bims-medica 2026-04-19 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–04–19
twenty-one papers selected by
Brett Chrest, Wake Forest University

SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
β-hydroxybutyrate supplementation boosts the tumor-killing potential of CAR T cells.
Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.
Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress.
Tumour promotion through the lens of evolution.
Efficacy of hypomethylating agents in combination with venetoclax in relapsed/refractory acute myeloid leukemia: A systematic review and meta-analysis.
Roles of Subunit ND2/NuoN in the Proton Pumping Coupling Mechanism of Complex I.
Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape.
Cytochrome c as a central regulator of mitochondrial function in cancer metabolism.
Fructose: metabolic signal and modern hazard.
Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle.
Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models.
[3-11C]Pyruvate PET detects alterations in cardiac pyruvate metabolism induced by doxorubicin chemotherapy.
Disparities in blood cancer survival in the UK 2009-2019: national cohort studies.
Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
SNAT1 (SLC38A1) Is Not the Main Glutamine Transporter in Melanoma, but Controls Metabolism via Glutamine-Dependent Activation of P62 (SQSTM1)/cMYC-Axis.
ACLY-Driven Metabolic Reprogramming Promotes Histone Acetylation and Inflammation-Associated Fibrosis in Chronic Kidney Disease.
Preliminary study on ketone body metabolism in anaplastic thyroid cancer.
PGK1/PHGDH axis drives radioresistance in glioblastoma stem cells.
Fasting-Based Dietary Interventions in Cancer Patients and Survivors: A Scoping Review.

bioRxiv. 2026 Apr 07. pii: 2026.04.03.716311. [Epub ahead of print]

SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.

Dingcheng Sun, Guangrui Ding, Haonan Lin, Guo Chen, Chun-Chin Wang, Seema Bachoo, Sarah E Bohndiek, Ji-Xin Cheng.

Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.

DOI: https://doi.org/10.64898/2026.04.03.716311
Trends Mol Med. 2026 Apr 14. pii: S1471-4914(26)00083-3. [Epub ahead of print]

β-hydroxybutyrate supplementation boosts the tumor-killing potential of CAR T cells.

Christos Adamopoulos, Kostas A Papavassiliou, Athanasios G Papavassiliou.

  In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhances proliferation, persistence, and tumor control, suggesting that metabolic supplementation may offer a simple route to more effective adoptive immunotherapy.

Keywords:  CAR T cells; adoptive immunotherapy; immunometabolism; ketogenic diet; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.molmed.2026.04.001
Mol Cell Proteomics. 2026 Apr 15. pii: S1535-9476(26)00065-4. [Epub ahead of print] 101569

Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.

Colin Zenge, Brittany Q Pham, Kihong Nam, Elana Apfelbaum, Heeseon An, Alban Ordureau.

  Altered metabolism is a hallmark of cancer, making metabolic enzymes attractive therapeutic targets. However, metabolic inhibitors have shown limited clinical success, partly due to differences between standard culture media and physiological nutrient conditions. Human plasma-like medium (HPLM) better recapitulates in vivo metabolite concentrations, yet its effects on cellular proteomes remain poorly characterized. We performed comprehensive TMTpro-based quantitative proteomics and phosphoproteomics across nine cancer cell lines cultured in DMEM or HPLM, consistently quantifying over 10,000 proteins and 24,000 phosphorylation sites across all three biological replicates with high reproducibility. Physiological media induced profound cell-type-specific remodeling of metabolic networks, mitochondrial proteomes, and signaling pathways. While decreased mTORC1 and CDK activity represented universal responses across all cell lines, metabolic enzyme expression exhibited striking heterogeneity. Enzymes in folate metabolism and pyrimidine salvage pathways showed consistent reductions across all cell types, indicating that drug responses may vary with media choice. Mitochondrial proteome composition and morphology displayed cell-type-specific adaptations. Phosphoproteomic analysis revealed kinase signaling networks underlying these metabolic changes. This dataset, accessible via an interactive web application, provides a resource for metabolic research using physiological media, highlighting substantial cell-type-specific variability in how media affect proteomes and signaling pathways.

Keywords:  CDK activity; Cancer cell metabolism; Physiological Media; Proteomics; mTORC1 signaling

DOI:  https://doi.org/10.1016/j.mcpro.2026.101569
Blood Neoplasia. 2026 May;3(2): 100196

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.

Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.

