bims-medica 2026-01-11 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–01–11
twenty-one papers selected by
Brett Chrest, Wake Forest University

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.
MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.
Impacts of ketogenic diet intervention on cardiometabolic outcomes in obese, dysglycemic mice.
BDH1-Dependent Ketone Body Metabolism Maintains Müller Cell Homeostasis and Retinal Function.
CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins.
A clickable CoQ imaging probe reveals that cellular uptake and lysosomal trafficking depend on CD36 and NPC1.
The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.
Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.
Dextromethorphan Is a Novel Pharmacological Inhibitor of F1FO-ATPase That Targets the Membrane-Embedded Domain Impairing ATP Synthesis and Hydrolysis.
The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.
When heme is low, copper kills cancer.
Preclinical Comparison of 18F-Labeled Amino Acids Targeting Different Transporter Systems for PET Imaging of Triple-Negative Breast Cancer.
Cardiolipin Remodeling as a Regulatory Switch in Osteogenesis: Insights from Multimodal Metabolic Imaging and Molecular Profiling.
Molecular mechanism of exchange coupling in CLC chloride/proton antiporters.
Methionine Restriction Must Be Continuously Maintained to Selectively Inhibit Cancer Cells Co-cultured With Normal Cells.
Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions.
On the mechanisms of ultra-processed diet effects.
Visualization of de novo synthesized nascent purine and pyrimidine using carbon isotope imaging and spectral tracing (CIIST) in single microbial cell.
Daily briefing: The human cells in our bodies that aren't genetically ours.

Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.

Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.

  Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.

Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102316
Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01013-5. [Epub ahead of print]86(1): 6-8

Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.

Yury S Bykov, Johannes M Herrmann.

In this issue of Molecular Cell, Zhu et al.1 show that mitochondria of cancer cells rely on the import of glutamine not only to fuel metabolite synthesis via the tricarboxylic acid cycle but also to charge mt-tRNAGln to allow mitochondrial protein synthesis and respiration.

DOI: https://doi.org/10.1016/j.molcel.2025.12.014
Cell Death Dis. 2026 Jan 02.

MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.

Priyadarshika Pradhan, Tanvi Chaudhary, Shivali Mishra, Peter Konik, Eva Durinova, Roman Tuma, Abhijt De, Devanjan Sinha.

Mitochondrial metabolism plays a crucial role in cancer progression and is associated with effective channeling of electrons through Complex I. The ability to adapt this electron flow as per cellular demands is critical for energy homeostasis. Our observations suggest that proliferating cells regulate the electron entry point through alterations in the levels of Methylation-Controlled J-protein (MCJ). Elevated MCJ levels were found to promote aggressive proliferative and migratory phenotypes, leading to increased primary tumor burden. The phenotype was attributed to MCJ-mediated regulation of mitochondrial bioenergetic plasticity, enabling a preferential rerouting of electron flux through succinate dehydrogenase complex (Complex II). Consequently, cells exhibited suppressed glycolysis and a metabolic shift toward lipid-fueled mitochondrial respiration, marked by increased lipid accumulation and its oxidation. Despite Complex I uncoupling, these cells maintained better respiratory output and preserved NADH levels to support an increased redox potential. These findings decouple the reliance on Complex I for effective mitochondrial respiration and underscore the significance of Complex II-driven metabolism in tumor growth, an important consideration for development of future therapeutics, particularly when current strategies predominantly target Complex I-dependent respiration.

DOI: https://doi.org/10.1038/s41419-025-08398-y
Cardiovasc Diabetol. 2026 Jan 03.

Impacts of ketogenic diet intervention on cardiometabolic outcomes in obese, dysglycemic mice.

Cassandra A A Locatelli, My-Anh Nguyen, Nadya M Morrow, Elena Cameron, Natasha A Trzaskalski, Ilka Lorenzen-Schmidt, Arianne Morissette, Erin E Mulvihill.

