bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–07–26
nineteen papers selected by
Marc Segarra Mondejar, AINA
  1. Distinct sources and effects of mitochondrial reactive oxygen species.
  2. Numerical simulation of mitochondrial systems for ATP generation and membrane transport.
  3. Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.
  4. LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
  5. ER-mitochondria contact sites and organelle stress in asthma.
  6. Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection.
  7. Every scientist has a role in advocacy.
  8. The role of E3 ubiquitin ligases in selective types of macroautophagy.
  9. The role of exercise in MFN2 regulation in osteoarthritis.
  10. Measurement of Nitric Oxide Production in Mouse Tracheal Epithelial Cell Cultures Differentiated at the Air Liquid Interface.
  11. Development of Aryl Cyano Amides for Fluorescence Discrimination of Tau and Amyloid Beta Deposits in Tissue.
  12. Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
  13. VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
  14. Glucose metabolism meets mechanobiology.
  15. Metabolic remodeling of endometriosis microenvironment: Energy stress and immune evasion.
  16. DuoHexaBody-CD37 induces direct cytotoxic signaling in diffuse large B-cell lymphoma.
  17. Leiomodin 2 is a processive pointed-end elongator of actin filaments.
  18. FABP4 interacts with PPARγ to promote malignant progression in pancreatic cancer.
  19. Positive feedback loop via HIF-1α lactylation driven by kynurenine promotes glycolysis.
  1. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00473-9. [Epub ahead of print]
    Distinct sources and effects of mitochondrial reactive oxygen species.
    Daniel Barnett, Caroline Booraem, Anna G Orr, Adam L Orr.
      Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.
    Keywords:  cell metabolism; cell signaling pathways; complex I; complex III; disease mechanisms; electron leak; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.009
  2. Sci Rep. 2026 Jul 20.
    Numerical simulation of mitochondrial systems for ATP generation and membrane transport.
    Takashi Sato, Tsuyoshi Osawa.
      Simulating intracellular biochemical reactions remains a significant challenge in mathematical modeling because of the complex interactions among diverse molecular species. The natural number simulation (NNS) framework offers a dynamic approach to simulating these reactions using a novel algorithm based on reaction equations. In this study, we developed a computational cell model incorporating mitochondria to examine key metabolic processes, including glucose uptake, glycolysis, the tricarboxylic acid cycle, and ATP synthesis via the electron transport chain. Substrate transport mediated by membrane proteins, such as pyruvate and nicotinamide adenine dinucleotide transporters, and the electron transport chain, was replicated using simplified reaction equations. The simulation results showed that, with appropriately chosen rate constants, the ATP production rate reached approximately 155 molecules s- 1 per ATP synthase. Sensitivity analysis indicated that the number of mitochondrial phosphate transporters and the rate of phosphate transport into mitochondria strongly influence ATP production. The model also showed that intermittent glucose supply has a minimal impact on ATP production and that the framework is capable of incorporating the effects of deuterium-containing water on ATP synthesis. This framework provides a foundation for future efforts in simulating more detailed metabolic pathways and integrating experimental data.
    Keywords:  Glycolysis; Membrane transport proteins; Metabolic modeling; Mitochondrial ATP synthesis; Natural number simulation; Tricarboxylic acid cycle; stoichiometric equations
    DOI:  https://doi.org/10.1038/s41598-026-61463-0
  3. Front Immunol. 2026 ;17 1878140
    Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.
    Jingyun Chen, Xin Wang, Meiheng Gong, Yufeng Wang, Tingting Yu.