Resistance to combination regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor and BH3 mimetic venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively used agent. We previously established the antileukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML, and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supports leukemic survival and resistance to BH3 mimetics. Here, we report the antileukemic efficacy and mechanisms of cotargeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML data set revealed a positive relationship between increased AC gene expression and venetoclax resistance. Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was synergistically lethal when evaluated ex vivo across a cohort of venetoclax-resistant (n = 21) and venetoclax-sensitive (n = 46) primary samples from patients with AML. Moreover, the SACLAC + venetoclax combination was equipotent to the combination of venetoclax + cytarabine at reducing cell viability across primary patient samples. Mechanistically, cotargeting AC and BCL-2 increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.

DOI: https://doi.org/10.1016/j.bneo.2026.100196
Cell Chem Biol. 2026 Apr 13. pii: S2451-9456(26)00074-7. [Epub ahead of print]

Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress.

Alex E Ekvik, Megan M Kober, Denis V Titov.

  The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to alterations in the energy state by sensing changes in the ratio of ATP, ADP, AMP, and inorganic phosphate levels. A key barrier to understanding how this happens is a lack of tools for direct manipulation of the energy state in living cells. Here, we introduce ATPGobble-a genetically encoded tool that hydrolyzes ATP in vivo. ATPGobble increases the metabolic rate, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK in human cells. We performed a systematic analysis of proteome and phosphoproteome changes caused by ATPGobble, and found that it remodels cytoskeleton, cell cycle, and translation machinery. Our results establish ATPGobble as a powerful new tool for dissecting the regulatory roles of energy state in living cells.

Keywords:  AMPK; ATP; ATP/ADP ratio; F1 ATPase; cell fitness; energy status; energy stress; genetically encoded tools; phosphoproteomics; proteomics

DOI:  https://doi.org/10.1016/j.chembiol.2026.03.004
Nature. 2026 04;652(8110): 591-601

Tumour promotion through the lens of evolution.

Nuria Lopez-Bigas, Eve Kandyba, Abel Gonzalez-Perez, Paul Brennan, Allan Balmain.

Almost all tumours carry one or more cancer driver mutations, which are essential for cell transformation. However, recent advances in cancer genomics have demonstrated that normal human tissues contain millions of cells carrying known driver mutations, while preserving homeostasis. Most of these mutated cells will never transform into tumours. Moreover, studies of known or suspected human carcinogens have shown that the majority are not mutagens. These observations suggest that exogenous carcinogenic exposures might increase cancer risk by modifying selective constraints, promoting the expansion of pre-existing clones carrying specific oncogenic mutations. In this Review, we propose a synthesis between ideas put forward almost a century ago based on seminal experiments on carcinogen-induced tumours in mice, observations made by cancer epidemiologists over several decades, and the recent revelation that normal human tissues are a patchwork of mutant clones. The repeated interplay between variation and selection-the first principles of Darwinian evolution-underlies the clonal selection leading to tumorigenesis. A deeper understanding of these processes can enhance prospects for cancer prevention by eliminating or mitigating the effects of environmental or endogenous tumour promoters.

DOI: https://doi.org/10.1038/s41586-026-10386-x
Leuk Res. 2026 Apr 08. pii: S0145-2126(26)00071-8. [Epub ahead of print]165 108227

Efficacy of hypomethylating agents in combination with venetoclax in relapsed/refractory acute myeloid leukemia: A systematic review and meta-analysis.

Brittany Salter, Sarah Ge, Tobias Berg, Alejandro Garcia-Horton.

   BACKGROUND: Despite recent advances in the treatment of acute myeloid leukemia (AML), primary refractory disease and relapse (R/R) remain frequent, and there is no clearly established standard of care in this setting. While the combination of hypomethylating agents (HMA) with venetoclax (VEN) is a standard front-line therapy for patient's ineligible for intensive chemotherapy, its efficacy in the R/R setting remains poorly defined. The purpose of this systematic review and meta-analysis was to review the efficacy and safety of HMA/VEN for management of R/R AML.
METHODS: A systematic review was conducted using Embase and MEDLINE, identifying studies published between 2017 and 2025. Inclusion required adult R/R AML cohorts with at least 20 participants. The primary focus included treatment response and adverse events.
RESULTS: A total of 32 studies (N = 2289) were included. Patients were heavily pretreated, with 34% of patients having prior HMA exposure. Pooled efficacy estimates showed: complete remission (CR) 26% (95% CI: 24-48%), composite CR (CR/CRi) 43% (95% CI: 41-46%), overall response rate (ORR) 50% (95% CI: 48-53%), and measurable residual disease (MRD) negativity 42% (95% CI: 38-46%). The median overall survival (OS) was 8 months (IQR: 3-25) with one-year OS 40% (IQR: 23-55). Safety concerns were notable, with significant grade ≥ 3 toxicities, including febrile neutropenia, infection, and cytopenia. No significant publication bias was observed.
CONCLUSION: This study demonstrates that HMA/VEN is a potential re-induction regimen for patients with R/R AML. However, the high statistical heterogeneity identified underscores the need for further randomized studies to establish efficacy compared to more intensive salvage regimens.

