bims-cesirm Biomed News
on Cell Signaling mediated regulation of metabolism
Issue of 2026–02–22
nineteen papers selected by
Tigist Tamir, University of North Carolina
  1. Post-translational regulation of human D-3-phosphoglycerate dehydrogenase in Alzheimer's disease.
  2. Reduced Versus Oxidized NAD+ Precursors Drive Distinct Transcriptomic, Proteomic, and Metabolic Profiles in Hepatocytes.
  3. Integrative transcriptomics and metabolomics reveal distinct metabolic reprogramming in luminal and triple-negative breast cancer cells.
  4. Growth differentiation factor 15 mitigates lipotoxic steatosis by preserving mitochondrial morphodynamics and augmenting fatty acid oxidation in hepatocytes and liver organoids.
  5. PERCEPTRON-PTMKB: A Web Server for Residue-Based Post-Translational Modification Analysis and Propensity Scoring.
  6. Decoding cancer across scales with metabolomics.
  7. Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
  8. A Stable Isotope Tracing Primer for the Mass Spectrometrist.
  9. FK506-binding protein-5 in high-fat diet-induced metabolic dysfunction-associated steatotic liver disease.
  10. Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
  11. 16-h fasting optimizes cancer immunotherapy in mice and humans.
  12. Targeting Warburg effect: involvement of lactate transporter MCT1 and its chaperone in cancer cell killing by 18β-glycyrrhetinic acid.
  13. Role of lipoylation in mitochondrial supercomplex formation during C2C12 cell differentiation.
  14. A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.
  15. Post-translational modifications in ferroptosis: mechanisms and therapeutic potential.
  16. Metabolic labeling of glycerophospholipids.
  17. Dysregulated Lipid and Protein Networks in Osteochondrosis.
  18. Proteome-Wide Analysis of Functional Phosphosites in the FGFR Family of Proteins: Insights from Large-Scale Phosphoproteomic Analysis.
  19. mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2- breast cancer.
  1. Protein Sci. 2026 Mar;35(3): e70505
    Post-translational regulation of human D-3-phosphoglycerate dehydrogenase in Alzheimer's disease.
    Elena Zerbini, Daniele Riva, Elisa Maffioli, Gabriella Tedeschi, Silvia Sacchi, Loredano Pollegioni.
      Emerging evidence suggests that sex-specific differences in L-serine (L-Ser) metabolism play a key role in Alzheimer's disease (AD). While disruptions in amino acid balance are well known, recent findings point to a dimorphic regulation of the serine biosynthetic pathway. To explore this, we examined post-translational modifications (PTMs) of D-3-phosphoglycerate dehydrogenase (PHGDH)-the rate-limiting enzyme for de novo L-Ser synthesis-as a potentialmechanism underlying this difference. PHGDH was immunoprecipitated from hippocampal tissue of healthy and AD-affected males and females and analyzed by mass spectrometry. Five phosphorylation sites (S55, T60, T78, S383, and S473) were shared across all groups, but a unique deacetylation at K289 appeared exclusively in AD males. Functional assays using recombinant PHGDH variants revealed that changes at solvent-exposed sites (K289, S383, and S473) reduced solubility, while phosphomimetic substitutions at S55 and T78 within the catalytic cleft strongly impaired activity. Notably, mimicking acetylation at K289 improved protein stability. Overall, these PTMs act both as subtle modulators and as on/off switches, fine-tuning PHGDH function and potentially contributing to sex-dependent metabolic vulnerability in AD.
    Keywords:  PHGDH; acetylation; enzyme regulation; phosphorylation; serine
    DOI:  https://doi.org/10.1002/pro.70505
  2. FASEB J. 2026 Feb 28. 40(4): e71582
    Reduced Versus Oxidized NAD+ Precursors Drive Distinct Transcriptomic, Proteomic, and Metabolic Profiles in Hepatocytes.