      Tumor immune escape is increasingly recognized as an immunometabolic process shaped not only by immune checkpoints and suppressive cell populations, but also by nutrient competition and metabolic signaling within the tumor microenvironment. This nutrient-competitive environment is not limited to tryptophan depletion, but also involves glucose restriction, glutamine dependence, arginine metabolism, amino acid transporter competition, and impaired mitochondrial fitness of effector T cells. Among amino acid pathways, tryptophan metabolism has emerged as a central regulator of tumor-immune interactions. Through the activity of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), kynurenine-producing branches, and both AHR-dependent and AHR-independent downstream programs, tumors establish a metabolic state that couples tryptophan depletion, metabolite signaling, redox adaptation, and immune suppression. Recent evidence further shows that tryptophan metabolism is not restricted to tumor cells, but also involves cancer-associated fibroblasts, macrophages, and T cells, thereby shaping multicellular crosstalk within immunosuppressive niches. Beyond immune suppression, this pathway contributes to ferroptosis resistance, stemness, metastatic adaptation, and resistance to chemotherapy, targeted therapy, and immune checkpoint blockade. In parallel, circulating metabolites and tissue-level metabolic profiling are being explored as potential biomarkers for patient stratification and treatment response prediction. In this review, we summarize the molecular basis of tryptophan catabolism in cancer, discuss its role in tumor-immune-stromal communication, and highlight emerging translational and therapeutic opportunities. Rather than reviewing tryptophan metabolism as a linear IDO1/TDO2-centered pathway, we define it as a multicellular immunometabolic communication network in which tumor cells, stromal fibroblasts, myeloid cells, and lymphocytes exchange metabolic and signaling cues to create spatially organized immunosuppressive niches. This network-based view helps explain why single-enzyme inhibition is often insufficient and supports the development of biomarker-guided, multi-branch, and cell-context-specific therapeutic strategies.
    Keywords:  immunometabolism; kynurenine; tryptophan metabolism; tumor immune escape; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1878140
  4. Cell Death Dis. 2026 Jul 20. pii: 649. [Epub ahead of print]17(1):
    LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
    Zhefang Wang, Qiu Huang, Jiangang Zhao, Zicheng Lyu, Feng Ju, Bo You, Jie Wang, Qiongzhu Dong, Margarete Odenthal, Alexander Quaas, Kalliope N Diakopoulos, Hana Algül, Maximilian Reichert, Christiane J Bruns, Yue Zhao.
      Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09075-4
  5. Mol Biol Rep. 2026 Jul 22. pii: 1236. [Epub ahead of print]53(1):
    ER-mitochondria contact sites and organelle stress in asthma.
    Sihao Zhu, Xinxin Xing, Jia Zheng, Hai Wang.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.
    Keywords:  Asthma; ER–mitochondria contact sites; Mitochondria-associated endoplasmic reticulum membranes; NLRP3 inflammasome; Organelle stress
    DOI:  https://doi.org/10.1007/s11033-026-12441-2
  6. Mol Cell. 2026 Jul 21. pii: S1097-2765(26)00456-9. [Epub ahead of print]
    Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection.
    Guangda Shi, Jaeseung Lee, Smita Bhutda, Zienab Etwebi, Jesse Miller, Kasirajan Ayyanathan, Yue Li, David Nguyen, Yongqing Zhu, Wujuan Zhang, Aaron R Goldman, David C Schultz, Sara Cherry.
      RNA viruses require diverse metabolic intermediates for replication, including nucleotides, which are synthesized through two pathways: de novo biosynthesis and salvage. De novo nucleotide biosynthesis is required for viral replication, but the role of nucleotide salvage is less clear. Genetic screening of purine and pyrimidine salvage pathways revealed a requirement for pyrimidine salvage in SARS-CoV-2 viral replication. Although both UCK1 and UCK2 catalyze the rate-limiting monophosphorylation of pyrimidines for pyrimidine salvage, we show that UCK2 is the major enzyme for cytoplasmic salvage of extracellular pyrimidines, functioning redundantly with de novo biosynthesis for RNA replication, and is thus dispensable for SARS-CoV-2 infection under conditions where de novo biosynthesis is active. In contrast, we find that UCK1 supports SARS-CoV-2 replication by specifically promoting nuclear cytidine triphosphate (CTP) synthesis for phosphatidylcholine (PC) biosynthesis, regulating peroxisomal lipid metabolism, and facilitating organelle interactions with double-membrane vesicles (DMVs), lipid structures required for SARS-CoV-2 RNA replication.
