bims-cesirm Biomed News
on Cell Signaling mediated regulation of metabolism
Issue of 2025–06–01
twelve papers selected by
Tigist Tamir, University of North Carolina



  1. Mol Cell. 2025 May 21. pii: S1097-2765(25)00412-5. [Epub ahead of print]
      Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.
    Keywords:  GSTP1; IDH1; UMPS; cell signaling; computational modelling; metabolism; metabolomics; obesity; oxidative stress response; phosphoproteomics
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.007
  2. Discov Oncol. 2025 May 26. 16(1): 929
      Metabolic reprogramming occurs alongside tumor development. As cancers advance from precancerous lesions to locally invasive tumors and then to metastatic tumors, metabolic patterns exhibit distinct changes, including mutations in metabolic enzymes and modifications in the activity of metabolic regulatory proteins. Alterations in metabolic patterns can influence tumor evolution, either establishing or alleviating metabolic burdens and facilitating cancer growth. To fully understand how metabolic reprogramming helps tumors grow and find the metabolic activities that are most useful for treating tumors, we need to have a deeper understanding of how metabolic patterns are controlled as tumors grow. Post-translational modifications (PTMs), a critical mechanism in the regulation of protein function, can influence protein activity, stability, and interactions in several ways. In tumor cells, PTMs-mediated metabolic reprogramming is a crucial mechanism for adapting to the challenging microenvironment and sustaining fast growth. This article will deeply explore the intricate regulatory mechanism of PTMs on metabolic reprogramming and its role in tumor progression, with the expectation of providing new theoretical basis and potential targets for tumor treatment.
    Keywords:  Cancer metabolic; Post-translational modifications; Tumor metabolic reprogramming
    DOI:  https://doi.org/10.1007/s12672-025-02674-1
  3. Biomolecules. 2025 May 12. pii: 702. [Epub ahead of print]15(5):
      Multiple myeloma (MM) remains an incurable hematologic malignancy due to the inevitable development of drug resistance, particularly in relapsed or refractory cases. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, and glycosylation, play pivotal roles in regulating protein function, stability, and interactions, thereby influencing MM pathogenesis and therapeutic resistance. This review comprehensively explores the mechanisms by which dysregulated PTMs contribute to drug resistance in MM, focusing on their impact on key signaling pathways, metabolic reprogramming, and the tumor microenvironment. We highlight how PTMs modulate drug uptake, alter drug targets, and regulate cell survival signals, ultimately promoting resistance to PIs, IMiDs, and other therapeutic agents. Furthermore, we discuss emerging therapeutic strategies targeting PTM-related pathways, which offer promising avenues for overcoming resistance to treatment. By integrating preclinical and clinical insights, this review underscores the potential of PTM-targeted therapies to enhance treatment efficacy and improve patient outcomes in MM.
    Keywords:  drug resistance; immunomodulatory drugs (IMiDs); multiple myeloma; post-translational modifications; proteasome inhibitors (PIs); signaling pathways; therapeutic targets; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom15050702
  4. J Biol Chem. 2025 May 22. pii: S0021-9258(25)02124-6. [Epub ahead of print] 110274
      Sirtuin 2 (SIRT2) is a ubiquitously expressed cellular enzyme that deacylates protein lysine residues using NAD+ as a cofactor. SIRT2-mediated post-translational modifications on a plethora of protein targets position the enzyme to exert a wide-ranging regulatory role in many physiological and pathological processes. More than 39 SIRT2 crystal structures in complex with substrates, products, mimetics of substrates and products, and modulators, have been reported. The Rossmann fold of the catalytic core presents inducible acyl and cofactor binding cavities that accommodate acyl chains of diverse lengths. These structures have provided information for the design of mechanism- and substrate-based inhibitors. Indeed, a specific SIRT2 selectivity pocket has been described and can be targeted by different chemotypes. Despite the determination of many crystal structures, numerous open questions remain, especially relating to the development of small molecule modulators, full or partial activation or inhibition, and relating these effects to different therapeutic applications. Additional questions include understanding the role of the disordered termini, and the role of potential quaternary states (monomer, dimer, and trimer). Deeper insight into these issues may facilitate the development of SIRT2 selective modulators that can be tailored to different pathological scenarios, such as viral infections and cancers, in which either activation or inhibition of SIRT2 may be of therapeutic benefit. This review