    Kasper T Vinten, Bauke V Schomakers, Simone Denis, Michel van Weeghel, Aldo Jongejan, Rob Ofman, Sander R Piersma, Connie R Jimenez, Georges E Janssens, Rubén Zapata-Pérez, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) is a vital molecule, serving as a redox cofactor and the limiting substrate for numerous enzymes. NAD+ decline is a key feature of aging, while supplementation with NAD+ precursors can efficiently counteract aging traits and prevent age-associated conditions in preclinical models. However, clinical translation remains challenging, likely due to the limited NAD+ boosting capacity of classical precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). This has brought attention to their reduced forms, reduced NMN (NMNH) and reduced NR (NRH), which are more potent NAD+ boosters but remain poorly characterized. Here, we performed a comprehensive comparative analysis using RNA sequencing, proteomics, and metabolomics on cultured murine hepatocytes treated with NMN, NMNH, NR, or NRH. Global metabolic profiling revealed that NRH and NMNH induced substantially broader metabolic alterations than NR and NMN, with NRH uniquely suppressing metabolites involved in energy metabolism. The pronounced metabolic effects were reflected at a transcriptional level, with reduced precursors triggering a significantly higher number of differentially expressed genes than oxidized ones. Shared differentially expressed genes between NMNH and NRH revealed upregulation of stress-related glutathione-S-transferases (Gsts) which furthermore were reflected in our proteomic profiling. However, the upregulation of Gsts did not cause a depletion of glutathione or oxiglutathione, suggesting a pseudo-stress response to reduced NAD+ precursors. Together, our data demonstrate that reduced NAD+ precursors are unique and distinct from the market-available NAD+ precursors NR and NMN, not only as more potent NAD+ boosters, but also as compounds influencing a broader range of cellular processes.
    Keywords:  NAD+; NAD+ precursors; comparative analysis; hepatocytes
    DOI:  https://doi.org/10.1096/fj.202501925R
  3. Mol Omics. 2026 Jan 16. pii: aaiaf003. [Epub ahead of print]22(1):
    Integrative transcriptomics and metabolomics reveal distinct metabolic reprogramming in luminal and triple-negative breast cancer cells.
    Preeti Ranawade, Babasaheb Sonwane, Ganesh Bose, Revati Jadhav, Rakesh Joshi, Smriti Mittal.
      Breast cancer subtypes exhibit significant molecular and metabolic heterogeneity, influencing their aggressiveness and therapeutic responses. Among them, triple-negative breast cancer (TNBC) is highly aggressive and often resistant to conventional therapies. To investigate the metabolic programming of this aggressiveness, we conducted an integrated transcriptomics and metabolomics analysis comparing the MCF-7 (luminal A, ER+/PR+) and MDA-MB-231 (TNBC) breast cancer cell lines. Transcriptome analysis of MCF-7 and MDA-MB-231 revealed the differential expression of genes involved in key metabolic pathways. Metabolomics data, further corroborated by transcriptomics, suggest pathway enrichment in beta-alanine, histidine, glutathione, nucleotide metabolism, and the tricarboxylic acid cycle. MDA-MB-231 cells displayed a metabolically aggressive phenotype with enhanced oxidative phosphorylation, redox adaptation, and nucleotide turnover. In contrast, MCF-7 cells showed a more regulated amino acid and redox metabolism profile. The integration of transcriptomic and metabolite profiles highlighted potential metabolic vulnerabilities in TNBC, offering insights into subtype-specific differences at the molecular level.
    DOI:  https://doi.org/10.1093/momics/aaiaf003
  4. Diabetes Obes Metab. 2026 Feb 19.
    Growth differentiation factor 15 mitigates lipotoxic steatosis by preserving mitochondrial morphodynamics and augmenting fatty acid oxidation in hepatocytes and liver organoids.
    Jia Li, Qi Zhou, Mengmeng Xia, Yakun Li, Junyu Wang, Manon Buist-Homan, Vincent E de Meijer, Hans Blokzijl, Klaas Nico Faber, Han Moshage.
       AIMS: Growth differentiation factor 15 (GDF15) has emerged as a promising metabolic regulator with hepatoprotective properties in metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms remain elusive. Given that mitochondria are the primary site of fatty acid oxidation (FAO) and that mitochondrial morphodynamics are critical for normal hepatic lipid metabolism, we investigated how GDF15 regulates hepatic lipid homeostasis through mitochondrial dynamics.
