bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–01–12
seventeen papers selected by
Marc Segarra Mondejar
  1. Tumor Metabolic Reprogramming and Ferroptosis: The Impact of Glucose, Protein, and Lipid Metabolism.
  2. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  3. MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.
  4. CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
  5. Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
  6. Mechanisms of metabolism-coupled protein modifications.
  7. The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.
  8. The ability of pentose pathways to form all essential metabolites provides clues to the origins of metabolism.
  9. Systemic metabolic crosstalk as driver of cancer cachexia.
  10. NAD+ metabolism in acute kidney injury and chronic kidney disease transition.
  11. NAC regulates metabolism and cell fate in intestinal stem cells.
  12. SLC7A5 is required for cancer cell growth under arginine-limited conditions.
  13. Ferroptosis and PANoptosis under hypoxia pivoting on the crosstalk between DHODH and GPX4 in corneal epithelium.
  14. A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.
  15. Cross comparison of imaging strategies of mitochondria in C. elegans during aging.
  16. The role of GOT1 in cancer metabolism.
  17. FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction.
  1. Int J Mol Sci. 2024 Dec 14. pii: 13413. [Epub ahead of print]25(24):
    Tumor Metabolic Reprogramming and Ferroptosis: The Impact of Glucose, Protein, and Lipid Metabolism.
    Keyu Zhu, Yuang Cai, Lan Lan, Na Luo.
      Ferroptosis, a novel form of cell death discovered in recent years, is typically accompanied by significant iron accumulation and lipid peroxidation during the process. This article systematically elucidates how tumor metabolic reprogramming affects the ferroptosis process in tumor cells. The paper outlines the basic concepts and physiological significance of tumor metabolic reprogramming and ferroptosis, and delves into the specific regulatory mechanisms of glucose metabolism, protein metabolism, and lipid metabolism on ferroptosis. We also explore how complex metabolic changes in the tumor microenvironment further influence the response of tumor cells to ferroptosis. Glucose metabolism modulates ferroptosis sensitivity by influencing intracellular energetic status and redox balance; protein metabolism, involving amino acid metabolism and protein synthesis, plays a crucial role in the initiation and progression of ferroptosis; and the relationship between lipid metabolism and ferroptosis primarily manifests in the generation and elimination of lipid peroxides. This review aims to provide a new perspective on how tumor cells regulate ferroptosis through metabolic reprogramming, with the ultimate goal of offering a theoretical basis for developing novel therapeutic strategies targeting tumor metabolism and ferroptosis.
    Keywords:  ferroptosis; glucose metabolism; lipid metabolism; protein metabolism; tumor metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms252413413
  2. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  3. Bioinform Adv. 2025 ;5(1): vbae172
    MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.
    Stephen Chapman, Theo Brunet, Arnaud Mourier, Bianca H Habermann.
       Motivation: Mitochondria are essential for cellular metabolism and are inherently flexible to allow correct function in a wide range of tissues. Consequently, dysregulated mitochondrial metabolism affects different tissues in different ways leading to challenges in understanding the pathology of mitochondrial diseases. System-level metabolic modelling is useful in studying tissue-specific mitochondrial metabolism, yet despite the mouse being a common model organism in research, no mouse specific mitochondrial metabolic model is currently available.
    Results: Building upon the similarity between human and mouse mitochondrial metabolism, we present mitoMammal, a genome-scale metabolic model that contains human and mouse specific gene-product reaction rules. MitoMammal is able to model mouse and human mitochondrial metabolism. To demonstrate this, using an adapted E-Flux algorithm, we integrated proteomic data from mitochondria of isolated mouse cardiomyocytes and mouse brown adipocyte tissue, as well as transcriptomic data from in vitro differentiated human brown adipocytes and modelled the context specific metabolism using flux balance analysis. In all three simulations, mitoMammal made mostly accurate, and some novel predictions relating to energy metabolism in the context of cardiomyocytes and brown adipocytes. This demonstrates its usefulness in research in cardiac disease and diabetes in both mouse and human contexts.
    Availability and implementation: The MitoMammal Jupyter Notebook is available at: https://gitlab.com/habermann_lab/mitomammal.