covers the following topics: (1) primary to quaternary and catalytic structural biology; (2) structural insights into molecular modulation of SIRT2 (inhibition and selectivity by mechanism-based inhibitors, substrate-mimicking inhibitors, C pocket-binding inhibitors, and selectivity pocket binding inhibitors, including insights to activation; and (3) the impact of structural variations (mutations, post-translational modifications, polymorphs, protein interactions). Despite considerable progress, key knowledge gaps remain regarding the design of optimized SIRT2 modulators. Addressing these uncertainties, particularly within the realms of full/partial activation/inhibition, off-target effects, and tailoring modulators to specific pathologies, will require further investigation into the roles of the SIRT2 disordered termini, quaternary states, and post-translational modifications. Ultimately, unraveling these intricacies holds the key to unlocking the therapeutic potential of SIRT2 modulation.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110274
  5. Antioxidants (Basel). 2025 May 16. pii: 594. [Epub ahead of print]14(5):
      Receptor-mediated endocytosis (RME) is a commonly recognized receptor internalization process of receptor degradation or recycling. However, recent studies have supported that RME is closely related to signal propagation and amplification from the plasma membrane to the cytosol. Few studies have elucidated the role of H2O2, a mild oxidant among reactive oxygen species (ROS) in RME and second messenger of signal propagation. In the present study, we investigated the regulatory function of H2O2 in early endosomes during signaling throughout receptor-mediated endocytosis. In mammalian cells with a physiological amount of H2O2 generated during epidermal growth factor (EGF) activation, fluorescence imaging showed that the levels of two activating phosphorylations on Ser473 and Thr308 of Akt were transiently increased in the plasma membrane, but the predominant p-Akt on Ser473 appeared in early endosomes. To examine the role of endosomal H2O2 molecules as signaling mediators of Akt activation in endosomes, we modulated endosomal H2O2 through the ectopic expression of an endosomal-targeting catalase (Cat-Endo). The forced removal of endosomal H2O2 inhibited the Akt phosphorylation on Ser473 but not on Thr308. The levels of mSIN and rictor, two components of mTORC2 that work as a kinase in Akt phosphorylation on Ser473, were also selectively diminished in the early endosomes of Cat-Endo-expressing cells. We also observed a decrease in the endosomal level of the adaptor protein containing the PH domain, the PTB domain, and the Leucine zipper motif 1 (APPL1) protein, which is an effector of Rab5 and key player in the assembly of signaling complexes regulating the Akt pathway in Cat-Endo-expressing cells compared with those in normal cells. Therefore, the H2O2-dependent recruitment of the APPL1 adaptor protein into endosomes was required for full Akt activation. We proposed that endosomal H2O2 is a promoter of Akt signaling.
    Keywords:  Akt/PKB; early endosome; hydrogen peroxide; receptor-mediated endocytosis; the Leucine zipper motif 1 (APPL1)
    DOI:  https://doi.org/10.3390/antiox14050594
  6. Cancer Lett. 2025 May 28. pii: S0304-3835(25)00402-1. [Epub ahead of print] 217835
      Tumor microenvironment (TME) is a highly intricate and variable system. The Warburg effect has made researchers further realize that TME is a highly hypoxic microenvironment. Currently, it is reported that lactate is not merely a metabolic waste but also serves important biological functions, which provides a large number of reaction substrates for lactylation. Post-translational modification (PTM) is crucial for signaling and physiological regulation in both normal and cancer cells. Various PTMs play pathological roles in tumor proliferation, metabolism, and the remodeling of the tumor immunosuppressive microenvironment (TIME). Lactylation, as a newly reported PTM, plays an important role in shaping TIME and aggravating tumor immunotherapy resistance. Numerous studies have demonstrated that histone lactylation can directly stimulate gene transcription within chromatin, thereby contributing to tumor promotion and diminishing the efficacy of therapeutic agents against tumors. Advancements in multi-omics technology enable researchers to investigate lactylation-related substrates more effectively. By precisely targeting these sites, it is possible to reduce histone lactylation in order to mitigate their effects on tumor immune resistance. Despite the existence of numerous studies, there remains a notable deficiency of systematic reviews in this field. Therefore, this review focuses on the novel mechanisms of lactylation that promote tumor progression and its impact on tumor immune resistance. Finally, we propose relevant therapeutic regimens for reversing lactylation to guide tumor combined therapy, thus providing benefits upon more patients with tumor immune resistance.