    MATERIALS AND METHODS: We established cellular steatosis models using primary rat hepatocytes exposed to lipotoxic palmitate (PA) or non-lipotoxic free fatty acid mixture (FFA, oleate: palmitate = 2: 1). Following GDF15 administration, we quantified lipid droplet content, expression of lipid metabolism genes, mitochondrial fatty acid translocation, and mitochondrial morphodynamics and function. The mechanistic role of ERK1/2 signalling was assessed through pharmacological inhibition. These findings were subsequently validated in adult progenitor cell-derived human liver organoids.
    RESULTS: GDF15 significantly mitigated both PA- and FFA-induced lipid accumulation by upregulating key FAO genes and down regulating lipid synthesis genes. Importantly, GDF15 corrected PA-induced mitochondrial fusion-fission imbalance by increasing mitochondrial fusion proteins MFN1 and OPA1 while modulating the activation of fission regulator DRP1. GDF15 enhanced fatty acid translocation into mitochondria and improved FAO. Mechanistically, GDF15 exerted these effects partially through inhibition of the ERK1/2 signalling pathway. Human liver organoid models further corroborated this protective mechanism of GDF15 against hepatic steatosis.
    CONCLUSIONS: Our study reveals that, specifically under lipotoxic conditions, GDF15 alleviates hepatocyte steatosis by preserving mitochondrial morphodynamics homeostasis and enhancing mitochondrial FAO capacity via ERK1/2 inhibition. These condition-specific mechanisms provide critical insights into GDF15's hepatoprotective effects and support its further investigation as a potential therapeutic target for MASLD.
    Keywords:  GDF15; MASLD; lipid metabolism; mitochondrial morphodynamics
    DOI:  https://doi.org/10.1111/dom.70561
  5. J Mol Biol. 2026 Feb 12. pii: S0022-2836(26)00082-3. [Epub ahead of print] 169709
    PERCEPTRON-PTMKB: A Web Server for Residue-Based Post-Translational Modification Analysis and Propensity Scoring.
    Abdullah Bin Faiz, Muhammad Shoaib, Safee Ullah Chaudary.
      The identification of post-translational modifications (PTMs) of protein residues is vital for understanding protein functions and their subsequent role in cellular processes. Researchers have collected substantial experimental data on PTMs along with their validation and assortment into online databases. However, these databases do not offer integration with protein search and identification tools which then prevent researchers from seamlessly employing them in deciphering PTMs in biological samples. Additionally, there is a lack of tools that evaluate protein residues in light of their neighborhoods for the variety of PTMs found in PTM databases. Here, we propose PERCEPTRON-PTMKB, a web server designed for the analysis and evaluation of PTM sites using empirical datasets. PERCEPTRON-PTMKB provides a quantitative evaluation of per-residue PTM site through its propensity scoring algorithm. The search and propensity calculation pipelines are also served via a secure RESTful API, which enables their seamless integration into protein sequence search engines. PERCEPTRON-PTMKB is available freely at https://perceptronptmkb.lums.edu.pk.
    Keywords:  PTM analysis in protein search; PTM prediction; PTM propensity scoring; post-translational modifications
    DOI:  https://doi.org/10.1016/j.jmb.2026.169709
  6. Nat Rev Cancer. 2026 Feb 20.
    Decoding cancer across scales with metabolomics.
    Joe L Rowles, Gary J Patti.
      It is well established that malignant cells alter their metabolism to support proliferation, but the nutrients required to meet the anabolic demands of different cancers located at various anatomical sites throughout the body remain largely unknown. Moreover, the extent to which nutrients are supplied by neighbouring stromal cells or distant tissues, possibly due to metabolic reprogramming, is poorly understood. Metabolomics provides a unique biochemical approach to address these gaps in our knowledge, but cancer studies require careful consideration because it is challenging to identify appropriately matched control samples for comparison. Here, we detail a collection of metabolomics workflows designed to interrogate cancer across three discrete scales. First, we describe experiments to define the nutrient demands of cancer cells themselves. Second, we focus on identifying metabolic relationships between neighbouring cells in the tumour microenvironment. Finally, we highlight strategies to explore the metabolic crosstalk between cancer cells and distant tissues in the tumour macroenvironment. The approaches outlined span cells in culture, animal models and human specimens from patients with cancer. Special emphasis is dedicated to the application of emerging technologies and computational pipelines in the field of mass spectrometry that enable global profiling of metabolites and lipids.