   BACKGROUND: The ketogenic diet (KD) is widely recognized for its potential benefits in individuals with type 2 diabetes, but findings from both human and animal studies remain inconsistent. Type 2 diabetes is often comorbid with liver steatosis and atherosclerosis which are characterized by inflammation and dysregulated lipid metabolism. Moreover, whereas KD has shown mixed, sometimes detrimental, effects on circulating cholesterol levels in humans, it is currently unclear the whole-body balance of risk and benefit across hepatic, atherosclerotic, and pancreatic effects.
METHODS: We used lean, diet-induced obese, and diet-induced obese, atherosclerotic (PCSK9 overexpression (OE)) mouse models to assess the impact of an extreme KD on cardiometabolic outcomes. Obese and PCSK9 OE mice received 10 weeks of cholesterol-supplemented HFD before 12 weeks of KD intervention whereas lean mice received KD, chow, or HFD for 12 weeks.
RESULTS: KD intervention induced weight loss in obese female and PCSK9 OE male mice, but not male, wildtype mice. Across models, KD did not improve glucose tolerance or ex vivo insulin secretion, despite elevated levels of insulinotropic GLP-1 after glucose gavage. Pancreas lipids were similar between diet groups in obese mice, but liver steatosis or inflammation were generally improved in all models on KD. All KD groups had increased hepatic expression of genes for fatty acid oxidation, ketone body production, and ketone utilization. KD-intervened PCSK9 OE mice had lower circulating TNFα and chemokines (CCL2, CCL4, CXCL1, CXCL2) as well as smaller atherosclerotic lesion area relative to mice that continued on the HFD. The PCSK9 OE male mice on KD intervention also had reduced circulating LDL cholesterol but this effect was lost in mice with intact LDL receptor signaling, which also had fasting hypertriglyceridemia in line with HFD continuers.
CONCLUSIONS: This study demonstrates that, in mice, a high cholesterol KD can improve hepatic steatosis particularly when weight loss is achieved, compared to maintaining the western-style HFD. However, no improvements to insulin secretion and glucose tolerance were observed despite elevated post-glucose GLP-1 levels and long-term diminished requirements for insulin.

Keywords:  Atherosclerosis; Cholesterol; Glucagon like peptide 1-; Inflammation; Islets; Ketogenic diet; Steatosis

DOI:  https://doi.org/10.1186/s12933-025-03046-3
bioRxiv. 2025 Dec 27. pii: 2025.12.27.696636. [Epub ahead of print]

BDH1-Dependent Ketone Body Metabolism Maintains Müller Cell Homeostasis and Retinal Function.

Richa Garg, Eshani Karmakar, David DeBruin, Shauna Prasad, Ethan Naquin, Michelle Brennan, Niloofar Piri, Oleg Kisselev, Jaya P Gnana-Prakasam.

  Ketone body metabolism serves as an auxiliary regulator of cellular energetics and redox balance, particularly during prolonged fasting and carbohydrate restriction, yet its role in retinal homeostasis under physiological conditions remains poorly defined. β-hydroxybutyrate dehydrogenase 1 (BDH1) is a mitochondrial enzyme that interconverts acetoacetate and β-hydroxybutyrate, and is required for efficient ketone utilization. Here, we investigated the impact of impaired endogenous ketone metabolism on retinal function using global and retinal pigment epithelium (RPE)-specific BDH1 knockout (KO) mice. Global BDH1 KO mice showed reduced circulating β-hydroxybutyrate and blunted fasting-induced ketone elevations, accompanied by ganglion cell loss, structural abnormalities on fundus and OCT imaging, and diminished scotopic and photopic electroretinogram (ERG) a- and b-wave amplitudes, consistent with impaired photoreceptor responses and downstream bipolar and Müller cell signaling. In contrast, RPE-specific BDH1 KO mice exhibited no changes in ERG responses or retinal morphology. Transcriptomic and molecular analyses in global KO retinas revealed disrupted Müller cell homeostasis, including reduced CAMKII-CREB activation, which is required for EAAT1 glutamate transporter expression. Administration of exogenous β-hydroxybutyrate, in vitro and in vivo, restored CAMKII-CREB-EAAT1 signaling, glutamate uptake, and antioxidant gene expression in BDH1 KO mice, demonstrating a central role for ketone bodies in Müller cell metabolic support, glutamate homeostasis, and redox balance. Together with reduced BDH1 expression in human AMD retinas, these findings identify the BDH1-β-hydroxybutyrate axis as a critical metabolic pathway for Müller cell function and retinal integrity, and highlight ketone metabolism as a potential therapeutic target in degenerative retinal diseases.