Keywords:  Acute myeloid leukemia; Hypomethylating agents; Refractory; Relapsed; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2026.108227
Int J Mol Sci. 2026 Mar 25. pii: 2990. [Epub ahead of print]27(7):

Roles of Subunit ND2/NuoN in the Proton Pumping Coupling Mechanism of Complex I.

Andrew E Wadley, Madhavan Narayanan, Eiko Nakamaru-Ogiso.

  Complex I (NADH:quinone oxidoreductase, CI) is central to cellular aerobic energy metabolism. The L-shaped structure of CI is unique, where the hydrophilic arm is responsible for the electron transfer function and the membrane arm operates proton pumping. These two functional sites are spatially far apart yet functionally connected. This basic core subunit architecture is highly conserved from bacterial to mammalian CI. Here, to gain detailed mechanistic insight into the role of the membrane subunit ND2 in the coupling mechanism, we mutated several highly conserved residues in the middle of the membrane axis of NuoN, the E. coli CI homolog of ND2. To more precisely investigate the consequences of mutational effects on highly conserved residues, we purified each mutant CI and compared the mutational effects on electron transfer and proton pumping activity using our instant membrane reconstitution method with E. coli double knockout (DKO) membrane vesicles lacking both CI and alternative NADH dehydrogenase (NDH-2). Thre results were corroborated by conventional proteoliposome reconstitution experiments. We found that Lys247 and Lys395 are absolutely essential for both electron transfer and proton pumping activities, while about 50% reduction of NADH oxidase activity but no reduction in proton pumping activity was observed in Lys217, and no significant decrease was detected in Glu133. Furthermore, unexpectedly, we were able to purify an NuoN knockout (ΔNuoN) mutant, which contained stoichiometric peripheral subunits NuoB, NuoCD, NuoE, NuoF, NuoG, and NuoI; and a substoichiometric amount of NuoH and a reduced amount of quinone. However, surprisingly, this isolated ΔNuoN CI showed CI activities (~30% of the WT) after being reconstituted into DKO membranes but not into proteoliposomes. Later, we confirmed by blue native PAGE that the wild-type CI was partially formed from ΔNuoN CI by recruiting its missing membrane subunits that existed in DKO membranes. Our data strongly suggest that ND2/NuoN plays an essential role in the coupling mechanism in CI. CI is the entry respiratory chain enzyme and is central to cellular energy metabolism. Two highly conserved lysine residues in the center of the antiporter-like membrane subunit ND2 are essential for the coupling mechanism between electron transfer and proton translocation.

Keywords:  CI; ND2; energy coupling; proton pumping; ubiquinone

DOI:  https://doi.org/10.3390/ijms27072990
Eur J Pharmacol. 2026 Apr 15. pii: S0014-2999(26)00359-6. [Epub ahead of print] 178877

Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape.

Livia Bassani Lins de Miranda, Keli Lima, Diego A Pereira-Martins, Juan Luiz Coelho-Silva, Victoria Tomaz, Luiz Gustavo Ferreira Cortez, Marina de Franca Basto Silva, Rafael Lucas Muniz Guedes, Paulo Vidal Campregher, Dominique Sternadt, Eduardo Magalhães Rego, Fabiola Traina, Jan Jacob Schuringa, João Agostinho Machado-Neto.