    DOI:  https://doi.org/10.1038/s41568-026-00908-0
  7. Nat Metab. 2026 Feb 17.
    Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
    Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.
      Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.
    DOI:  https://doi.org/10.1038/s42255-026-01454-7
  8. Annu Rev Anal Chem (Palo Alto Calif). 2026 Feb 17.
    A Stable Isotope Tracing Primer for the Mass Spectrometrist.
    Ashley Solmonson, Brandon Faubert, Thomas P Mathews.
      Metabolic function plays a key role in our understanding of both biological and pathophysiological processes. Metabolism is a complex combination of intrinsic processes and environmental cues across a heterogeneous mix of cell types. To investigate metabolism, stable isotope tracing is a versatile approach to assess metabolism across scales, including in cultured cells, animal models, and humans. From the first tracing studies over a century ago, the development and utility of these studies have gone hand-in-hand with technological advances in detecting these labeled atoms, particularly with mass spectrometry. In this review, we describe the instrumentation used to measure isotopically labeled metabolites and approaches to analyze and interpret stable isotope tracing data, and discuss current challenges and opportunities for discovery with these methods.
    DOI:  https://doi.org/10.1146/annurev-anchem-080524-014717
  9. Sci Rep. 2026 Feb 16.
    FK506-binding protein-5 in high-fat diet-induced metabolic dysfunction-associated steatotic liver disease.
    Li-Ling Wu, Yu-Jen Liao, Wei-Hao Peng, Luen-Kui Chen, Yi-Chen Huang, Chia-Yen Chen, Chi-Chang Juan.
      A high-fat diet (HFD) alters the gut microbiota (GM), impairs metabolic efficiency, and increases gut permeability and inflammation. Obesity and insulin resistance are associated with GM dysbiosis. The GM is strongly associated with metabolic disorders and fatty liver disease. The co-chaperone protein FK506-binding protein-5 (FKBP5) regulates several vital cellular processes. Although FKBP5 has been implicated in stress-related disorders, it has not been directly linked to HFD-induced metabolic fatty liver disease. This study aimed to elucidate how FK506 binding protein 5 impairment affects the GM in HFD-induced metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatotic liver disease (MASLD). Wild-type and FKBP5-knockout (FKKO) mice were fed a normal chow diet or a high-fat diet for 16 weeks. Mouse GM was examined using 16 S rRNA metagenomic analysis. The number of gut-liver immune cells was measured using flow cytometry. HFD-induced hepatic steatosis and inflammation were prevented in FKBP5-deficient mice. FKKO animals showed higher butyric acid levels and GM resistance to diet-induced obesity alterations according to 16 S ribosomal rRNA gene analysis and displayed an HFD-specific gut-liver immunological response that maintained gut barrier failure and mucosal immunity, which are important for GM homeostasis. FKBP5 helps the GM address inadequate immunological responses, including lower gut and liver CD11b+Ly6C+ monocytes and neutrophils, and protects against obesity by improving the GM response to HFD-induced MASLD. FKBP5 protects against HFD-induced MASLD through metabolic coordination between the gut barrier and intrahepatic immunity.
    Keywords:  FK506-binding protein-5; Gut barrier; Gut microbiota; Metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1038/s41598-026-38549-w
  10. Cell Death Discov. 2026 Feb 19.
    Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
    Àngela Llop-Hernández, Sara Verdura, Júlia López, Begoña Martin-Castillo, Javier A Menendez, Elisabet Cuyàs.