    Keywords:  Immunotherapy resistance; Lactylation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217835
  7. Trends Biochem Sci. 2025 May 28. pii: S0968-0004(25)00104-5. [Epub ahead of print]
      Ferroptosis is a distinctive form of regulated cell death driven by iron-dependent phospholipid peroxidation. Its initiation and suppression are finely tuned by metabolic pathways, transcription factors, and nuclear receptors that control lipid peroxidation levels. Significantly, nutrients such as vitamins and trace elements play a pivotal role in this regulation, directly linking diet and nutrients to cellular fate. This review conveys the latest insights into the metabolic components that influence ferroptosis. We highlight how metabolic and transcriptional regulators and key nutrients, micronutrients, and metabolites orchestrate this process. Charting these interactions will be essential for developing new avenues for therapeutic interventions targeting ferroptosis in various diseases.
    Keywords:  ferroptosis; lipid peroxidation; lipids; metabolites; nutrients; vitamins
    DOI:  https://doi.org/10.1016/j.tibs.2025.04.007
  8. Methods Mol Biol. 2025 ;2933 127-139
      Multiple types of protein posttranslational modifications (PTMs) play vital roles in the regulation of normal cellular functions and pathogenesis. Two of the most relevant and well-studied PTMs are protein thiol oxidation (redox) and phosphorylation. Both processes involve the reversible addition of a chemical group to a specific amino acid residue, altering the protein activity, stability, or interaction with other molecules. Environmental stressors are known to trigger rapid and dynamic regulation of both thiol oxidation and phosphorylation, and these PTMs on key proteins serve as molecular switches in response to external stimuli. Studies have also shown interplay between phosphorylation and redox modifications, as one PTM type can alter the conformation of a protein, thus exposing or masking the sites for another type of PTM. Such crosstalk represents a complex regulatory mechanism that fine-tunes cellular signaling pathways such as those involved in DNA damage responses (DDR). Despite significant advances in our ability to analyze the redox proteome and phosphoproteome individually, a method that allows the detection of both PTM types from the same sample is still lacking. Herein, we describe a method for simultaneous analysis of protein thiol oxidation and phosphorylation in the same sample. This integrated workflow consists of cell lysis, acetone precipitation, tryptic digestion and isobaric labeling, and subsequent enrichment of thiol-containing peptides utilizing resin-assisted capture (RAC) and phosphopeptides using immobilized metal affinity chromatography (IMAC), respectively. The immediate alkylation of samples and other measures incorporated throughout the protocol prevents artificial oxidation of nascent free thiols and preservation of phosphorylation sites to ensure accurate identification and quantification.
    Keywords:  Phosphorylation; Proteomics; Radiation; Redox; Thiol oxidation
    DOI:  https://doi.org/10.1007/978-1-0716-4574-1_17
  9. Arch Physiol Biochem. 2025 May 24. 1-20
      Context: Coenzyme Q10 (CoQ10) is a vital compound found in nearly all cells, and in mitochondria, it facilitates ATP production, and its reduced form acts as a powerful antioxidant, neutralizing reactive oxygen species (ROS) and preventing oxidative damage. Notably, during intense or endurance exercise, the body's increased energy demands and ROS production can lead to oxidative stress, muscle fatigue, inflammation, and exercise-induced muscle damage (EIMD).
