bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–07–12
nineteen papers selected by
Marc Segarra Mondejar, AINA
  1. Mitochondria produce lactate to vent redox pressure.
  2. Metabolic determinants of autoimmune kidney diseases.
  3. Mitochondria setting the stage for ferroptosis.
  4. Submicromolar imaging of intrinsic chromophores by two-photon photothermal microscopy captures mitochondrial response to chemotherapy.
  5. A bioenergetic understanding of "aerobic glycolysis".
  6. PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
  7. Optical photothermal infrared imaging of fatty acid esterification in the ER of living cells.
  8. De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
  9. Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
  10. Dynamic control of nucleotide metabolism in physiology and disease.
  11. Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
  12. Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
  13. N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
  14. Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
  15. Cell competition overcomes host tissue resistance to unleash tumor growth in a Drosophila brain cancer model.
  16. NME3 promotes clear cell renal cell carcinoma progression and modulates TKI response through MFN1/2-dependent mitochondrial fusion and mitophagy suppression.
  17. Metabolic regulation and immunosuppressive functions of lipid-associated macrophages in pancreatic ductal adenocarcinoma.
  18. ACSL3 inhibits ferroptosis in gastric cancer through the activation of unfolded protein response following endoplasmic reticulum stress.
  19. Spatial transcriptomic profiling of ovarian clear cell carcinoma reveals heterogeneity in OXPHOS and EMT gradients.
  1. Trends Endocrinol Metab. 2026 Jul 04. pii: S1043-2760(26)00149-9. [Epub ahead of print]
    Mitochondria produce lactate to vent redox pressure.
    Serwah A Danquah, Lucas B Sullivan.
      Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.
    DOI:  https://doi.org/10.1016/j.tem.2026.06.005
  2. Nat Rev Nephrol. 2026 Jul 06.
    Metabolic determinants of autoimmune kidney diseases.
    Yogesh Scindia, Laurence Morel.
      Autoantibody-driven autoimmune diseases, such as systemic lupus erythematosus, frequently affect organs such as the kidney. The differentiation and function of pathogenic immune cells that drive these diseases are in part controlled by their metabolic programming. For diseases that affect the kidney, the response of kidney cells to immune-mediated injury is also in part controlled by metabolic changes. Immune cells that promote the production of autoantibodies and/or infiltrate the kidney in lupus nephritis are sustained by enhanced glycolysis and mitochondrial oxidation. These metabolic processes are also enhanced in the mesangial and glomerular endothelial cells of patients with lupus nephritis and animal models of lupus nephritis, which may contribute to tissue injury. Similar alterations in metabolic processes might be involved in other autoimmune diseases that affect the kidney, including IgA nephropathy and ANCA-associated vasculitis. Insights into metabolic changes that occur in the context of autoimmune-mediated kidney diseases might have therapeutic implications. Despite the complexity of metabolic alterations presented by specific immune and renal cells in these autoimmune diseases, targeting of glycolysis, mitochondrial oxidation or iron metabolism could offer novel opportunities to enhance existing treatments for autoimmune-mediated kidney injury.
    DOI:  https://doi.org/10.1038/s41581-026-01096-8
  3. Trends Endocrinol Metab. 2026 Jul 07. pii: S1043-2760(26)00150-5. [Epub ahead of print]
    Mitochondria setting the stage for ferroptosis.
    Sofia Ahola.
      Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron-sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.
    Keywords:  coenzyme Q; ferroptosis; iron–sulfur cluster; lipid peroxidation; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.tem.2026.06.006
  4. Sci Adv. 2026 Jul 10. 12(28): eaee7678
    Submicromolar imaging of intrinsic chromophores by two-photon photothermal microscopy captures mitochondrial response to chemotherapy.
    Nathaniel Hai, Chinmayee Vallabh Prabhu Dessai, Dingcheng Sun, Jianpeng Ao, Pin-Tian Lyu, Yifan Zhu, Ji-Xin Cheng.
