bims-medica 2026-08-02 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–08–02
twelve papers selected by
Brett Chrest, Wake Forest University

Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.
PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer.
Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.
Integrative Multi-Omics Reveal Metabolic Reprogramming by Ketogenic Diet in Melanoma Xenografts.
Oxygen-stable streptolysin O variant enables mitochondrial ATP synthesis analysis in minimal cells blood and tissues.
Genetically distinct microenvironment determines cancer survival and response to therapy in mice.
70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy.
iG6PSnFR: A genetically encoded fluorescent sensor for observing glucose-6-phosphate dynamics in living preparations.
Is glutamate an adipose redox signal that regulates lipolysis?
ATP-Red enables single-cell bioenergetic phenotyping by flow cytometry.
Back to Biochemistry: Evaluation for and Prognostic Significance of SDH Mutations in Paragangliomas and Pheochromocytomas.

bioRxiv. 2026 Jul 13. pii: 2026.07.10.737821. [Epub ahead of print]

Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.

Matthew T Villaume, Haley E Ramsey, Valeria Impedovo, Michael Davidson, Maria P Arrate, Anand K Singh, Yujin Lee, Anna Skwarska, Yara F Almadani, Natalia Baran, Sovira Chaudhry, Benjamin J Reisman, Eden G TenBarge, Ming Jiang, Sarah Olmstead, Agnieszka E Gorska, Zhiguo Zhao, Andrew J Monteith, Peter M Grace, Brian O Bachmann, Marina Konopleva, Stefano Tiziani, Michael R Savona.

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

DOI: https://doi.org/10.64898/2026.07.10.737821
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2618349123

PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer.

Xiongjian Rao, Derek B Allison, Robert M Flight, Penghui Lin, Daheng He, Zhiguo Li, Yanquan Zhang, Ruixin Wang, Chaohao Li, Jianlin Wang, Xinyi Wang, Jia Peng, Ka Wing Fong, Qing Shao, Chi Wang, Eunus S Ali, Hunter N B Moseley, Xiaoqi Liu.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet their increased biosynthetic and energetic demands. Although cells possess the capacity for de novo serine biosynthesis, most transformed cancer cells preferentially rely on exogenous serine uptake to sustain their growth, yet the regulatory mechanisms driving this metabolic dependency remain poorly understood. Here, we uncover a mechanism by which Polo-like kinase 1 (PLK1), frequently overexpressed in prostate cancer, orchestrates a metabolic shift in serine and sphingolipid metabolism through phosphorylation of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine synthesis pathway (SSP). Specifically, PLK1 directly phosphorylates PHGDH at S512, S513, and S517, leading to a marked reduction in its protein level and enzymatic activity. This downregulation of de novo serine biosynthesis forces cancer cells to increase their reliance on exogenous serine uptake via the ASCT2 transporter, which in turn fuels the biosynthesis of lipids, including sphingolipids essential for tumor growth and survival. Our findings suggest that targeting the SSP, serine uptake, or downstream lipid biosynthesis pathways may represent promising therapeutic strategies in advanced cancers characterized by PLK1 dysregulation.

Keywords:  PHGDH; PLK1; metabolism; serine; sphingolipids

DOI:  https://doi.org/10.1073/pnas.2618349123
Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140
bioRxiv. 2026 Jul 20. pii: 2026.07.17.739092. [Epub ahead of print]

Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.

Cynthia A Harris, Shunji Kato, Yurika Otoki, Elisa Martin Perez, Dylan Boone, Juan Lorenzo B Pablo, Anna Greka, James A Olzmann.

Ferroptosis is driven by the accumulation of oxidatively damaged membrane phospholipids, making membrane lipid composition a central determinant of cell death sensitivity. While fatty acid chain length and degree of unsaturation are well-established regulators of ferroptosis, whether fatty acid stereochemistry contributes to ferroptosis susceptibility is mostly unexplored. Here, we systematically screened structurally diverse fatty acids for their ability to modulate ferroptosis and unexpectedly identified trans-unsaturated fatty acids as potent sensitizers. Compared with its cis counterpart linoleic acid, the trans polyunsaturated fatty acid (PUFA) linoelaidic acid more strongly enhanced lipid peroxidation and promoted the accumulation of ferroptosis-susceptible phospholipid species. Unexpectedly, the trans monounsaturated fatty acid petroselaidic acid also sensitized cells to ferroptosis, whereas its cis stereoisomer petroselinic acid suppressed ferroptosis. Mechanistically, petroselaidic acid required stearoyl-CoA desaturase-dependent conversion to a PUFA, directly demonstrating that double-bond geometry can redirect fatty acid metabolic fate through altered recognition by lipid metabolic enzymes. Although linoelaidic acid and petroselaidic acid followed distinct metabolic pathways, both converged on phospholipid remodeling that expanded pools of ferroptosis-susceptible membrane lipids. Together, our findings demonstrate that fatty acid double-bond geometry determines their metabolic fate and the membrane phospholipid composition, establishing lipid stereochemistry as a previously unrecognized structural determinant of ferroptosis sensitivity.