    Objectives: This review will explore the mechanisms of CoQ10, its impact on exercise performance to be addressed.
    Results: CoQ10 has been shown to counteract these effects by supporting mitochondrial function, cell membranes, and reducing ROS. Research has demonstrated that CoQ10 supplementation lowers lipid peroxidation, reduces muscle damage indicators like creatine kinase (CK), lactate dehydrogenase (LDH-5 or LDH M), and myoglobin (Mb), and accelerates recovery from EIMD. Nevertheless, the impact of CoQ10 on performance has varied depending on factors such as dosage, duration, exercise type, and individual characteristics.
    Keywords:  Coenzyme Q10; exercise; exercise performance; exercise-induced muscle damage; psychical activity
    DOI:  https://doi.org/10.1080/13813455.2025.2507746
  10. Gene. 2025 May 27. pii: S0378-1119(25)00384-1. [Epub ahead of print] 149595
      Lactylation, an emerging form of post-translational modification derived from lactate, plays a pivotal role in numerous cellular processes such as tumor proliferation, metabolism, inflammation, and embryonic development. However, the precise molecular mechanisms by which lactylation controls these biological functions in both physiological and pathological contexts remain elusive. This review summarizes the latest reported regulatory mechanisms of protein lactylation in various diseases since 2024, introducing the latest research progress regarding the regulatory functions of protein lactylation in pathological processes, with particular attention to the regulatory mechanisms of non-histone lactylation modification in diseases. Finally, it outlines the potential of targeted lactylation therapy, proposes the main directions for future research, and emphasizes its scientific significance for future studies.
    Keywords:  Cardiovascular diseases; Inflammatory diseases; Lactylation; Neurological diseases; Non-histone protein; Tumors
    DOI:  https://doi.org/10.1016/j.gene.2025.149595
  11. Biochim Biophys Acta Mol Basis Dis. 2025 May 26. pii: S0925-4439(25)00258-3. [Epub ahead of print]1871(7): 167910
      Reactive oxygen species (ROS) production and antioxidant levels are out of equilibrium, which leads to oxidative stress. When ROS levels rise, tissues are destroyed by protein oxidation, lipid peroxidation, DNA oxidation, and mutagenesis, which activates the cell death pathway. Low levels of ROS can regulate cell survival and metabolic pathways to stimulate cell proliferation. Normal cells don't create as much ROS as cancer cells do. The endolysosomal cation channel MCOLN channels have been shown to integrate multiple processes of cell growth, division, and metabolic activities, according to recent investigations. Dysregulation of MCOLN channels activity is associated with cancer development. This review aims to discuss the current role of MCOLN channels in cancer as novel regulators of redox homeostasis, with the aim of exploiting the oncogenic potential of MCOLN channels to inspire therapeutic interventions.
    Keywords:  Autophagy; MCOLN; Oxidative stress; TRP channels; cancer
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167910
  12. Mol Cell Biochem. 2025 May 28.
      Advancements in tumor research have highlighted the potential of epigenetic therapies as a targeted approach to cancer treatment. However, the application of these therapies has faced challenges due to the issue of substrate availability since the discovery of epigenetic modifications. Interestingly, metabolic changes are closely associated with epigenetic changes, and notably, certain metabolic enzymes exhibit nuclear localization within epigenetically active cellular contexts. This suggests that nuclear localization of metabolic enzymes may provide a mechanistic foundation for addressing substrate availability issues in epigenetic regulation. To date, there has been limited progress in synthesizing this information systematically. In this study, we provide an overview of the interplay between metabolic enzymes and epigenetic mechanisms, highlighting their critical roles. Subsequently, we summarize recent advances regarding the nuclear localization of metabolic enzymes, shedding light on their emerging roles in epigenetic regulation and oncogenesis.
    Keywords:  DNA demethylation; Epigenetic modifications; Histone modifications; Lactylation; Nuclear localization of metabolic enzymes
    DOI:  https://doi.org/10.1007/s11010-025-05316-w