2+III2 supercomplex rescues respiratory chain defects.

Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R L Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A Stroud, James A Letts, Lena Ho.

  Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.

Keywords:  complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex

DOI:  https://doi.org/10.1016/j.cmet.2024.11.011
J Cereb Blood Flow Metab. 2025 Jan 07. 271678X241310729

Glutamine metabolism is systemically different between primary and induced pluripotent stem cell-derived brain microvascular endothelial cells.

Callie M Weber, Bilal Moiz, Marzyeh Kheradmand, Arielle Scott, Claire Kettula, Brooke Wunderler, Viviana Alpízar Vargas, Alisa Morss Clyne.

  Human primary (hpBMEC) and induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (hiBMEC) are interchangeably used in blood-brain barrier models to study neurological diseases and drug delivery. Both hpBMEC and hiBMEC use glutamine as a source of carbon and nitrogen to produce metabolites and build proteins essential to cell function and communication. We used metabolomic, transcriptomic, and computational methods to examine how hpBMEC and hiBMEC metabolize glutamine, which may impact their utility in modeling the blood-brain barrier. We found that glutamine metabolism was systemically different between the two cell types. hpBMEC had a higher metabolic rate and produced more glutamate and GABA, while hiBMEC rerouted glutamine to produce more glutathione, fatty acids, and asparagine. Higher glutathione production in hiBMEC correlated with higher oxidative stress compared to hpBMEC. α-ketoglutarate (α-KG) supplementation increased glutamate secretion from hiBMEC to match that of hpBMEC; however, α-KG also decreased hiBMEC glycolytic rate. These fundamental metabolic differences between BMEC types may impact in vitro blood-brain barrier model function, particularly communication between BMEC and surrounding cells, and emphasize the importance of evaluating the metabolic impacts of iPSC-derived cells in disease models.

Keywords:  Blood-brain barrier; brain microvascular endothelial cells; glutamate metabolism; glutamine metabolism; metabolic flux analysis

DOI:  https://doi.org/10.1177/0271678X241310729
Commun Biol. 2025 Jan 07. 8(1): 18

Dietary caloric input and tumor growth accelerate senescence and modulate liver and adipose tissue crosstalk.

José Xavier do Nascimento Júnior, Júlia da Conceição Gomes, Ricardo Imbroisi Filho, Helber de Maia Valença, Jéssica Ristow Branco, Amanda Bandeira Araújo, Amanda de Oliveira Esteves Moreira, Letícia Diniz Crepaldi, Larissa Pereira Paixão, Alan C Ochioni, Thainá M Demaria, João Gabriel Bernardo Leandro, Livia Marques Casanova, Mauro Sola-Penna, Patricia Zancan.

Metabolic alterations are related to tumorigenesis and other age-related diseases that are accelerated by "Westernized" diets. In fact, hypercaloric nutrition is associated with an increased incidence of cancers and faster aging. Conversely, lifespan-extending strategies, such as caloric restriction, impose beneficial effects on both processes. Here, we investigated the metabolic consequences of hypercaloric-induced aging on tumor growth in female mice. Our findings indicate that a high-fat high-sucrose diet increases tumor growth mainly due to the boosted oxidation of glucose and fatty acids. Consequently, through an increased expression of lactate, IGFBP3, and PTHLH, tumors modulate liver and white adipose tissue metabolism. In the liver, the induced tumor increases fibrosis and accelerates the senescence process, despite the lower systemic pro-inflammatory state. Importantly, the induced tumor induces the wasting and browning of white adipose tissue, thereby reversing diet-induced insulin resistance. Finally, we suggest that tumor growth alters liver-adipose tissue crosstalk that upregulates Fgf21, induces senescence, and negatively modulates lipids and carbohydrates metabolism even in caloric-restricted-fed mice.

DOI: https://doi.org/10.1038/s42003-025-07451-y
Am J Clin Nutr. 2025 Jan 07. pii: S0002-9165(25)00005-X. [Epub ahead of print]

Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study.

Matthew A Devall, Stephen Eaton, Gaizun Hu, Xiangqing Sun, Ethan Jakum, Samyukta Venkatesh, Steven M Powell, Cynthia Yoshida, Daniel J Weisenberger, Gregory S Cooper, Joseph Willis, Seham Ebrahim, Jamie Zoellner, Graham Casey, Li Li.

   BACKGROUND: An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults.
OBJECTIVE: We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology.
METHODS: Deoxyribonucleic acid (DNA) methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of food frequency questionnaire data on fructose consumption in normal colon biopsies (n=79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA (n=5) and EA (n=5) adults were exposed to 4.4mM of fructose for 72 hours. Differentially expressed genes (DEGs) were identified using DESeq2.
RESULTS: We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P=3.28E-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveals potential roles for ankyrin repeat domain-containing protein 23 (ANKRD23) and phosphofructokinase, platelet (PFKP) in fructose-mediated CRC risk for AA individuals.
CONCLUSIONS: Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.

Keywords:  African American adults; DNA methylation; colon cancer; colon cancer risk; colon cancer sidedness; disparities; fructose; high fructose corn syrup; race; sugar sweetened beverages

DOI:  https://doi.org/10.1016/j.ajcnut.2025.01.005
PLoS One. 2025 ;20(1): e0310320

Increased consumption of ultra-processed foods and worse diet quality in colorectal cancer patients after colostomy: A prospective study.

Arenamoline Xavier Duarte, Karine de Almeida Silva, Isabela Borges Ferreira, Cristiana Araújo Gontijo, Geórgia das Graças Pena.

Colorectal cancer (CRC) is commonly treated with intestinal resections that lead to colostomy, which can influence changes in eating habits. This study aimed to analyze energy and nutrient intake, diet quality, and food consumption based on the processing level in CRC patients after colostomy. A prospective study was carried out at three time points (T0-recent colostomy, T1-3 months after colostomy, and T2-6 months after colostomy). Food intake was assessed by 24-hour dietary recall. Macro-micronutrient consumption, the Brazilian Healthy Eating Index-Revised (BHEI-R), and food consumption according to processing level by NOVA classification (raw or minimally processed, processed, and ultra-processed foods) were estimated. Generalized estimating equations were used to compare the food intake variables with time points. Of the 46 patients, 52.2% were women, and the mean age was 60.6±12.2 years old. There was a change in food consumption over time, with an increase in energy consumption (kcal and kcal/kg), lipids, and sodium, in addition to a reduction in some nutrients such as protein (g and g/kg), fiber, vitamin B1 and C and phosphorus. Regarding the key outcomes, BHEI-R and NOVA classification showed a poor diet quality with a reduction in total index (p = 0.022), raw food (p = 0.001), total fruits, and whole fruit consumption (p = 0.001), and an increase in sodium (p = 0.001) at 3 and/or 6 months after colostomy concomitant an increase in ultra-processed food (p = 0.015). Nutritional counseling is essential in care, effective eating changes habits improvement of symptoms and nutritional status, besides avoiding potential cancer recurrence.

DOI: https://doi.org/10.1371/journal.pone.0310320
Cell Signal. 2025 Jan 03. pii: S0898-6568(24)00559-X. [Epub ahead of print]127 111583

HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.

Ruipeng Bian, Yingying Shang, Nahua Xu, Baiping Liu, Yanni Ma, Hui Li, Jieping Chen, Qi Yao.

  Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.

Keywords:  AML; Ferroptosis; HDAC inhibitors; Iron metabolism

DOI:  https://doi.org/10.1016/j.cellsig.2024.111583