Keywords:  AMD; CAMKII-CREB; Müller cells; glutamate transporter; neurodegeneration; retinal dysfunction; β-hydroxybutyrate

DOI:  https://doi.org/10.64898/2025.12.27.696636
bioRxiv. 2025 Dec 26. pii: 2025.12.24.696284. [Epub ahead of print]

CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins.

Muhammad Daniyal, Rajesh Rajaiah, Upendarrao Golla, Marudhu Pandiyan Shanmugam, Koby Duke, Katherine Mercer, Yasin Uzun, Hannah Valensi, Jeremy Hengst, Sinisa Dovat, Yi Qiu, Suming Huang, Chandrika G Behura.

Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38-) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy.

DOI: https://doi.org/10.64898/2025.12.24.696284
Redox Biol. 2025 Nov 26. pii: S2213-2317(25)00449-5. [Epub ahead of print]89 103936

A clickable CoQ imaging probe reveals that cellular uptake and lysosomal trafficking depend on CD36 and NPC1.

Irene Liparulo, Arkadiy Bazhin, Grace Katherine Van Wyhe, Amanda Lestari Gunawan, Neville Dadina, Justin Hyunwoo Kwon, Alanna Schepartz, Elena Goun, Andreas Stahl.

Coenzyme Q (CoQ) is a crucial lipid-soluble antioxidant and electron transporter vital for mitochondrial respiration and cellular redox balance. Despite the role of CoQ in oxidative phosphorylation being well established, the mechanisms by which CoQ is internalized, distributed among subcellular compartments, and trafficked to mitochondria remain poorly defined. Here, we present the development of a minimally modified, azide-tagged CoQ analogue that enables high-resolution visualization of CoQ localization using fluorescence-based imaging. Using this probe, we focus our investigation on brown adipose tissue (BAT), a mitochondria-rich, highly metabolically active tissue with elevated CoQ demand. On a cellular level, we demonstrate that CoQ is internalized via receptor-mediated endocytosis, predominantly localizing to lysosomes. Genetic knockdown and pharmacological studies identify CD36 and NPC1 as essential transporters in this process. Our work provides both a technical advance for the redox biology field, with the development and characterization of a CoQ probe, and the essential new biological insight that NPC1 is linked to CoQ homeostasis and thus provides a foundation for further dissection of CoQ biology in health and disease.

DOI: https://doi.org/10.1016/j.redox.2025.103936
bioRxiv. 2025 Dec 22. pii: 2025.12.19.695528. [Epub ahead of print]

The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells.

CUIJBP consortium

High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPCs). The current standard of care for HR-MDS patients is hypomethylating agents; however, the response rate is poor. There is thus a need to explore vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that HR-MDS HSPCs have significant upregulation of metabolic proteins required for glycolysis, citric acid cycle, and oxidative phosphorylation. Consistently, we see increased oxygen consumption rate in HR-MDS HSPCs compared to healthy, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of mitochondrial complex I proteins, which are NADH dehydrogenases, and crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on NAMPT, the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition significantly decreased NAD(H) in HR-MDS HSPCs. Consequently, NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS-HSPCs compared to healthy. Importantly, NAMPT inhibition significantly impaired the self-renewal and colony-forming potential, increased cell death and reduced disease burden specifically of HR-MDS HSPCs, compared to healthy controls. Collectively, our data suggest that NAMPT is selectively required for the function and survival of HR-MDS HSPCs representing a promising therapeutic target.

DOI: https://doi.org/10.64898/2025.12.19.695528
Transl Cancer Res. 2025 Dec 31. 14(12): 8448-8461

Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.

Siegfried Hélage, Marie-Céline Blanc-Quintin, Nathalie Neveux, Antonin Ginguay, Jean-Pascal De Bandt, Luc Cynober, Jérôme Alexandre, François Goldwasser, Élisabeth Dion.