  FLT3 inhibitors have become a cornerstone in the treatment of FLT3-mutated acute myeloid leukemia (AML), however, durable clinical responses are frequently limited by the emergence of acquired resistance. In this study, we established and comprehensively characterized a quizartinib-resistant FLT3-ITD AML model to elucidate the molecular and functional mechanisms underlying therapeutic failure. Prolonged exposure of MV4-11 cells to escalating concentrations of quizartinib resulted in the selection of quizartinib resistant clones (MV4-11QR), displaying an increase in IC50 and a shift from cytotoxic to predominantly cytostatic responses. Resistant cells maintained MAPK signaling despite FLT3 inhibition. Global proteomic profiling revealed extensive reprogramming, with enrichment of pathways related to energy metabolism, RNA processing, and translational regulation, accompanied by enhanced mitochondrial respiration and glycolytic capacity. Whole-genome sequencing identified acquisition of the FLT3D835H mutation and clonal expansion of TP53R248W with loss of the wild-type TP53 allele, indicating strong treatment-driven clonal selection. Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

Keywords:  Acute myeloid leukemia; Clonal selection; FLT3 inhibitor resistance; Multidrug resistance; Quizartinib; TP53 mutation

DOI:  https://doi.org/10.1016/j.ejphar.2026.178877
Discov Oncol. 2026 Apr 13.

Cytochrome c as a central regulator of mitochondrial function in cancer metabolism.

Aisha Shabir, Shazia Sofi, Nusrat Jan, Burhan Ul Haq, Hina Qayoom, Manzoor A Mir.

  Cytochrome c (Cytc) becomes a crucial regulator, determining the fate of cells at the confluence of apoptosis and metabolism. From its primary origin as an electron transporter in the mitochondrial electron transport chain (ETC), Cytc has ascended to a crucial role in apoptosis, triggering cascades of cellular deathupon liberation from the mitochondria.The intricate interplay between Cytc and apoptosis protease-activating factor-1 (Apaf-1) culminates in the apoptosome formation and activation of the cascade of caspase, underscoring the significance of Cytc in regulating cell death pathways. Moreover, tale of Cytc is adorned with post-translational modifications, particularly phosphorylation, which fine-tune its functions in respiration and apoptosis, adding layers of complexity to its regulatory effectiveness. Cytc becomes a lighthouse in the intricate web of cancer, its expression patterns providing hints about prognosis and paths toward treatment. Nevertheless, the story becomes more complex as Cytc becomes entangled in the metabolic reprogramming of cancer cells, implying a crucial involvement in tumor progression and treatment resistance. Collectively, these findings highlight Cytc as a multifunctional regulator of cellular fate that integrates mitochondrial respiration, apoptotic signalling, and metabolic reprogramming, suggesting new opportunities for cancer diagnosis and therapeutic intervention. Even if progress has been made, the story of Cytc is far from over, demanding more investigation into its complexities and biological consequences related to cancer. It represents a therapeutic target in the fight against cancer considering its substantial role in tumor metabolism. It promises a future in which creative solutions to the challenges of cellular destiny will be found. In this review, we have tried to highlight the multidimensional realm of Cytc, connecting threads between apoptosis, metabolic reprogramming, and the Warburg effect in line with cancer.

Keywords:  Apoptosis; Cytochrome c; Electron transport chain; Metabolic reprogramming; Mitochondrial outer membrane permeability; Warburg effect

DOI:  https://doi.org/10.1007/s12672-026-05014-z
Nat Metab. 2026 Apr 17.

Fructose: metabolic signal and modern hazard.

Richard J Johnson, Miguel A Lanaspa, Dean R Tolan, Marcus D Goncalves, Samir Softic, Kimber L Stanhope, Laura G Sánchez-Lozada, Mark A Herman, Joshua D Rabinowitz.

There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose's well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular and physiological distinctions between fructose and glucose, as well as the endogenous fructose pathway that makes fructose from glucose. Through this Review, we highlight the role of fructose not only as a caloric source, but also as a regulator of metabolic health and disease.

DOI: https://doi.org/10.1038/s42255-026-01506-y
Elife. 2026 Apr 17. pii: RP107332. [Epub ahead of print]14

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle.

Yibo Fan, Senuri De Silva, Nishat I Tabassum, Xiangyuan Peng, Vernise J T Lim, Xiangru Cheng, Keshava K Datta, Rohan Lowe, Terrance G Johns, Mark P Mattson, Suresh Mathivanan, Christopher G Sobey, Eitan Okun, Yong U Liu, Guobing Chen, Mitchell Kim Peng Lai, Dong-Gyu Jo, Jayantha Gunaratne, Thiruma V Arumugam.

  Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

Keywords:  Serpin A1c; bioinformatics; cell biology; intermittent fasting; medicine; metabolic reprogramming; mouse; proteomics; transcriptomics

DOI:  https://doi.org/10.7554/eLife.107332
Leukemia. 2026 Apr 15.

Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models.

Malathi Kandarpa, Luke F Peterson, Harish Potu, Megha Ramappan, Yihong Liu, Avery Polk, Shaomeng Wang, Moshe Talpaz.

MDM2 is an E3 ubiquitin ligase that promotes p53 tumor suppressor degradation and has emerged as a therapeutic target in the treatment of wild-type (wt) TP53 tumors. In acute myeloid leukemia (AML), TP53 mutations are infrequent (15-20%), but wt-p53 is often inactivated through overexpression of MDM2. Thus, MDM2 inhibitors are currently in clinical trials for AML. However, p53 stabilization with inhibitors upregulates MDM2, which limits their clinical efficacy. Proteolysis-targeting chimeric (PROTAC) molecules that degrade MDM2 may overcome this feedback. MD-265 is a PROTAC that recruits CRBN, degrades MDM2, restores p53 and induces apoptosis. We tested MD-265 in ex vivo cultures of 105 primary leukemic stem cells (LSCs). The median cytotoxic IC50 for MD-265 was 16 nM, median IC50 for MI-1061 was 150-fold higher. LSCs with IC50 > 1 µM were classified as MD-265 resistant and harbored mutations in TP53. Normal hematopoietic stem cells showed 100-fold higher IC50 (818 nM) than LSCs. AML patient-derived xenograft (PDX) models in NSG-SGM3 mice were treated with MD-265 or an oral MDM2 inhibitor. In PDX models, MD-265 was not toxic and prolonged survival. MD-265 is a potent and specific MDM2 degrader with broad pre-clinical activity and a promising drug candidate for the treatment of leukemias.

DOI: https://doi.org/10.1038/s41375-026-02957-8
Npj Imaging. 2026 Apr 16. pii: 28. [Epub ahead of print]4(1):

[3-11C]Pyruvate PET detects alterations in cardiac pyruvate metabolism induced by doxorubicin chemotherapy.

Chul-Hee Lee, Thomas Ruan, Shuvra Debnath, Anja S Wacker, Grace Figlioli, John W Babich, Sadek A Nehmeh, Kayvan R Keshari, James M Kelly.

Changes in cardiac metabolism typically precede cardiac dysfunction and therefore represent an important target for diagnosis and treatment designed to prevent progression to heart failure, a leading cause of death. Profound changes in pyruvate metabolism, including reduced expression of the mitochondrial pyruvate carrier (MPC), are increasingly recognized as early maladaptive alterations in cardiomyopathies, but no methods currently exist to determine MPC expression in vivo. We exposed mice to doxorubicin (DOX), an anthracycline chemotherapeutic known to perturb pyruvate metabolism, and demonstrated that cardiac tissue levels of MPC decrease within 4 weeks of initial DOX exposure. Using a combination of stable isotope tracing metabolomics, hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI), and [3-11C]pyruvate positron emission tomography (PET), we found that loss of MPC and monocarboxylate transporter 1 (MCT1) resulted in decreased utilization of pyruvate for mitochondrial oxidative metabolism and resulted in decreased cardiac carbon-11 clearance. Despite recovery of expression levels of pyruvate transporters, including MPC, 16 weeks after initial DOX exposure, cardiac carbon-11 clearance still trends towards differences between control mice and the mice exposed to this chemotherapeutic. [3-11C]Pyruvate PET is therefore a promising approach to imaging cardiac pyruvate transport with potential applications to the identification of early maladaptive changes in pyruvate metabolism and monitoring response to therapy.

DOI: https://doi.org/10.1038/s44303-026-00165-8
BJC Rep. 2026 Apr 15. pii: 19. [Epub ahead of print]4(1):

Disparities in blood cancer survival in the UK 2009-2019: national cohort studies.

Janice Hoang, Joshua Allen, Rebecca Capel, Rebecca Thomas, Stephanie Smits, Rubina Ahmed, Hilary Webb, Aziz Sheikh, Sally Cox, Ceri Bygrave, Julia Hippisley-Cox.