      Mitochondria integrate senescence and apoptotic fates, yet it is unclear whether their ability to oxidize different fuels for energy production influences their vulnerability to senolytics in therapy-induced senescence (TIS). Using MitoPlates™ technology, we functionally mapped the mitophenotypes of TIS cancer cells by quantifying electron transport chain (ETC) flux from various NADH/FADH2 substrates. We then related these profiles to the responsiveness of TIS cancer cells to BCL-xL-targeting BH3 senolytics, as well as to inflammatory SASP signaling sensed by an NF-κB/miR-146a reporter. Mechanistically distinct senogenic stressors produced markedly different bioenergetic outputs and substrate diversity, establishing mitochondria as an emergent, stress-encoded property of TIS phenomena. Increased mitochondrial bioenergetic flexibility corresponded with senolytic permissiveness within each cell lineage. However, the magnitude of the senolytic response was largely limited by the pre-senescent bioenergetic configuration of the parental mitochondria, and baseline succinate oxidation served as a functional indicator of this inherited threshold. TIS SASPs were restricted by the secretome of the cell-of-origin, but only the miR146a-positive, fatty acid β-oxidation-related inflammatory SASP states were senolytically responsive. Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells.
    DOI:  https://doi.org/10.1038/s41420-026-02967-6
  11. Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00014-8. [Epub ahead of print]
    16-h fasting optimizes cancer immunotherapy in mice and humans.
    Sheng Chen, Tianyi Hu, Kaixiang Zhu, Yue Liu, Yidong Yang, Xiangyuan Li, Jinjie He, Wenyu Cui, Zhexu Chi, Weiwei Yu, Duojiao Chen, Zhen Wang, Jian Zhang, Ruya Sun, Dehang Yang, Siqi Dai, Qianzhou Yu, Quanquan Wang, Qian Xiao, Junbin Qian, Kefeng Ding, Di Wang.
      Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8+ T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8+ clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.
    Keywords:  diet intervention; immune checkpoint therapy; immunometabolism; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.015
  12. Biochem Biophys Res Commun. 2026 Feb 17. pii: S0006-291X(26)00256-1. [Epub ahead of print]809 153492
    Targeting Warburg effect: involvement of lactate transporter MCT1 and its chaperone in cancer cell killing by 18β-glycyrrhetinic acid.
    Bingxin Xia, Chen Zhu, Yi Rao.
      One of the most commonly used Chinese medicinal herbs is licorice, whose major component is glycyrrizic acid, with a derived product 18β-glycyrrhetinic acid (18β-GA) possessing antitumor activity. Here we performed a genome-wide CRISPR screen to identify genes required for 18β-GA sensitivity. We discovered involvement of MCT1, a lactate transporter, and its membrane chaperone basigin (BSG) in 18β-GA killing of cancer cells. MCT1 was necessary and sufficient for 18β-GA uptake by cancer cells. BSG was required for MCT1 localization on the membrane, and hence 18β-GA uptake into and death of, cancer cells. While it is known that Warburg effects in cancers increased lactate production, followed by selection of higher MCT1 expression which enhanced cancer cell survival by exporting lactate, our findings reveal a new opportunity for killing cancer cells by increased 18β-GA sensitivities of cancer cells with higher MCT1 expression due to the Warburg effect. Thus, our results have revealed a biomarker for 18β-GA sensitivity and suggested the possibility of using Warburg effect to allow drug entry into tumor cells, and will stimulate further molecular mechanistic studies and improvements of traditional Chinese herb medicines.
    Keywords:  Chinese herb medicine; Transporters; Warburg effect; cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153492
  13. J Biochem. 2026 Feb 20. pii: mvag014. [Epub ahead of print]
    Role of lipoylation in mitochondrial supercomplex formation during C2C12 cell differentiation.
    Hijiri Oshio, Isshin Shiiba, Anju Takeda, Souichirou Matsumoto, Yuto Ishikawa, Shun Nagashima, Ryoko Inatome, Shigeru Yanagi.