    Keywords:  DMV; Kennedy pathway; SARS-CoV-2; double-membrane vesicle; lipidomics; metabolism; nucleotide biosynthesis; peroxisomes; phosphatidylcholine; pyrimidine salvage
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.040
  7. Nat Cell Biol. 2026 Jul 24.
    Every scientist has a role in advocacy.
    Veronica J Farmer, Amy S Gladfelter.
      
    DOI:  https://doi.org/10.1038/s41556-026-02012-9
  8. EMBO Rep. 2026 Jul 23.
    The role of E3 ubiquitin ligases in selective types of macroautophagy.
    Monja Müller, Konstanze F Winklhofer, Fulvio Reggiori.
      In contrast to the ubiquitin (Ub)-proteasome-system, which only degrades individual proteins, macroautophagy can eliminate protein complexes or aggregates, organelles and even pathogens. Terms such as mitophagy, aggrephagy, lysophagy and xenophagy have been coined based on the targeted substrate. In Ub-dependent selective macroautophagy, cargo selectivity is specified by E3 Ub ligases that append Ub chains that in turn are recognized by selective autophagy receptors (SARs), driving sequestration into autophagosomes. While several Ub-dependent SARs have been identified and characterized, the E3 Ub ligases that ultimately decide target fate remain poorly studied. In this review, we summarize what is known about the E3 Ub ligases involved in selective macroautophagy, with a particular emphasis on the degradation of mitochondria, protein aggregates, lysosomes and pathogens. A better characterization of these enzymes could improve therapeutic strategies for targeted degradation in acute and chronic diseases.
    DOI:  https://doi.org/10.1038/s44319-026-00887-1
  9. Mol Biol Rep. 2026 Jul 18. pii: 1206. [Epub ahead of print]53(1):
    The role of exercise in MFN2 regulation in osteoarthritis.
    Jamal Alshorman, Ruba Altahla, Muhammad Umar.
      Osteoarthritis (OA) is currently the most prevalent degenerative joint disorder worldwide, with hallmarks including cartilage deterioration, low-grade inflammation, and mitochondrial dysfunction. In spite of intensive studies conducted in decades, there is still no disease-modifying treatment available. Mitofusin 2 (MFN2), one of the major mitochondrial fusion regulators, was recently identified as a pivotal molecular interface between mitochondria dynamics and chondrocyte differentiation in osteoarthritic joints. MFN2 demonstrates contradictory functions in the development of OA: protective in the physiological state and pathological when its function is deregulated. Safe, economic, and non-pharmacologic approach, exercise is capable of altering MFN2 expression via various mechanisms including AMPK/PGC-1α-mediated mitochondrial biogenesis, mitophagy due to mechanical loading, and anti-inflammatory NF-κB signaling. This review synthesizes current evidence, primarily from preclinical studies, suggesting that MFN2 may be a key molecular hub linking exercise to mitochondrial homeostasis in OA. We propose a testable model wherein exercise regulates MFN2 expression and function, potentially contributing to chondroprotection. However, we emphasize that the causal relationship remains to be established through targeted validation studies.
    Keywords:  AMPK; Autophagy; Exercise therapy; Ferroptosis; Mitochondrial dynamics; Mitofusin 2; Osteoarthritis; PGC-1α
    DOI:  https://doi.org/10.1007/s11033-026-12415-4
  10. J Vis Exp. 2026 Jul 03.
    Measurement of Nitric Oxide Production in Mouse Tracheal Epithelial Cell Cultures Differentiated at the Air Liquid Interface.
    Muddassar Iqbal, David Mahan, Adam Clark, Akueba Bruce, Anthony W DeMartino, Paola Corti.