DOI: https://doi.org/10.64898/2026.07.17.739092
Biomolecules. 2026 Jul 22. pii: 1071. [Epub ahead of print]16(7):

Integrative Multi-Omics Reveal Metabolic Reprogramming by Ketogenic Diet in Melanoma Xenografts.

Rohit Dnyansagar, Natalie Bordag, Rodolphe Poupardin, Julia Tevini, Victoria E Stefan, Sophia Derdak, Martin Bilban, Nikolaus Fortelny, Barbara Kofler, Roland Lang, Daniela D Weber.

  The ketogenic diet (KD) has demonstrated anti-proliferative effects across multiple tumor types, yet the underlying metabolic and transcriptomic mechanisms remain incompletely understood. This study employed integrated multi-omics analysis combining targeted metabolomics and RNA sequencing to elucidate KD-induced metabolic reprogramming in BRAF/NRAS wild-type, BRAF mutant, and NRAS mutant melanoma xenografts, which showed delayed tumor growth when treated with the KD. Despite pronounced metabolic and transcriptional heterogeneity across models with minimal overlap in individual KD-responsive genes, pathway-level analysis revealed convergent biological signatures. Using VIP score-based integration and supervised latent variable modeling (mixOmics DIABLO), we identified consistent KD-associated alterations in cancer-related pathways including the PI3K-Akt, MAPK, sphingolipid as well as HIF-1 signaling pathways. The KD enhanced sphingomyelin and ceramide levels and additionally induced transcriptional signatures, indicating increased ceramide synthesis and reduced ceramide breakdown. Moreover, the KD reduced transcript levels of genes encoding critical tumor regulators, including PI3K, AKT, HIF, MEK, and ERK. These findings demonstrate that despite metabolic and transcriptomic heterogeneity, the KD drives coordinated metabolic reprogramming at the pathway level, indicative of shifting lipid metabolism toward pro-apoptotic ceramides and attenuating key oncogenic signaling cascades. Our results provide insights into the KD's anti-tumor efficacy and identify metabolic nodes amenable to therapeutic intervention in melanoma.

Keywords:  cancer metabolism; ketogenic diet; melanoma; metabolomics; multi-omics integration; transcriptomics

DOI:  https://doi.org/10.3390/biom16071071
iScience. 2026 Aug 21. 29(8): 116788

Oxygen-stable streptolysin O variant enables mitochondrial ATP synthesis analysis in minimal cells blood and tissues.

Makoto Fujikawa, Natsuhiko Yamada, Shuhei Yasuda, Tsutomu Tanabe, Kenta Maruyama.

  Quantifying mitochondrial ATP synthesis remains inaccessible in rare cells, blood, and microdissected tissues because of the biochemical instability of streptolysin O (SLO)-based permeabilization. Here, we introduce an oxygen-stable SLO variant, streptolysin O tolerant (SLOT), and an improved mitochondrial ATP synthesis capacity (iMASC) assay to enable sensitive analysis across diverse samples. SLOT combines non-essential N-terminal deletion (Δ1-77) with a C530A substitution, conferring reductant-independent activity and long-term stability. Temperature-controlled activation restricts permeabilization to the plasma membrane, preserving mitochondrial function. iMASC assay supports continuous measurement for more than 1 h from 10 to 20 cells and applies to adherent and suspension cells, whole blood, and microdissected tissues. Using this platform, we identify platelets as dominant contributors to glycerol-3-phosphate-driven ATP synthesis in murine blood and enable sequential dissection of respiratory chain and ATP synthase activities within single tissues. This framework establishes a broadly applicable approach for mitochondrial metabolism analysis.