      In mitochondria, the pyruvate dehydrogenase complex (PDHC) serves as a key metabolic regulator by converting glycolysis-derived pyruvate into acetyl-CoA, thereby controlling carbon flux into the tricarboxylic acid (TCA) cycle. PDHC activity is tightly regulated by two post-translational modifications: phosphorylation of the E1 subunit and lipoylation of the E2 subunit. While phosphorylation of E1 reversibly suppresses pyruvate dehydrogenase (PDH) activity, lipoylation of E2 is essential for intracomplex electron transfer reactions, and together these modifications define PDHC enzymatic activity. Mitochondrial respiratory supercomplexes (SCs) play a critical role in efficient electron transfer during mitochondrial respiration, and PDH has been reported to regulate SC organization. However, it remains unclear whether this regulatory mechanism, including subunit phosphorylation, is linked to protein lipoylation. In this study, we examined the impact of protein lipoylation on the phosphorylation status of the PDHC E1 subunit and on mitochondrial respiratory supercomplex formation during C2C12 differentiation. To this end, suppression of lipoic acid synthase (LIAS), a key enzyme responsible for mitochondrial protein lipoylation, in C2C12 cells resulted in dephosphorylation of the PDHC E1 subunit and formation of specific mitochondrial respiratory supercomplexes. These findings suggest that PDHC E1 dephosphorylation and specific mitochondrial respiratory supercomplex assembly can occur under conditions of impaired E2 lipoylation.
    Keywords:  C2C12 differentiation; LIAS; Mitochondria; PDHC; Respiratory supercomplexes
    DOI:  https://doi.org/10.1093/jb/mvag014
  14. Nat Metab. 2026 Feb 16.
    A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity.
    Xingxiu Pan, Subrata Munan, Austin L Zuckerman, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Nirajan Shrestha, Sara Violante, Justin R Cross, Russell P Goodman, Hardik Shah, Valentin Cracan.
      Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD⁺) are key metabolites of the Gro3P shuttle, which transfers reducing equivalents between the cytosol and mitochondria. Targeted activation of Gro3P biosynthesis has recently emerged as a promising strategy to alleviate reductive stress. However, because Gro3P constitutes the backbone of triglycerides, its accumulation can promote extensive lipogenesis. Here we show that a genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from the alga Chlamydomonas reinhardtii (CrGPDH) effectively operates both the alternative Gro3P shunt, which regenerates NAD⁺ while converting DHAP to Gro3P, and the glycerol shunt, which converts Gro3P to glycerol and inorganic phosphate, across transformed and primary mammalian cell cultures as well as mouse liver. CrGPDH expression supported proliferation of cancer cells under respiratory chain inhibition or hypoxia, as well as patient-derived fibroblasts with mitochondrial dysfunction. Moreover, CrGPDH decreased triglyceride levels in kidney cancer cell lines and reversed ethanol-induced triglyceride accumulation in mouse liver. Thus, CrGPDH represents a promising xenotopic tool to alleviate redox imbalance and associated impaired lipogenesis in conditions ranging from primary mitochondrial diseases to steatosis.
    DOI:  https://doi.org/10.1038/s42255-025-01450-3
  15. Int J Biol Sci. 2026 ;22(4): 1868-1905
    Post-translational modifications in ferroptosis: mechanisms and therapeutic potential.
    Xiaoting Xie, Qianghu Pang, Lianxiang Luo.
      Ferroptosis has been demonstrated to play pivotal roles in a spectrum of pathological processes, including multi-organ dysfunction, retinal degeneration, neurodegenerative disorders, autoimmune diseases, and tumorigenesis. Notably, its pivotal role in counteracting cancer drug resistance positions ferroptosis as a promising therapeutic target. The precise regulation of this cell death pathway is fundamentally dependent on the functional orchestration of associated proteins, where subtle modifications can exert profound effects on ferroptotic progression. Post-translational modifications (PTMs) serve as sophisticated molecular switches that dynamically regulate protein structure, activity, subcellular localization, and functional interactions through covalent attachment of biochemical groups or regulatory subunits. These modifications - including proteolytic processing, partial degradation, or complete protein turnover - significantly expand the functional repertoire of the proteome, thereby exerting crucial regulatory control over cellular survival decisions. This comprehensive review systematically examines the intricate crosstalk between ferroptosis and major PTM pathways, with particular emphasis on ubiquitination, phosphorylation, acetylation, SUMOylation, methylation, oxidative modifications, glycosylation, S-nitrosylation, lactylation, and lipidation. Through critical analysis of current research advances, we elucidate the mechanistic basis by which PTMs modulate ferroptotic pathways and discuss their therapeutic implications. Furthermore, we provide prospective insights into emerging research directions and potential clinical applications targeting PTM-mediated ferroptosis regulation.