      Airway epithelial cultures differentiated at the air-liquid interface (ALI) provide a physiologically relevant model to study nitric oxide (NO) signaling in ciliated cells. Here, we describe a protocol to quantify NO production by measuring nitrite (NO₂⁻), a stable oxidation product of NO, in samples collected from ALI-differentiated mouse tracheal epithelial cells. Apical washes, basal media and cell lysates are collected and analyzed using a triiodide-based chemiluminescence assay coupled to a nitric oxide analyzer (NOA). Upon injection into the reaction vessel, nitrite is chemically reduced to NO, which is detected by ozone-based chemiluminescence. Signal intensity is quantified and converted to picomoles of nitrite using a standard calibration curve, and values are normalized to total cellular protein content. Assay performance is validated using pharmacological modulation of NO levels. Upon treatment with the NO donor Diethylenetriamine NONOate (DETA-NONOate) and the NO synthase inhibitor N(ω)-Nitro-L-arginine methyl ester (L-NAME) we observe significant differences in nitrite levels across conditions. The most robust and reproducible signal is observed in apical washes, corresponding to the amount of NO released from the airway epithelium. This method reliably detects NO in samples from ALI-differentiated airway epithelia, providing an accurate in vitro platform to quantify NO production and model diseases associated with abnormal NO metabolism.
    DOI:  https://doi.org/10.3791/70311
  11. ACS Chem Neurosci. 2026 Jul 19.
    Development of Aryl Cyano Amides for Fluorescence Discrimination of Tau and Amyloid Beta Deposits in Tissue.
    R Erin Jessup, Rachel S Ehrlich, Kristine L Teppang, Saswata Dasgupta, Christina J Sigurdson, Jerry Yang.
      The accumulation of amyloid aggregates such as amyloid beta (Aβ) and tau deposits in the brain is a hallmark of many neurodegenerative diseases including Alzheimer's disease. Recent advances in optical imaging have shown that fluorescent probes can detect amyloids in living patients, potentially aiding in diagnosis. Here, we investigate structural modifications of amyloid-targeting Aryl Cyano Amide-based fluorophores aimed at enhancing their ability to discriminate between different amyloid aggregates, such as Aβ and tau. We identify two structural parameters that synergistically enable increased sensitivity to environmental polarity, which makes it possible to discriminate these amyloids through inspection of the color of fluorescence emission. This colorimetric discrimination can provide detailed information on amyloid composition and could expand the use of fluorescence imaging for diagnosis and monitoring of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; amyloid-β; amyloids; fluorescence; imaging; tau
    DOI:  https://doi.org/10.1021/acschemneuro.6c00316
  12. Aging Cell. 2026 Aug;25(8): e70639
    Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
    Heng Zhang, Guangyu Liang, Anding Liu.
      During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age-related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post-translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence-associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver-brain, liver-muscle, and liver-gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia-lowering agents, senotherapeutics, and microbiota-directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.
    Keywords:  aging; ammonia; liver
    DOI:  https://doi.org/10.1111/acel.70639
  13. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123
    VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
    Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.
      Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.
    Keywords:  VAMP7; glia; mitochondrial dynamics
    DOI:  https://doi.org/10.1073/pnas.2603069123
  14. Trends Endocrinol Metab. 2026 Jul 23. pii: S1043-2760(26)00173-6. [Epub ahead of print]
    Glucose metabolism meets mechanobiology.
    Wataru Katano, Atsuki En, Kohta Ikegami.
      Tissue stiffening is widespread in pathology. A new study by Vite et al. reveals a mechanistic link between tissue stiffness and impaired glucose uptake in cardiac muscle cells. The study bridges glucose metabolism and mechanobiology and suggests tissue stiffness may contribute to metabolic inflexibility and insulin resistance in heart failure.
    Keywords:  GLUT4; detyrosination; glucose transporter; magnetorheological elastomer; microtubule
    DOI:  https://doi.org/10.1016/j.tem.2026.07.002
  15. iScience. 2026 Jul 17. 29(7): 116592
    Metabolic remodeling of endometriosis microenvironment: Energy stress and immune evasion.
    Pusheng Yang, Tao Wang, Wenwen Liu, Yaxin Miao, Yiping Zhu, Jing Sun.