    DOI:  https://doi.org/10.1093/bioadv/vbae172
  4. Nat Commun. 2025 Jan 09. 16(1): 541
    CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
    Dorian V Ziegler, Kanishka Parashar, Lucia Leal-Esteban, Jaime López-Alcalá, Wilson Castro, Nadège Zanou, Laia Martinez-Carreres, Katharina Huber, Xavier Pascal Berney, María M Malagón, Catherine Roger, Marie-Agnès Berger, Yves Gouriou, Giulia Paone, Hector Gallart-Ayala, George Sflomos, Carlos Ronchi, Julijana Ivanisevic, Cathrin Brisken, Jennifer Rieusset, Melita Irving, Lluis Fajas.
      The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.
    DOI:  https://doi.org/10.1038/s41467-024-55605-z
  5. Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00487-X. [Epub ahead of print]37(1): 5-6
    Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
    Sijie Tan, Nora Kory.
      Mitochondria produce energy and building blocks essential for cell growth. How these competing processes are balanced and sustained during nutrient scarcity remains unclear. Ryu et al. uncover distinct mitochondrial subpopulations, one dedicated to ATP production and another to macromolecule synthesis, enabling cell growth and proliferation under nutrient-limiting conditions.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.006
  6. Nat Chem Biol. 2025 Jan 07.
    Mechanisms of metabolism-coupled protein modifications.
    Bingsen Zhang, Frank C Schroeder.
      Intricate coupling between metabolism and protein post-translational modifications (PTMs) has emerged as a fundamental aspect of cellular regulation. Recent studies demonstrate that protein modifications can originate from diverse metabolites, and that their regulation is closely tied to the cellular metabolic state. Here we explore recently uncovered PTMs, including the concept of 'modification of a modification', as well as associated feedback and feedforward regulatory mechanisms, in which modified proteins impact not only related metabolic pathways but also other signaling cascades affecting physiology and diseases. The recently uncovered role of nucleus-localized metabolic enzymes for histone modifications additionally highlights the importance of cell-compartment-specific metabolic states. We further comment on the utility of untargeted metabolomics and proteomics for previously unrecognized PTMs and associated metabolic patterns. Together, these advances have uncovered a dynamic interplay between metabolism and PTMs, offering new perspectives for understanding metabolic regulation and developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41589-024-01805-z
  7. Nat Metab. 2025 Jan 06.
    The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.
    Julius Palme, Ang Li, Michael Springer.
      Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction. However, in the galactose-responsive (GAL) pathway of Saccharomyces cerevisiae, we find that induction is stabilized by flux sensing. Previously proposed mechanisms for flux sensing postulate the existence of metabolites whose concentrations correlate with flux. The GAL pathway flux sensor uses a different principle: the galactokinase Gal1p both performs the first step in GAL metabolism and reports on flux by signalling to the GAL repressor, Gal80p. Both Gal1p catalysis and Gal1p signalling depend on the concentration of the Gal1p-GAL complex and are therefore directly correlated. Given the simplicity of this mechanism, flux sensing is probably a general feature throughout metabolic regulation.
    DOI:  https://doi.org/10.1038/s42255-024-01181-x
  8. PLoS Biol. 2025 Jan;23(1): e3002996
    The ability of pentose pathways to form all essential metabolites provides clues to the origins of metabolism.
    Steffen N Lindner, Markus Ralser.
      The structure of the early metabolic network is unknown. Here, we report that when considered together, pentose utilization pathways form all life-essential precursors. We speculate that the chemistry preserved in pentose metabolism could therefore have been a central structural element in early metabolism.
    DOI:  https://doi.org/10.1371/journal.pbio.3002996
  9. Trends Endocrinol Metab. 2025 Jan 04. pii: S1043-2760(24)00327-8. [Epub ahead of print]
    Systemic metabolic crosstalk as driver of cancer cachexia.
    Elisabeth Wyart, Giovanna Carrà, Elia Angelino, Fabio Penna, Paolo E Porporato.
      Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of cachexia itself, no longer viewed merely as a secondary consequence of cancer but as an active process. However, metabolic dysregulations in cachexia are currently studied in an organ-specific manner, failing to be fully integrated into a comprehensive framework that explains their functional roles in disease progression. Thus, in this review, we aim to provide a general overview of the various metabolic alterations with a potential systemic impact.
    Keywords:  cachexia; cross-talk; metabolism; muscle wasting
    DOI:  https://doi.org/10.1016/j.tem.2024.12.005
  10. Trends Mol Med. 2025 Jan 04. pii: S1471-4914(24)00337-X. [Epub ahead of print]
    NAD+ metabolism in acute kidney injury and chronic kidney disease transition.
    Rahil Alhumaidi, Huihui Huang, Marie Christelle Saade, Amanda J Clark, Samir M Parikh.