    Keywords:  ferroptosis; molecular regulation; phosphorylation; post-translational modifications; ubiquitination
    DOI:  https://doi.org/10.7150/ijbs.120624
  16. Methods Enzymol. 2026 ;pii: S0076-6879(25)00491-4. [Epub ahead of print]726 289-319
    Metabolic labeling of glycerophospholipids.
    Robert J Maraski, Christelle F Ancajas, Jinchao Lou, Michael D Best.
      The approach of metabolic labeling provides an invaluable tool for elucidating previously unknown and poorly understood metabolic processes within cells. By introducing clickable versions of substrates into cells, the products of these biomolecule mimics can be conveniently tracked via post-derivatization of the clickable tag with a variety of reporter groups. Here, we will describe lipid metabolic labeling as an invaluable approach for interrogating lipid metabolic pathways, which can yield crucial information regarding complex lipid biosynthesis and trafficking networks that can open new therapeutic targets involving downstream natural products. In this chapter, we present detailed experimental procedures for the development of clickable serine probes for the labeling of phosphatidylserine (PS) and other lipids, including probe design and synthesis as well as analysis of biological incorporation via confocal microscopy, thin-layer chromatography (TLC), and liquid chromatography mass spectrometry (LCMS). This strategy provides a powerful approach for interrogating lipid biosynthetic pathways centered around PS.
    Keywords:  Click chemistry; Fluorescence microscopy; Lipids; Membranes; Metabolic labeling; Phosphatidylserine; Phospholipids
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.010
  17. J Proteome Res. 2026 Feb 15.
    Dysregulated Lipid and Protein Networks in Osteochondrosis.
    Christel Kuik, Matteo Seccaroni, Kim Freulings, Maria Chiara Pressanto, Monica Sforna, Martina Bordoni, Eleonora Calzoni, Carla Emiliani, Marco Pepe, Berta Cillero-Pastor, Elisabetta Chiaradia.
      Osteochondrosis is an orthopedic developmental disease that affects subchondral bone and articular cartilage in humans and domestic animals, resulting in lameness and joint effusion. Here, we compared the molecular compositions of cartilage from healthy and osteochondrotic equine metacarpophalangeal joints to investigate the pathogenic processes of the disease. This comparison was carried out using an SP3-label-free proteomics workflow, analyzing the differences in protein abundance. Furthermore, mass spectrometry imaging (MSI) was employed for spatially resolved lipid analysis, providing a deeper understanding of osteochondrosis pathogenesis through molecular pathway analysis. Lipid readouts showed increased phosphatidylcholine (PC) lipid species and a downregulation of sphingomyelin (SM) lipids in osteochondrosis biopsies compared to healthy cartilage. Furthermore, spatial analysis of lipids revealed a higher presence of PC lipids in the superficial layer of the cartilage compared with the deep layer. Osteochondrosis-downregulated proteins were mainly involved in extracellular matrix (ECM) organization, protein folding, and hydroxylation, highlighting the importance of ECM imbalance in the osteochondrosis development. Protein-metabolite integration analysis reported a downregulation of glycolysis in the osteochondrosis group, which might lead to chondrocyte hypertrophy and ECM degradation. Our work provides novel insights into the underlying mechanisms associated with the development of osteochondrosis.
    Keywords:  lipids; mass spectrometry imaging; molecular imaging; osteochondrosis; proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00774
  18. Proteomes. 2026 Feb 13. pii: 8. [Epub ahead of print]14(1):
    Proteome-Wide Analysis of Functional Phosphosites in the FGFR Family of Proteins: Insights from Large-Scale Phosphoproteomic Analysis.