      Intracellular chromophores {e.g., NADH [reduced form of nicotinamide adenine dinucleotide (oxidized form)] and FAD (flavin adenine dinucleotide)} play a central role in regulation of cellular metabolism. Although autofluorescence has been extensively used for label-free mapping of chromophores inside a cell, its sensitivity and molecular specificity are constrained by the low quantum yield and the fluorescence spectral overlap. Here, we address these challenges by using a photothermal approach to measure the optical absorption of chromophores rather than its autofluorescence. Our two-photon photothermal (2PPT) microscope exploits localized thermal transients generated through two-photon absorption, enabling detection of chromophore-specific signatures beyond the reach of autofluorescence. We demonstrate submicromolar limits of detection for the metabolic coenzymes NADH and FAD of 0.87 and 0.99 μM, respectively. Such high sensitivity enables differentiating the influence of mitochondrial shapes on metabolism. 2PPT can identify the biomolecular source of contrast from cellular mitochondria in a label-free manner on the basis of spectroscopy. 2PPT microscopy is used to study metabolic alterations of mitochondria in cancer under chemotherapy at the single-organelle level.
    DOI:  https://doi.org/10.1126/sciadv.aee7678
  5. Commun Biol. 2026 Jul 09. pii: 928. [Epub ahead of print]9(1):
    A bioenergetic understanding of "aerobic glycolysis".
    Valerie L Wasem, Shona A Mookerjee.
      "Aerobic glycolysis" is a widely used term whose current meaning has drifted from its original usage in a way that has created confusion and inaccuracy. This drift has weakened "aerobic glycolysis" as a hypothesis-testing framework, despite the critical importance of glycolysis in understanding cellular bioenergetic behavior. Here, we examine the historical and contemporary uses of "aerobic glycolysis" and the related "Warburg effect". We argue that "aerobic glycolysis" as originally investigated was essentially a bioenergetic phenomenon. We review the bioenergetic model of glycolysis and mitochondrial respiration as ATP supply pathways operating together to meet cellular ATP demand. A bioenergetic view of aerobic glycolysis clarifies that it is not a less desirable contingency or indicator of pathology, but rather a part of a kinetically regulated system of cellular energy supply. On this basis, the operation of glycolysis under many different physiological and pathological conditions can be better interrogated and understood.
    DOI:  https://doi.org/10.1038/s42003-026-10601-5
  6. Cell Death Dis. 2026 Jul 10.
    PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
    José Manuel Rodríguez-Vargas, Jerónimo Borrego-Pérez, Vanesa Cabeza-Fernández, Esteban Zamudio-Martínez, Francisco Javier Ríos-Sola, David Martín-Oliva, Francisco Abadía-Molina, Françoise Dantzer, F Javier Oliver.
      Hypoxia, or low oxygen availability, is one of the main factors that determine tumor growth and metastatic survival. The hypoxic response is orchestrated by HIF transcription factors, which activate genetic and metabolic programs that promote angiogenesis, metabolic reprogramming, migration, and ultimately a clinically aggressive phenotype. Mitochondria play a central role in this process, as they are not only the main consumers of oxygen but also undergo morphological and biochemical adaptations that shape how tumor cells respond to a hostile microenvironment. Because the contribution of ADP ribosylation to these mitochondrial adaptations remains unclear, we aimed to define how PARP inhibition influences mitochondrial behavior during hypoxia. To address this question, we first examined how PARP inhibitors affect mitochondrial structure and function under oxygen deprivation. We found that PARP inhibition drives a shift toward a small, globular mitochondrial phenotype characterized by membrane depolarization (ΔΨm) and enhanced fission. Given that mitochondrial morphology is tightly linked to metabolic state, we next investigated whether these structural changes altered hypoxia induced metabolic reprogramming. PARP inhibition prevented the typical shift toward anaerobic glycolysis, forcing tumor cells to activate the AMPk/mitophagy axis as an alternative survival pathway. Finally, to determine the functional consequences of this adaptive response, we assessed tumor cell fitness when mitophagy was impaired. Blocking mitophagy markedly reduced the proliferative and malignant potential of hypoxic tumor cells, thereby increasing their sensitivity to PARP inhibition. Collectively, our results uncover a previously unrecognized pathway of mitochondrial adaptation to hypoxia and reveal a therapeutically relevant crosstalk between mitochondrial dynamics and ADP ribosylation that may be exploited in future anticancer strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09079-0
  7. Sci Adv. 2026 Jul 10. 12(28): eaed6477
    Optical photothermal infrared imaging of fatty acid esterification in the ER of living cells.