ABSTARCT: BACKGROUND: Blood cancers are among the most common and deadliest in the UK, affecting over 40,000 people annually. Survival varies by subtype, but this is not routinely reported for the UK. This study estimated survival for haematological malignancies in the UK stratified by time period, age, sex, ethnicity, deprivation, and rurality.
METHODS: Four retrospective cohorts of patients aged 15-99 diagnosed with haematological malignancies (2009-2019) across UK cancer registries were used to estimate 1-, 5-, and 10-year net survival by subtype.
RESULTS: We identified 413,286 blood cancer cases. Survival in all blood cancer combined significantly improved in England (3.8%), Northern Ireland (5.1%), and Wales (3%), but not Scotland. Men had ≥3% lower survival than women in many subtypes. Older age and higher deprivation were significantly linked to lower survival. In England, white ethnic groups had ≥3% lower survival than non-white groups for myelodysplastic syndrome, myeloid malignancies, plasma cell neoplasms, myeloproliferative neoplasms. In Wales, rural areas showed ≥3% higher survival than urban and mixed regions for lymphoid malignancies, myeloid malignancies, plasma cell neoplasms, Hodgkin lymphoma, mature B-cell neoplasms, acute myeloid leukaemia.
CONCLUSION: Net survival varied markedly by subtype and demographic factors across the UK. Given possible differences in case ascertainment, findings are descriptive and hypothesis‑generating.

DOI: https://doi.org/10.1038/s44276-026-00222-0
EMBO Rep. 2026 Apr 14.

Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.

Manami Tanaka, Takako Hishiki, Tomomi Matsuura, Masato Yasui, Shunsuke Chikuma, Mariko Hara-Chikuma.

  Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes.　In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.

Keywords:  Glycerol; Inflammation; Macrophage; Metabolism; Obesity

DOI:  https://doi.org/10.1038/s44319-026-00747-y
Cancers (Basel). 2026 Mar 25. pii: 1068. [Epub ahead of print]18(7):

SNAT1 (SLC38A1) Is Not the Main Glutamine Transporter in Melanoma, but Controls Metabolism via Glutamine-Dependent Activation of P62 (SQSTM1)/cMYC-Axis.

Sandra Lörentz, Ines Böhme-Schäfer, Jörg König, Heinrich Sticht, Anja Katrin Bosserhoff.

  Background: Tumor cells can reprogram their metabolism, constituting a hallmark of cancer that plays a crucial role in tumor progression. As tumor cells exhibit an increased demand for nutrients, e.g., amino acids, they rely on extracellular sources and show deregulation of transport proteins. Among these, SNAT1 (SLC38A1) is described as the loader for glutamine that is responsible for the main influx of this amino acid. The aim of this study was to assess the molecular function of SNAT1 in melanoma regarding its role in amino acid transport and regulation of cellular metabolism. Methods: siPool-mediated downregulation of SNAT1 expression in melanoma cell lines was used to investigate the molecular function of this protein. Glutamine transport was assessed by measuring the intracellular and extracellular concentrations of glutamine. Regulation of downstream effectors was evaluated with qRT-PCR and Western Blot. Metabolism was investigated by performing Seahorse flux analysis. Mitochondrial staining was examined via flow cytometry. Protein interaction was assessed with Co-IP, and in silico modeling of protein interaction was performed with AlphaFold3. Results: In this study, we uncovered the new finding that SNAT1 is not primarily implicated in glutamine influx into melanoma cells but in signaling in response to extracellular glutamine. We identified P62 and cMYC as downstream effectors of SNAT1. By activating the P62/cMYC-axis and target genes of cMYC, SNAT1 modulates the metabolism of melanoma cells depending on the glutamine level. SNAT1 and P62 are interaction partners. Conclusions: This finding newly suggests that SNAT1 may function as a sensor or receptor ("transceptor") for glutamine rather than being a direct and primary glutamine transporter, and could open up new therapeutic options targeting melanoma cells.

Keywords:  SNAT1 (SLC38A1); glutamine transport; melanoma; transceptor; tumor metabolism

DOI:  https://doi.org/10.3390/cancers18071068
Adv Sci (Weinh). 2026 Apr 16. e75247

ACLY-Driven Metabolic Reprogramming Promotes Histone Acetylation and Inflammation-Associated Fibrosis in Chronic Kidney Disease.

Chunxiu Du, Dhanunjay Mukhi, Lingzhi Li, Chenyu Li, Siyu Pan, Bernhard Dumoulin, Eunji Ha, Lakshmi P Kolligundla, Yanjuan Hou, Jonathan Levinsohn, Chaelin Kang, Konstantin Adrian Klötzer, Junnan Wu, Samer Mohandes, Kathryn E Wellen, Katalin Susztak.