Keywords:  SLOT; iMASC assay; improved mitochondrial ATP synthesis capacity assay; mitochondrial ATP synthesis; mitochondrial metabolism; rare and complex biological samples; respiratory chain complexes; streptolysin O tolerant; temperature-controlled permeabilization; whole blood

DOI:  https://doi.org/10.1016/j.isci.2026.116788
bioRxiv. 2026 Jul 13. pii: 2026.07.10.737486. [Epub ahead of print]

Genetically distinct microenvironment determines cancer survival and response to therapy in mice.

Mark A Warner, Jennifer K Sargent, Shawnna R Farley, Beth L Dumont, Muneer G Hasham.

  Genetic uniqueness of the tumor microenvironment significantly influences cancer growth, survival, and response to therapy, independent of the cancer cell's intrinsic properties or the adaptive immune system. Using genetically distinct Rag1-/- mouse models, this study shows that different strains exhibit varied tumor growth kinetics and survival outcomes when xenografted with identical leukemic and solid tumor cell lines. This study further highlights the critical role of the myeloid immune compartment and shows that disrupting both lymphoid and myeloid systems alters cancer progression. These results also reveal that the tumor microenvironment can permanently alter cancer cell phenotypes and significantly affect chemotherapy efficacy, as seen with Cisplatin's varying effects across strains. These findings underscore the importance of considering genetic background in preclinical cancer models, suggesting that reliance upon a single mouse strain may lead to incomplete conclusions about cancer biology and treatment efficacy.

Keywords:  cancer; genetic diversity; preclinical; tumor microenvironment; xenograft

DOI:  https://doi.org/10.64898/2026.07.10.737486
Pharmaceutics. 2026 Jul 13. pii: 850. [Epub ahead of print]18(7):

70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy.

José A Campos-Sandoval, Juan De Los Santos-Jiménez, Javier Márquez, José M Matés.

  Personalized oncology seeks to selectively block specific dysregulated pathways to arrest cancer development. Increased glutamine metabolism is a hallmark of cancer, and 6-diazo-5-oxo-L-norleucine (DON), a structural analog of L-glutamine, was the first compound used to target the exacerbated nitrogen metabolism observed in cancer cells. However, its clinical application was limited by unacceptable toxicity. With the same goal of blocking glutamine metabolism, several specific glutaminase inhibitors have been characterized in recent decades, showing promising antitumor activity. Nevertheless, this strategy frequently induces adaptive metabolic resistance that must be counteracted. In this context, glutaminase has become a key target in combination therapies for several tumor types aimed at restricting anabolic adaptation when single metabolic therapy fails, emerging as a possible synergistic therapeutic intervention. Consequently, combination therapies that include glutaminase inhibition alongside additional agents to counteract the metabolic plasticity of cancer have emerged as a promising approach in personalized antitumor pharmacology. This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor-immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology.

Keywords:  BPTES; CB-839; DON; DRP-104; combination therapy; glutaminase; synergistic effects

DOI:  https://doi.org/10.3390/pharmaceutics18070850
bioRxiv. 2026 Jul 23. pii: 2026.07.22.740099. [Epub ahead of print]

iG6PSnFR: A genetically encoded fluorescent sensor for observing glucose-6-phosphate dynamics in living preparations.

Jonathan S Marvin, Anastasia Tsives, Shih Ming Huang, Zhanat Koshenov, Raghabendra Adhikari, Aaron D Wolfe, Ian J Gonzalez, Daniel Feliciano, Timothy A Ryan, Matthew J Merrins, Daniel A Colón-Ramos, Timothy A Brown.

Glucose-6-phosphate (G6P) is a key intermediate in multiple energetic and anabolic pathways, and quantifying its dynamics is essential for understanding cellular physiology. We have previously developed a syndicate of intensity-based, genetically encoded sensors based on the insertion of circularly permuted GFP into a Venus-flytrap-like analyte-binding protein. Here we use the same approach to develop an intensity-based G6P Sensing Fluorescent Reporter (iG6PSnFR). We present two variants: a G6P-activated sensor that increases fluorescence and a G6P-inactivated sensor that decreases fluorescence. We validate performance across progressively more complex preparations, including purified protein in vitro, immortalized and primary neuronal cultures, isolated pancreatic islets, in an intravital liver model, and finally in vivo in C. elegans neurons. In each context, iG6PSnFR reports G6P changes consistent with expected responses to physiological perturbations.