    Akhina Palollathil, Althaf Mahin, Athira Perunelly Gopalakrishnan, Tejaswini R Poojari, Alimath Sambreena, Prathik Basthikoppa Shivamurthy, Rajesh Raju.
       BACKGROUND: Fibroblast growth factor receptors (FGFRs) play a crucial role in tissue homeostasis and organ development by regulating cellular processes, including proliferation, differentiation, and survival. Dysregulation of FGFRs contributes to developmental disorders and carcinogenesis. As membrane-bound receptors, they represent promising targets for therapeutic intervention and drug development.
    METHODS: This study employed a systematic in silico analysis of publicly available phosphoproteomics datasets to provide a comprehensive overview of the phosphorylation regulatory network of the FGFR family.
    RESULTS: We identified predominant phosphosites in FGFR1-4 that exhibited differential abundance across diverse experimental conditions, specifically, Y653 in FGFR1; S453, Y586, Y656, and Y657 in FGFR2; S444 and S445 in FGFR3; and S573 in FGFR4. Our analysis identified 32 and 89 significantly co-modulated phosphosites on other proteins with FGFR3 and FGFR4, respectively. Beyond the upstream kinases from the FGFR family, we also identified MAPK1 as a potential upstream kinase of FGFR4. Furthermore, disease enrichment analysis revealed that proteins co-modulated with FGFR3 were primarily involved in skeletal developmental disorders, such as brachydactyly, short toe, and syndactyly of fingers, whereas those associated with FGFR4 were linked to various cancers.
    CONCLUSIONS: Our findings highlight key disease-associated phosphosites within the FGFRs and offer a foundation for advancing phosphosite-focused therapeutic research.
    Keywords:  cancer; mass spectrometry; phosphoproteomics; phosphorylation; post-translational modification; receptor tyrosine kinases; skeletal dysplasia
    DOI:  https://doi.org/10.3390/proteomes14010008
  19. Cell Death Dis. 2026 Feb 19.
    mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4/6 inhibitor-resistant HR+/HER2- breast cancer.
    Luise von Wichert, Alina Stroh, Marie Witt, Michael Wanzel, Marco Mernberger, Sebastian Griewing, Thomas Wündisch, Berit M Pfitzner, Julia Teply-Szymanski, Anne-Sophie Litmeyer, Carsten Denkert, Uwe Wagner, Thorsten Stiewe, Niklas Gremke.
      Breast cancer (BC) is the most prevalent malignancy in women, with hormone receptor-positive, HER2-negative (HR+/HER2-) tumors representing ~70% of cases. While CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have transformed treatment for metastatic HR+/HER2- BC, acquired resistance remains a major obstacle. Using HR+/HER2- BC models with acquired resistance to the CDK4/6 inhibitors Palbociclib or Ribociclib, we uncovered a metabolic vulnerability in highly resistant clones, mediated by mTORC1 hyperactivation and autophagy suppression. Gene expression profiling revealed enrichment of glycolysis and mTORC1 pathways in CDK4/6i-resistant cells, which manifested as heightened sensitivity to the metabolic inhibitors Metformin and Dichloroacetate (DCA). Mechanistically, mTORC1 overactivation impaired autophagy via ULK1-Ser757 phosphorylation, as confirmed by LC3 flux assays, leaving resistant cells unable to adapt to energy stress. Treatment with metabolic drugs triggered AMPK activation, ACC inhibition, and PARP cleavage, culminating in apoptosis. Clinically, immunohistochemical analysis of a BC cohort revealed a significant correlation between mTORC1 activity (p4E-BP1T37/46) and autophagy suppression (p62 accumulation), supporting the translational relevance of this axis. Our findings propose mTORC1-mediated autophagy defects as a biomarker for metabolic vulnerability in CDK4/6i-resistant BC, offering a rationale for targeting these tumors with metabolic therapies to overcome resistance.
    DOI:  https://doi.org/10.1038/s41419-026-08496-5
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