  The mechanisms by which metabolic stress drives epigenetic dysregulation and fibrosis in chronic kidney disease (CKD) remain incompletely understood. Using quantitative histone proteomics in murine fibrosis models, we uncovered a selective increase in histone H3 lysine 27 acetylation (H3K27ac) as a conserved epigenetic feature. Unbiased metabolomics revealed citrate accumulation, nominating ATP-citrate lyase (ACLY) as a driver of acetyl-CoA-dependent histone acetylation. In murine models of folic acid and unilateral ureteral obstruction, ACLY expression, acetyl-CoA levels, and H3K27ac were increased in injured kidneys. Tubule-specific Acly deletion reduced acetyl-CoA, H3K27ac, and attenuated tubulointerstitial fibrosis. Chromatin accessibility profiling revealed that loss of Acly decreased accessibility at pro-inflammatory loci, including Jak1 and Jak2, with reduced transcriptional output. These transcriptional and epigenetic signatures were observed in human CKD samples, where higher ACLY expression correlated with worse kidney function and increased JAK1/2 expression. Notably, ACLY inhibitors, including bempedoic acid and BMS-303141 recapitulated the antifibrotic effects of Acly deletion in vivo in mice, supporting the therapeutic repurposing of ACLY inhibitors for CKD. Together, our findings position ACLY as a key metabolic-epigenetic checkpoint of kidney fibrosis and a promising, druggable target for halting CKD progression.

Keywords:  H3K27ac; acetyl‐CoA metabolism; chromatin accessibility; kidney fibrosis

DOI:  https://doi.org/10.1002/advs.75247
Eur Thyroid J. 2026 Apr 13. pii: ETJ-25-0305. [Epub ahead of print]

Preliminary study on ketone body metabolism in anaplastic thyroid cancer.

Jiaqi Wang, Yuting Mao, Ziyang Xuan, Zhihao Li, Xi Tang, Ke Yang, Mingluan Xing, Xin Zhu.

   Background: Anaplastic thyroid cancer (ATC) is characterized by high invasiveness, rapid progression, and has a poor prognosis. The aim of this study was to investigate the role of ketone body metabolism in ATC and provide a novel approach for ATC treatment.
Methods: Human ATC cell lines, including 8505C and CAL-62, were used as the research objects. Cell Counting Kit-8 and colony formation assays appraised cell proliferation. Flow cytometry was performed to evaluate the cell cycle and apoptosis. Wound healing and transwell assays verified the migration and invasion of cells. Further, tumor xenograft models were established to investigate the therapeutic effect of ketogenic diet in vivo. Immunohistochemistry was used to quantify the expression level of Ki67, Bcl-2, Caspase3 in tumor tissues. Importantly, autophagy analyses included fluorescence microscopy for observation of monodansylcadaverine staining, western blotting, and tissue immunofluorescence to determine autophagic protein (LC3, Beclin1, and p62) expression.
Results: Acetoacetate (AcAc) inhibited the proliferation, migration, and invasion of ATC cells (8505C and CAL-62) and induced cell cycle arrest. Ketogenic diet significantly inhibited tumor growth in vivo. AcAc markedly elevated the level of autophagy. Autophagy inhibitor weakened the extent to which AcAc hindered cell proliferation, migration, and invasion and blocked cell cycle.
Conclusions: The study demonstrated that ketone body metabolite AcAc inhibits the proliferation, migration, and invasion of ATC cells and induces cell cycle arrest by inducing autophagy. Ketogenic diet provides a new strategy for the treatment of ATC.

Keywords:  Acetoacetate; Anaplastic thyroid cancer; Autophagy; Ketogenic diet; Ketone body metabolism

DOI:  https://doi.org/10.1530/ETJ-25-0305
Cancer Lett. 2026 Apr 15. pii: S0304-3835(26)00280-6. [Epub ahead of print] 218517

PGK1/PHGDH axis drives radioresistance in glioblastoma stem cells.

Zhangchun Cheng, Fangshu Ding, Jianxing Yin, Yingyi Wang, Yapeng Gao, Xin Ge, Junxia Zhang, Xiefeng Wang, Minghui Zhao, Ningwei Zhao, Chuanjun Shu, Xiuxing Wang, Xu Qian, Chunfa Qian, Jing Ji, Yongping You, Zhumei Shi.

  Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and radiotherapy is a key treatment option. However, glioblastoma stem cells (GSCs) can develop resistance to radiotherapy through metabolic reprogramming, which often results in tumor recurrence. Here we found that glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was phosphorylated at threonine 8 (T8) by ataxia telangiectasia mutated (ATM) upon irradiation (IR), leading to enhanced binding of PGK1 to phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for the serine synthesis pathway (SSP). PGK1 subsequently functioned as a protein kinase to phosphorylate PHGDH at T60, which resulted in enhanced PHGDH enzymatic activity and increased serine synthesis to fuel the production of S-adenosylmethionine (SAM). Increased SAM then promoted the levels of histone H3K36 trimethylation (H3K36me3) to recruit RAD51 to engage homologous recombination (HR)-mediated DNA damage repair to confer resistance of GSCs to IR. Importantly, both inhibiting PHGDH T60 phosphorylation and suppressing its enzymatic activity sensitized GSCs to IR, inhibited growth of orthotopic xenografts, and prolonged survival of tumor-bearing mice. Furthermore, clinical analysis indicated that phosphorylation levels at both PHGDH T60 and PGK1 T8 corresponded closely with the poor prognosis of GBM patients. This study revealed an ATM-PGK1-PHGDH signaling axis that promotes serine synthesis to confer resistance of GSCs to IR, and suggested that targeting PHGDH may serve as a potential strategy to overcome radioresistance in GBM.

Keywords:  GSCs; PGK1; PHGDH; SAM; radioresistance; serine

DOI:  https://doi.org/10.1016/j.canlet.2026.218517
Nutrients. 2026 Mar 25. pii: 1035. [Epub ahead of print]18(7):

Fasting-Based Dietary Interventions in Cancer Patients and Survivors: A Scoping Review.

Kuang-Yi Wen, Julianne Freedman, Abenezer Tafese, William Kelly, Nicole Simone.

  Background: Fasting-based interventions are increasingly investigated as adjuncts to cancer treatment for the potential to reduce therapy-related toxicities, improve metabolic health, and enhance quality of life. However, clinical evidence regarding their efficacy, tolerability, and acceptability remains limited and fragmented. This scoping review aimed to systematically map the current evidence on fasting-based interventions in cancer patients and survivors. Methods: A literature search was conducted in PubMed, Scopus, Web of Science, and CINAHL up to 10 June 2025. Eligible interventional studies included cancer patients or survivors and evaluated fasting-based interventions, such as time-restricted eating, intermittent fasting, short-term fasting, or fasting-mimicking diets. Studies were categorized by fasting types and outcomes like fatigue, treatment toxicity, metabolic and hematologic parameters, weight, quality of life, adherence, acceptability, illness perception, and adverse events were assessed. Result: Twenty interventional studies of FMD, TRE, STF, IF, or fasting combined with altered dietary approaches conducted across 10 countries were included, comprising a total of 871 participants. Participant ages ranged from 28 to 75 years. Overall, 9 of 20 studies exclusively enrolled breast cancer patients or survivors, and chemotherapy was the most common treatment context in 11 studies. Five of six studies reported reductions in fatigue. Among the five studies assessing quality of life, one demonstrated improvement, three reported no change, and one yielded mixed results. Six of eight studies reported reductions in chemotherapy-related toxicity, and weight loss was observed in 10 of 12 studies. Reductions in IGF-1 and insulin levels were reported in six of seven and four of five studies, respectively. Hematologic changes were noted in six studies, and only one study assessed illness perceptions, reporting positive findings. Fasting-related adverse events, reported in nine studies, were generally mild and transient. High adherence and acceptability were observed across studies; however, findings were heterogeneous across intervention types and were largely derived from small or moderate-strength studies. A descriptive quality metric assessment indicated that most studies were of moderate methodological strength. More intensive fasting protocols, such as FMD and STF, appeared to demonstrate more consistent metabolic effects, whereas TRE showed higher adherence but more variable clinical outcomes. Conclusions: Fasting-based interventions have the potential to be feasible and well tolerated among cancer patients and survivors, with early evidence suggesting benefits in reducing fatigue, minimizing treatment-related toxicities, and favorable metabolic effects. Large, well-designed trials including diverse cancer populations are needed to confirm long-term outcomes and guide clinical integration.

Keywords:  cancer; intermittent fasting; survivorship; time-restricted eating

DOI:  https://doi.org/10.3390/nu18071035