    Hannah B Castillo, Caitlin M Davis.
      Lipotoxicity is an accumulation of lipids that leads to cell death and metabolic disease. Saturated fatty acids are more likely to cause lipotoxicity; however, the mechanism remains unclear due to challenges visualizing reactions in live cells. Here, we use optical photothermal infrared microspectroscopy to investigate palmitic acid (PA) metabolism in hepatocytes with submicron spatial resolution. Upon PA feeding, we found a time-dependent ester carbonyl stretch localized to the endoplasmic reticulum (ER) near lipid droplets with abnormal morphology. This stretch is assigned to diacylglycerol intermediates in the glycerol-3-phosphate pathway. C─D stretches of deuterated PA provide complementary molecular details, supporting a model whereby PA acyl chain packing in the ER reduces enzyme diffusion slowing PA metabolism. Our results provide a deeper understanding of how phase changes induced by high melting temperature fatty acids and their metabolites change ER chemistry as well as provide a tool for detecting chemical and environmental changes associated with lipotoxicity in live cells.
    DOI:  https://doi.org/10.1126/sciadv.aed6477
  8. EMBO Rep. 2026 Jul 07.
    De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
    Mindong Ren, Yang Xu, Colin K L Phoon, Hediye Erdjument-Bromage, Thomas A Neubert, Michael Schlame.
      Postnatal maturation of the mammalian heart requires a vast increase in respiratory enzymes. The mitochondria-specific lipid cardiolipin (CL) is essential for respiratory chain integrity but has no defined function in heart maturation. Here, we determined how the two steps of CL biogenesis, de novo synthesis and acyl chain remodeling, affect the maturation of cardiac mitochondria in mice. Cardiomyocyte-restricted deletion of the CL synthase Crls1 in late gestation does not affect CL levels at birth but blocks the increase in the tissue concentration of CL observed during normal postnatal maturation. Deletion of Crls1 prevents the postnatal rise in cristae density and in the intramitochondrial concentration of respiratory proteins. This inhibits cardiac development, precipitates heart failure, and causes death by the age of 2 weeks. In contrast, ablation of CL remodeling by cardiomyocyte-restricted deletion of Tafazzin does not disrupt mitochondrial maturation or cardiac development, although it has a similar effect on the CL concentration and profoundly alters the CL species composition. Our data show that CL synthesis, but not CL remodeling, controls expression of the respiratory chain by a mechanism independent of the CL concentration.
    DOI:  https://doi.org/10.1038/s44319-026-00864-8
  9. J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):
    Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
    Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.
      Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.
    DOI:  https://doi.org/10.1083/jcb.202511211
  10. Nat Cell Biol. 2026 Jul 08.
    Dynamic control of nucleotide metabolism in physiology and disease.
    Dohun Kim, Gerta Hoxhaj.
      Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02004-9
  11. Stem Cell Rev Rep. 2026 Jul 09.
    Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
    Hao-Cheng Liu, Si-Yuan Chen, Nan-Nan Yu, Mei-Hua Jin, Hu-Nan Sun, Ying-Hao Han.
      Stem cell fate decisions-whether to self-renew, differentiate, or senesce-are inextricably linked to the metabolic identity and quality-control status of mitochondria. The ubiquitin-proteasome system and selective autophagy pathways assemble into an integrated surveillance network at the mitochondrial outer membrane that gauges organelle health, sculpts morphology, and transduces metabolic information into lineage-determining transcriptional programmes. This Review examines how the ubiquitination machinery-spanning the canonical PINK1-Parkin axis and non-Parkin E3 ligases including MARCH5, MUL1, and the emerging Cullin-RING component RBX2-orchestrates outer-membrane protein degradation, mitochondria-derived vesicle biogenesis, and the balance between fusion and fission. We discuss how these post-translational events govern stem cell identity across haematopoietic, muscle, neural, mesenchymal, and pluripotent compartments. Recent 2024-2025 advances include an Nicotinamide Adenine Dinucleotide (NAD+)-dependent metabolic checkpoint governing haematopoietic stem cell activation and aging, the crystallographic resolution of USP30 inhibitor binding, molecular glue activators that allosterically enhance Parkin RING-domain activity, ClpP-based mitochondria-targeted PROTAC platforms, and HIF-1α/BNIP3-mediated pharmacological rejuvenation of aged mesenchymal stem cells. We further discuss the WAC-PINK1-Parkin axis in mesenchymal stem cell aging, the bidirectional interplay between reactive oxygen species and E3 ligase activity, and the ACC1-FIS1 ubiquitination axis. Finally, we consider the cell-type-specific calibration of mitochondrial ubiquitination as a unifying principle for precision therapeutics and the inverted quality-control logic exploited by cancer stem cells. We propose that the cell-type-specific calibration of mitochondrial ubiquitination-whereby identical molecular events carry divergent functional consequences across stem cell compartments-offers a unifying framework for precision therapeutics.