      Disturbances in kidney tubular cell metabolism are increasingly recognized as a feature of acute kidney injury (AKI). In AKI, tubular epithelial cells undergo abnormal metabolic shifts that notably disrupt NAD+ metabolism. Recent advancements have highlighted the critical role of NAD+ metabolism in AKI, revealing that acute disruptions may lead to lasting cellular changes, thereby promoting the transition to chronic kidney disease (CKD). This review explores the molecular mechanisms underlying metabolic dysfunction in AKI, with a focus on NAD+ metabolism, and proposes several cellular processes through which acute aberrations in NAD+ may contribute to long-term changes in the kidney.
    Keywords:  NAD(+); acute kidney injury; chronic kidney disease; fatty acid oxidation; metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molmed.2024.12.004
  11. Sci Adv. 2025 Jan 10. 11(2): eadn9750
    NAC regulates metabolism and cell fate in intestinal stem cells.
    Sofia Ramalho, Ferhat Alkan, Stefan Prekovic, Katarzyna Jastrzebski, Eric Pintó Barberà, Liesbeth Hoekman, Maarten Altelaar, Cecilia de Heus, Nalan Liv, Maria J Rodríguez-Colman, Mehmet Yilmaz, Rob van der Kammen, Juliette Fedry, Mark C de Gooijer, Saskia Jacoba Elisabeth Suijkerbuijk, William J Faller, Joana Silva.
      Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
    DOI:  https://doi.org/10.1126/sciadv.adn9750
  12. 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
  13. Free Radic Biol Med. 2025 Jan 04. pii: S0891-5849(24)01159-6. [Epub ahead of print]228 173-182
    Ferroptosis and PANoptosis under hypoxia pivoting on the crosstalk between DHODH and GPX4 in corneal epithelium.
    Ming-Feng Wu, Xi Peng, Ming-Chang Zhang, Huan Guo, Hua-Tao Xie.
      Cell death under stress conditions like hypoxia, involves multiple interconnected pathways. In this study, a stable dihydroorotate dehydrogenase (DHODH) knockdown human corneal epithelial cell line was established to explore the regulation of hypoxic cell death, which was mitigated by various cell death inhibitors, particularly by a lipid peroxyl radical scavenger liproxstatin-1 (Lip-1), suggesting that hypoxic cell death involves crosstalk of ferroptosis and PANoptosis. We discovered that both DHODH and Glutathione peroxidase 4 (GPX4) protected cells from hypoxic death by inhibiting lipid peroxidation, mitochondrial reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. However, upregulation of DHODH suppressed GPX4 upstream, exhibiting a trade-off in the expression levels between DHODH and GPX4 under hypoxia, with DHODH exerting a more decisive impact on cell survival. DHODH knockdown under hypoxia did not significantly alter lipid peroxidation levels, demonstrating the balance between DHODH and GPX4 expression finely regulated cellular ferroptosis homeostasis. This study highlights the complex interplay between ferroptosis and PANoptosis in hypoxic cell death, particularly the dual role of DHODH in regulating both pathways. DHODH is not merely maintaining the quantity of mitochondria but is promoting the selection of mitochondria favorable to cell survival. These findings not only deepen our understanding of cell death but also suggest potential therapeutic strategies for diseases involving oxidative stress and mitochondrial dysfunction.
    Keywords:  Dihydroorotate dehydrogenase; Ferroptosis; Glutathione peroxidase 4; PANoptosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.050
  14. Biochim Biophys Acta Mol Cell Res. 2025 Jan 05. pii: S0167-4889(25)00005-9. [Epub ahead of print] 119900
    A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.
    Martin Hirtl, Benjamin Gottschalk, Olaf A Bachkoenig, Furkan E Oflaz, Corina Madreiter-Sokolowski, Morten Andre Høydal, Wolfgang F Graier.
      The uptake of Ca2+ by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca2+ elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca2+. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.
    Keywords:  Inner mitochondrial membrane (IMM); Mitochondrial calcium uniporter (MCU); Mitochondrial calcium uptake 1 (MICU1); Stimulated-emission depletion (STED); Structured illumination microscopy (SIM)
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119900
  15. bioRxiv. 2024 Dec 25. pii: 2024.12.24.630282. [Epub ahead of print]
    Cross comparison of imaging strategies of mitochondria in C. elegans during aging.
    Juri Kim, Naibedya Dutta, Matthew Vega, Andrew Bong, Maxim Averbuhk, Rebecca Aviles Barahona, Athena Alcala, Jacob T Holmes, Gilberto Garcia, Ryo Higuchi-Sanabria.