DOI: https://doi.org/10.64898/2026.07.22.740099
Trends Endocrinol Metab. 2026 Jul 31. pii: S1043-2760(26)00177-3. [Epub ahead of print]

Is glutamate an adipose redox signal that regulates lipolysis?

Martina Beretta, Elizabeth J New, Kelsey H Fisher-Wellman, James R Krycer.

  Uncontrolled adipose lipolysis is a defining feature of insulin resistance and metabolic disease. Although insulin potently suppresses lipolysis, the mechanisms that override antilipolytic control in insulin resistance remain poorly defined. Building on recent advances in metabolic tracing, redox biology, and adipose-neuronal crosstalk, we propose that adipocyte metabolism actively regulates lipolysis. We outline a model whereby redox imbalance within adipocytes promotes the diversion of glucose-derived carbon towards glutamate synthesis. This, in turn, may activate sympathetic drive within white adipose tissue, derepressing lipolysis even under fed conditions. This could reposition 'selective insulin resistance' as a consequence of metabolic rewiring rather than solely due to defective insulin signalling. This suggests that future studies should explore adipose redox balance and neurometabolic signalling as avenues for treating metabolic disease.

Keywords:  adipose tissue; glutamate; insulin resistance; lipolysis; sympathetic neurons

DOI:  https://doi.org/10.1016/j.tem.2026.07.006
Cell Rep Methods. 2026 Jul 30. pii: S2667-2375(26)00238-9. [Epub ahead of print] 101537

ATP-Red enables single-cell bioenergetic phenotyping by flow cytometry.

Jose Marin, Bharati Singh, Amanda Fuchs, Tatiana Tarasenko, Emily Warren, Martha Kirby, Stacie Anderson, Stephen M Wincovitch, Eliza M Gordon-Lipkin, Shannon Kruk, A Phillip West, Peter J McGuire.

  Most established bioenergetic assays lack single-cell resolution and may mask metabolic heterogeneity. The main flow-cytometry-based approach for bioenergetic analysis infers energetic state from protein synthesis, although translation can become uncoupled from ATP availability under physiologic and pathologic conditions. Here, we evaluated ATP-Red as a flow-cytometry-compatible readout of energetic state at single-cell resolution. We benchmarked ATP-Red against orthogonal approaches, including colorimetric ATP quantification, the ATP/ADP biosensor PercevalHR, and extracellular flux analysis, across ATPase inhibition, glycolytic and oxidative blockade, mitochondrial dysfunction, and immune activation. Across these settings, ATP-Red tracked biologically meaningful energetic changes as a relative ATP-linked fluorescence readout. When combined with immunophenotyping, ATP-Red also captured bioenergetic heterogeneity and pathway use in T cells following activation and during influenza virus infection. These findings support ATP-Red as a practical and scalable approach for single-cell bioenergetic phenotyping.

Keywords:  ATP-Red; CP: metabolism; flow cytometry; glycolysis; immunometabolism; metabolic phenotyping; mitochondrial dysfunction; oxidative phosphorylation; single-cell bioenergetics

DOI:  https://doi.org/10.1016/j.crmeth.2026.101537
Clin Lab Med. 2026 Sep;pii: S0272-2712(26)00055-7. [Epub ahead of print]46(3): 563-576

Back to Biochemistry: Evaluation for and Prognostic Significance of SDH Mutations in Paragangliomas and Pheochromocytomas.

Sounak Gupta, Lori A Erickson.

  There is increasing recognition of the high prevalence of hereditary predisposition syndromes in patients diagnosed with paraganglioma/pheochromocytoma. It is widely acknowledged that germline pathogenic alterations of the succinate dehydrogenase complex genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) contribute to the pathogenesis of most of these tumors. Herein, we have provided an update on the biology and diagnosis of succinate dehydrogenase-deficient paraganglioma/pheochromocytoma, including the molecular biology of the succinate dehydrogenase complex, mechanisms and consequences of inactivation of this complex, the prevalence of pathogenic alterations, and patterns of inheritance.

Keywords:  Paraganglioma; Pheochromocytoma; SDHA; SDHAF2; SDHB; SDHC; SDHD; Succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.cll.2026.06.010