    Keywords:  Mitochondrial dynamics; Mitochondrial ubiquitination; Mitophagy; PINK1-Parkin; Stem cell fate
    DOI:  https://doi.org/10.1007/s12015-026-11189-3
  12. Elife. 2026 07 08. pii: RP107953. [Epub ahead of print]14
    Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
    Joy Omini, Inga Krassovskaya, Taiwo Adeolu Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.
      The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1-CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1-CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1-CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.
    Keywords:  S. cerevisiae; biochemistry; chemical biology; citrate synthase; malate dehydrogenase; metabolon; mitochondria; oxidative respiration; tricarboxylic acid cycle
    DOI:  https://doi.org/10.7554/eLife.107953
  13. bioRxiv. 2026 Jul 02. pii: 2026.06.29.735215. [Epub ahead of print]
    N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
    Narayanan Puthillathu, John R Moffett, Barbara S Slusher, Aryan M Namboodiri.
      N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic "relief valve" for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 µ M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.
    DOI:  https://doi.org/10.64898/2026.06.29.735215
  14. Cell Rep. 2026 Jul 08. pii: S2211-1247(26)00708-4. [Epub ahead of print]45(7): 117630
    Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
    Kenkyo Matsuura, Ririko Shinonaga, Mizuki Yamamoto, Yoshiki Yamamoto, Hsin Chen, Ayaka Maeno, Kayo Okuda, Haruki Inoue, Sota Imotani, John Glushka, Koji Miki, Yukako Watanabe, Mamoru Takada, Hironori Kaji, Jun-Ichiro Inoue, Ayuna Hattori, Hiromi Imamura, Takahiro Ito.
      Triple-negative breast cancer (TNBC) lacks effective molecularly targeted therapies. Here, we identify branched-chain amino acid (BCAA) metabolism as a selective vulnerability in human TNBC, particularly in the claudin-low subtype. TNBC cells show greater dependence on BCAAs than other breast cancer subtypes, and intracellular BCAA levels are heterogeneous within tumors in vivo. Cells with high BCAA levels exhibit enhanced sphere formation and cancer stem cell potential in xenograft models. BCAT1, a cytoplasmic BCAA aminotransferase, is upregulated in claudin-low TNBC and enables tumor growth by promoting BCAA production from branched-chain ketoacids. BCAT1 knockdown impairs TNBC growth in vivo, and high BCAT1 expression predicts poor prognosis in patient cohorts. Conversely, BCAA catabolism via the BCKDH complex is suppressed in TNBC, and reactivation of BCKDH by BCKDK knockout blocks clonogenic growth. These findings reveal BCAA metabolic balance as a key regulator of TNBC stemness and malignancy.
    Keywords:  CP: cancer; TNBC; branched-chain amino acid; claudin-low; metabolic vulnerability; metabolite imaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117630
  15. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2523832123
    Cell competition overcomes host tissue resistance to unleash tumor growth in a Drosophila brain cancer model.
    Marco Gualtieri, Saline Jabre, Damien Mornico, Maëlwenn Hamon, Gaëlle Letort, Cédric Maurange, Pauline Spéder.