      Endometriosis (EMs) is an estrogen-dependent chronic inflammatory gynecological disease characterized by ectopic growth of endometrial tissues, leading to dysmenorrhea, pelvic pain, and infertility. Although the retrograde menstruation theory clarifies the dissemination of endometrial fragments to ectopic sites, the mechanisms behind the survival of ectopic lesions and their immune evasion in hostile microenvironments remain unclear. Endometrial stromal cells (ESCs) are chronically exposed to a microenvironment of hypoxia, nutrient deprivation and oxidative stress, and this energy stress state drives the ESCs to develop adaptive metabolic reprogramming. Through remodeling glucose, lipid, and amino acid metabolic pathways, ESCs not only fulfill their own proliferative requirements but also utilize metabolites as signaling mediators to modulate immune cell functions. This review elaborates on the characteristics of energy stress-driven metabolic reprogramming in EMs, deciphers its mechanisms underlying immune evasion, and discusses the therapeutic potential of combined metabolic-immune intervention strategies.
    Keywords:  endometriosis; energy Stress; immune evasion; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.isci.2026.116592
  16. Elife. 2026 Jul 20. pii: RP106425. [Epub ahead of print]14
    DuoHexaBody-CD37 induces direct cytotoxic signaling in diffuse large B-cell lymphoma.
    Simar Pal Singh, Kumar Mangalam, Michelle D van den Beukel, Sjoerd van Deventer, Marije B Overdijk, M Guy Roukens, Kim C M Santegoets, Esther C W Breij, Martin Ter Beest, Willem P J Cox, Annemiek B van Spriel.
      Diffuse large B-cell lymphoma (DLBCL) is a common aggressive form of non-Hodgkin lymphoma. Tetraspanin CD37 is highly expressed on mature B cells and being studied as a therapeutic target for NHL, including DLBCL. DuoHexaBody-CD37 is a biparatopic antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes shown to promote complement-dependent cytotoxicity. However, the impact of DuoHexaBody-CD37 on direct cytotoxic signaling has not yet been studied. Here, we demonstrate that DuoHexaBody-CD37 induces direct cytotoxicity in DLBCL-derived tumor cell lines independent of the subtype. DuoHexaBody-CD37 induced significant CD37 clustering and was retained at the cell surface in contrast to rituximab, which was internalized. Unbiased screening identified the modulation of 26 (phospho)proteins upon DuoHexaBody-CD37 treatment of primary B cells or DLBCL cells. Whereas DLBCL cells predominantly upregulated p-SHP1(Y564) upon DuoHexaBody-CD37 treatment, primary B cells showed significantly increased p-AKT(S473) and MAPK signaling which is linked to cell survival. Studies using CD37-mutants identified the N-terminus to be involved in DuoHexaBody-CD37-induced signaling. Finally, DuoHexaBody-CD37 treatment inhibited cytokine pro-survival signaling in DLBCL cells. These findings provide novel insights into the signaling functions of CD37 upon DuoHexaBody-CD37 treatment, and open up opportunities for developing CD37-targeted immunotherapy in combination with small molecule inhibitors to maximize tumor cell death.
    Keywords:  antibody therapy; cancer biology; cell biology; human; lymphoma; plasma membrane; signaling; tetraspanin
    DOI:  https://doi.org/10.7554/eLife.106425
  17. Nat Commun. 2026 07 20. pii: 6674. [Epub ahead of print]17(1):
    Leiomodin 2 is a processive pointed-end elongator of actin filaments.
    Sudipta Biswas, Tania M Larrinaga, Sandeep Choubey, Carol C Gregorio, Shashank Shekhar.