      Mitochondria are double membrane-bound organelles with pleiotropic roles in the cell, including energy production through aerobic respiration, calcium signaling, metabolism, proliferation, immune signaling, and apoptosis. Dysfunction of mitochondria is associated with numerous physiological consequences and drives various diseases, and is one of twelve biological hallmarks of aging, linked to aging pathology. There are many distinct changes that occur to the mitochondria during aging including changes in mitochondrial morphology, which can be used as a robust and simple readout of mitochondrial quality and function. Although mitochondrial morphology alone cannot be used to conclude the quality of mitochondria, it is highly correlated with mitochondrial function whereby mitochondria exhibit increased fragmentation with age in multiple cell types of the nematode C. elegans. Thus, C. elegans serve as a robust model for rapidly measuring mitochondrial morphology changes during aging. To standardize imaging methods for mitochondrial morphology in C. elegans, we provide a detailed comparative characterization of several transgenic constructs, highlighting benefits and caveats for aging biology studies.
    DOI:  https://doi.org/10.1101/2024.12.24.630282
  16. Front Oncol. 2024 ;14 1519046
    The role of GOT1 in cancer metabolism.
    Huan Peng, Huihong Dou, Sheng He, Yu-An Xie, Qinle Zhang, Jianqiu Zheng.
      GOT1, a cytoplasmic glutamic oxaloacetic transaminase, plays a critical role in various metabolic pathways essential for cellular homeostasis and dysregulated metabolism. Recent studies have highlighted the significant plasticity and roles of GOT1 in metabolic reprogramming through participating in both classical and non-classical glutamine metabolism, glycolytic metabolism, and other metabolic pathways. This review summarizes emerging insights on the metabolic roles of GOT1 in cancer cells and emphasizes the response of cancer cells to altered metabolism when the expression of GOT1 is altered. We review how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT1 is inhibited and delineate the molecular mechanisms of GOT1's interaction with specific oncogenes and regulators at multiple levels, including transcriptional and epigenetic regulation, which govern cellular growth and metabolism. These insights may provide new directions for cancer metabolism research and novel targets for cancer treatment.
    Keywords:  GOT1; cancer; cell metabolism; metabolic reprogramming; therapeutic target
    DOI:  https://doi.org/10.3389/fonc.2024.1519046
  17. Cell Commun Signal. 2025 Jan 07. 23(1): 13
    FOXC1-mediated serine metabolism reprogramming enhances colorectal cancer growth and 5-FU resistance under serine restriction.
    Zhukai Chen, Jiacheng Xu, Kang Fang, Hanyu Jiang, Zhuyun Leng, Hao Wu, Zehua Zhang, Zeyu Wang, Zhaoxing Li, Mingchuang Sun, Ziying Zhao, Anqi Feng, Shihan Zhang, Yuan Chu, Lechi Ye, Meidong Xu, Lingnan He, Tao Chen.
      Colorectal cancer (CRC) is the most common gastrointestinal malignancy, and 5-Fluorouracil (5-FU) is the principal chemotherapeutic drug used for its treatment. However, 5-FU resistance remains a significant challenge. Under stress conditions, tumor metabolic reprogramming influences 5-FU resistance. Serine metabolism plasticity is one of the crucial metabolic pathways influencing 5-FU resistance in CRC. However, the mechanisms by which CRC modulates serine metabolic reprogramming under serine-deprived conditions remain unknown. We found that exogenous serine deprivation enhanced the expression of serine synthesis pathway (SSP) genes, which in turn supported CRC cell growth and 5-FU resistance. Serine deprivation activate the ERK1/2-p-ELK1 signaling axis, leading to upregulated FOXC1 expression in CRC cells. Elevated FOXC1 emerged as a critical element, promoting the transcription of serine metabolism enzymes PHGDH, PSAT1, and PSPH, which in turn facilitated serine production, supporting CRC growth. Furthermore, through serine metabolism, FOXC1 influenced purine metabolism and DNA damage repair, thereby increasing 5-FU resistance. Consequently, combining dietary serine restriction with targeted therapy against the ERK1/2-pELK1-FOXC1 axis could be a highly effective strategy for treating CRC, enhancing the efficacy of 5-FU.
    Keywords:  5-Fluorouracil resistance; Colorectal cancer; De novo serine synthesis; FOXC1; Metabolic reprogramming
    DOI:  https://doi.org/10.1186/s12964-024-02016-8
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