      Primary tumors of the central nervous system are extremely aggressive and often incurable. While tumor cells are known to interact with their microenvironment, the complexity and temporal dynamics of this interplay and its impacts on tumor progression remains to be fully understood. We addressed this question in a Drosophila model of cancer stem cell-driven tumor which originates during development and grows extensively within a network of cortex glia cells through adulthood. We revealed a biphasic interplay between tumor and cortex glia cells, characterized by morphological, molecular, and functional changes. In early stages, glial cells infiltrate the tumor, display a distinct transcriptional signature, and resist its growth, supported by the intrinsic neuroprotective activity of the c-Jun N-terminal kinase (JNK) signaling pathway. However, cancer stem cell-driven competition takes place, eliminating cortex glia by apoptosis and ultimately unleashing tumor growth. This second phase sees the breakdown of the glial meshwork and adhesions to neurons, along with the downregulation of the JNK pathway and a decline in essential cellular functions. Ultimately, the host tissue collapses, in turn curbing tumor growth. This study uncovers a dynamic and complex interplay between host tissue resistance and tumor-driven competition, which shapes tumor progression.
    Keywords:  brain; cancer; cell competition; drosophila; glia
    DOI:  https://doi.org/10.1073/pnas.2523832123
  16. Oncogene. 2026 Jul 10.
    NME3 promotes clear cell renal cell carcinoma progression and modulates TKI response through MFN1/2-dependent mitochondrial fusion and mitophagy suppression.
    Senming Cao, Xinran Chen, Chi Zhang, Yi Feng, Changwei Shi, Jichen Wang, Qingjiang Xu, Xing Huang, Xin Ma, Wenmei Fan.
      Renal cell carcinoma (RCC), particularly the clear cell subtype (ccRCC), is a prevalent malignancy characterized by aggressive progression and heterogeneous therapeutic responses. Although mitochondrial dynamics are increasingly recognized as critical regulators of cancer metabolism and survival, the role of nucleoside diphosphate kinase 3 (NME3) in this process remains poorly understood. In this study, we integrated bioinformatic analyses of public datasets with validation in patient-derived tissues, in vitro functional assays, and in vivo xenograft models to elucidate the role of NME3 in ccRCC. We found that NME3 is significantly upregulated in ccRCC and correlates with poor survival, serving as an independent prognostic factor. Functionally, NME3 knockdown suppresses proliferation, migration, invasion, and xenograft tumor growth, while its overexpression promotes malignant phenotypes. Mechanistic investigations revealed that NME3 knockdown induces mitochondrial fragmentation, reduces ATP production, increases reactive oxygen species (ROS) levels, and activates PINK1/Parkin-mediated mitophagy; whereas NME3 overexpression enhances mitochondrial fusion and oxidative phosphorylation. Further analyses revealed that NME3 forms homomeric or heteromeric hexamers with NME2 and interacts with the mitochondrial fusion regulators MFN1 and MFN2 to facilitate mitochondrial fusion. Importantly, NME3 expression modulated the cellular response to tyrosine kinase inhibitors (TKIs), including sorafenib and sunitinib, with NME3 depletion enhancing drug sensitivity in vitro and in xenograft models. Collectively, these findings identify NME3 as a regulator of mitochondrial dynamics in ccRCC and highlight a potential link between mitochondrial remodeling and therapeutic response.
    DOI:  https://doi.org/10.1038/s41388-026-03892-9
  17. Front Immunol. 2026 ;17 1865859
    Metabolic regulation and immunosuppressive functions of lipid-associated macrophages in pancreatic ductal adenocarcinoma.
    Tongyuan Zhang, Mingze Zhang, Xiaoqin He, Yuefeng Zhang.
       Introduction: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumor microenvironment, with tumor-associated macrophages (TAMs) being the most abundant immune infiltrate. Among them, lipid-associated macrophages (LAMs) have emerged as a distinct subpopulation driving immune evasion through metabolic reprogramming.
    Methods: We conducted a narrative review by systematically searching PubMed, Web of Science, and Scopus for articles on LAMs in PDAC up to December 2023. Key themes were synthesized to cover defining markers, metabolic pathways, immunosuppressive functions, and therapeutic strategies.
    Results: LAMs are characterized by co-expression of TREM2, APOE, CD9, and lipid-handling genes, and their accumulation correlates with poor prognosis. They undergo metabolic rewiring involving CD36-mediated lipid uptake, dysregulated cholesterol efflux, fatty acid oxidation, and de novo lipogenesis, which collectively enforce an immunosuppressive phenotype. LAMs interact bidirectionally with cancer-associated fibroblasts and directly suppress CD8+ T cells and NK cells. Preclinical targeting of CD36, TREM2, or FAO shows promise but faces challenges in toxicity and delivery.