      The actin cytoskeleton drives essential processes like cell migration and muscle contraction. While barbed-end polymerization is well-established, pointed-end elongation was long considered impossible in vivo. Here, we demonstrate that Leiomodin 2 (Lmod2), which localizes to thin-filament pointed ends in striated muscle cells, functions as an actin polymerase for pointed-end elongation. Single-molecule and single-filament imaging reveal that Lmod2 remains processively bound to pointed ends in vitro, enabling elongation even in the presence of high profilin concentrations found in the cytoplasm that otherwise would cause depolymerization of free pointed ends. Kinetic analysis indicates that Lmod2-mediated elongation proceeds through a linked two-step mechanism, in which monomer addition is followed by a first-order transition at the Lmod2-bound pointed end that limits elongation at high actin concentrations. Lmod2's activity also persists in the presence of tropomyosin, underscoring its physiological relevance. Both processivity and elongation rate of Lmod2 are dependent on its WH2 domain. Remarkably, human dilated cardiomyopathy-associated mutations in Lmod2 greatly reduce Lmod2's pointed-end elongation activity, providing a potential mechanism for disease progression and supporting a role for Lmod2-mediated polymerization in the formation and maintenance of muscle sarcomeres.
    DOI:  https://doi.org/10.1038/s41467-026-74809-z
  18. iScience. 2026 Jul 17. 29(7): 116547
    FABP4 interacts with PPARγ to promote malignant progression in pancreatic cancer.
    Chen-Xi Yang, Cun-Xia Li, Qian Zhang, Jing Yun, Hui Wang, Jian Huangfu, Jian-Jun Ren, Rui Xiao.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with an exceptionally poor prognosis. Fatty acid-binding protein 4 (FABP4) has been implicated in tumorigenesis and peroxisome proliferator-activated receptor γ (PPARγ) signaling, but its precise functional role and underlying molecular mechanisms in PDAC remain poorly defined. Here, we showed that FABP4 is markedly upregulated in pancreatic cancer cells. Co-immunoprecipitation assays revealed an interaction between FABP4 and PPARγ, and FABP4 overexpression significantly enhanced pancreatic cancer cell viability, proliferation, and migratory capacity in vitro. Moreover, FABP4 overexpression was associated with increased lipid metabolic activity and reduced sensitivity to ferroptosis, and it substantially promoted the tumorigenic potential of PANC-1 cells in vivo. Notably, pharmacological inhibition of PPARγ effectively attenuated the malignant phenotypes elicited by FABP4 overexpression in pancreatic cancer cells, underscoring that PPARγ is critically involved in the FABP4-associated tumor progression phenotype.
    Keywords:  FABP4; PPARγ; fatty acid-binding protein 4; lipid metabolism; pancreatic ductal adenocarcinoma; peroxisome proliferator-activated receptor gamma
    DOI:  https://doi.org/10.1016/j.isci.2026.116547
  19. Oncogene. 2026 Jul 23.
    Positive feedback loop via HIF-1α lactylation driven by kynurenine promotes glycolysis.
    Shuoqi Lin, Yuxiang Yan, Junlin Zhou, Genggeng Zheng, Tesen Liao, Youguang Lu, Bohua Su, Dali Zheng.
      Tryptophan metabolism undergoes marked alterations in OSCC, leading to an abnormal accumulation of the metabolite kynurenine. Nonetheless, how kynurenine, a key intermediate of tryptophan metabolism, contributes to tumor metabolic reprogramming is still not well clarified. Here, we identify Kyn as a metabolic signal that drives glycolytic reprogramming and promotes tumor progression. Mechanistically, Kyn functionally associates with AKT and enhances AKT-dependent mTOR phosphorylation, leading to subsequent activation of the mTOR which facilitates the dissociation of eIF4EBP1 from eIF4E, thereby enhancing cap-dependent translation of HIF-1α. Elevated HIF-1α upregulates glycolytic enzymes, accelerating glycolytic flux and increasing lactate production. The accumulated lactate in turn stabilizes HIF-1α through lysine lactylation, thereby establishing a reinforcing feedback cycle that enhances glycolytic activity and supports continuous tumor expansion. Collectively, our results uncover an unappreciated metabolic regulatory loop in which kynurenine promotes glycolysis via AKT/mTOR-mediated translational activation and HIF-1α lactylation, highlighting a mechanistic link between tryptophan metabolism and glucose metabolism. These insights provide a rationale for combined therapeutic strategies targeting the kynurenine pathway and glycolysis in OSCC.
    DOI:  https://doi.org/10.1038/s41388-026-03916-4
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