    Discussion: LAMs represent a potential therapeutic vulnerability in PDAC, but the field is still in its early stages. Future work should focus on establishing causal evidence in PDAC-specific models, developing tumor-selective delivery systems, and validating biomarkers for patient stratification.
    Keywords:  immunosuppression; lipid metabolism; lipid-associated macrophages; pancreatic ductal adenocarcinoma; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1865859
  18. Cell Death Dis. 2026 Jul 07.
    ACSL3 inhibits ferroptosis in gastric cancer through the activation of unfolded protein response following endoplasmic reticulum stress.
    Honglei Wang, Jie Jiao, Wenshuo Yang, Danping Sun, Meng Wei, Guorui Sun, Zhibo Yan, Yize Liang, Zewei Cheng, Yongqi Yan, Menghui Wang, Yangjia Li, Xiaohan Cui, Wenbin Yu.
      The long-chain acyl-CoA synthetase (ACSL) family has been associated with tumor progression across various cancer types. However, the function of the ACSL family in gastric cancer (GC) remains poorly understood. Comprehensive investigations employing in vivo and in vitro experiments demonstrate that ACSL3 suppresses ferroptosis and drives GC progression. Mechanistically, ACSL3 facilitated YY1 nuclear translocation, triggering endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR). Genome-wide binding analysis revealed that YY1 directly binds to the USP37 promoter, enhancing its transcriptional activation. Furthermore, a novel interaction was identified between USP37 and PERK, a pivotal UPR regulator, wherein USP37 mediates K29-linked deubiquitination of PERK. PERK stabilization upregulated SLC7A11 expression, thereby inhibiting ferroptosis and promoting tumor progression. Collectively, the findings establish a molecular cascade wherein ACSL3 mediates ER stress-mediated UPR activation through the YY1/USP37/PERK axis, suppressing ferroptosis and accelerating GC progression, identifying ACSL3 as a potential therapeutic target for GC treatment.
    DOI:  https://doi.org/10.1038/s41419-026-09068-3
  19. Nat Commun. 2026 Jul 08.
    Spatial transcriptomic profiling of ovarian clear cell carcinoma reveals heterogeneity in OXPHOS and EMT gradients.
    Thang Truong Le, Duncan Yi-Te Wang, Sebastian Rui-Gu Yan, Yi-Cian Chen, Ko-Chen Chen, Tuan Zea Tan, Pei-Yu Chu, Denis Ting-Hsian Chen, Yi-Chia Chiu, Jia-Yuh Sheu, Sydney Rechie Necesario, Chen-Hao Huang, Jieru Ye, Ya-Ting Tai, Hsueh-Fen Juan, Feng-Chiao Tsai, Wei-Chou Lin, Ying-Cheng Chiang, Lin-Hung Wei, Ruby Yun-Ju Huang.
      Intratumoral heterogeneity is intrinsically comprised of molecular alterations of tumor cells and extrinsically from interconnections with microenvironments. This study explores the spatial heterogeneity of ovarian clear cell carcinoma (OCCC), a rare cancer with significance to East Asian women. We profile 21 primary-metastatic tumor pairs in a discovery cohort and 16 tumors in two validation cohorts using spatial transcriptomic (ST) platforms. Our integrative analysis revealed an inverse relationship between OXPHOS and inflammation along the EMT gradient. OCCC cells undergoing partial EMT have metabolic shifts and lose LCN2 expression, possibly via concomitant down-regulation of SOX9. Conversely, LCN2 expression correlated with OXPHOS-enriched tumor signature, low EMT, and better outcomes in OCCC. Single-cell ST profiling using CosMx further identifies nine spatially distinct cancer cell populations including the LCN2-high cancer subclone with a high epithelial score. SOX9 induction could partially restore epithelial-ness in LCN2-low cells suggesting that plasticity in OCCC is achieved via transcriptional reprogramming. Our findings provide further insights into epithelial-mesenchymal plasticity and the adaptive interactions between cancer cells and their microenvironments in OCCC.
    DOI:  https://doi.org/10.1038/s41467-026-74593-w
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