   Background: Glutamine, an essential nutrient for healthy cells, supports immunity and cytoprotection during anticancer treatments. However, intense glutaminolysis may promote proliferation and chemoresistance in ovarian carcinomas by activating the PI3K/AKT/mTORC1 pathway and overexpressing c-Myc. This study aimed to characterize glutamine metabolism in ovarian carcinomas and assess its impact on tumor aggressiveness and chemosensitivity, to inform nutritional supplementation or therapeutic targeting.
Methods: Glutamine and glucose consumption, chemosensitivity to cisplatin and paclitaxel, and doubling time were analyzed in three ovarian carcinoma cell lines (ES-2, TOV-21G: clear cell; OVCAR-3: serous papillary) and primary ascites cells under varying glutamine concentrations (0.5, 1, 2, 4 mM). Expression of glutaminase, glutamate dehydrogenase 1 (GDH1), and c-Myc, as well as PI3K/AKT/mTORC1 activation, were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.
Results: TOV-21G exhibited significantly higher glutamine consumption (13.3±1.3 vs. 6.5±0.3 and 7±0.5 U/mg protein, P<0.001), increased expression of glutaminase, GDH1, and c-Myc, marked PI3K/AKT/mTORC1 activation (P=0.045), and a shorter doubling time (11.5±1.5 h, P=0.04) compared to ES-2 and OVCAR-3. OVCAR-3 showed significantly greater resistance to cisplatin and paclitaxel (P=0.03). Varying glutamine concentrations did not affect chemosensitivity.
Conclusions: Intense glutaminolysis is associated with increased tumor aggressiveness, suggesting a prognostic role for 18F-(2S,4R)-4-fluoroglutamine (18F-fluoroglutamine) positron emission tomography (PET) imaging. Glutamine supplementation, without impacting chemoresistance, may mitigate iatrogenic effects, while targeting glutaminolysis offers a therapeutic perspective.

Keywords:  Ovarian carcinoma; chemoresistance; glutamine; glutaminolysis; metabolic imaging

DOI:  https://doi.org/10.21037/tcr-2025-1721
Biofactors. 2026 Jan-Feb;52(1):52(1): e70076

Dextromethorphan Is a Novel Pharmacological Inhibitor of F1FO-ATPase That Targets the Membrane-Embedded Domain Impairing ATP Synthesis and Hydrolysis.

Cristina Algieri, Antonia Cugliari, Silvia Granata, Patrycja Anna Glogowski, Fabiana Trombetti, Micaela Fabbri, Lucia Scainelli, Salvatore Nesci.

  Dextromethorphan (DXM), a widely used antitussive agent, was investigated for its effects on mitochondrial F1FO-ATPase activity and oxidative phosphorylation. Our results demonstrate that DXM inhibited F1FO-ATPase independently of the thiol redox state. Mutual exclusion analysis highlighted an overlapping binding site between DXM and dicyclohexylcarbodiimide (DCCD), indicating a shared or adjacent binding site in the membrane-embedded FO domain of the enzyme. These findings suggested that DXM selectively targeted the proton translocation mechanism of F1FO-ATPase during the ATP hydrolysis and synthesis of ATP. Moreover, kinetic analysis confirmed a high affinity of DXM for the enzyme, with an inhibitory efficiency of 2.37 mM-1⸱s-1. Importantly, DXM did not affect electron transport chain activity but impaired ATP synthesis, as evidenced by altered respiratory control ratios of oxidative phosphorylation. The data obtained offer new insights into its off-target mitochondrial effects and potential implications for bioenergetic regulation.

Keywords:  F1FO‐ATPase; dextromethorphan; enzyme kinetics; mitochondria

DOI:  https://doi.org/10.1002/biof.70076
Cancer Lett. 2026 Jan 07. pii: S0304-3835(26)00008-X. [Epub ahead of print] 218245

The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.

Chenggong Tu, Arne Van der Vreken, Sylvia Faict, Gamze Ates, Ann Massie, Kim De Veirman, Elke De Bruyne, Karin Vanderkerken, Eline Menu.

  Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells residing in the bone marrow. Despite advancements in treatment, including proteasome inhibitors (PIs) such as bortezomib (Bz), drug resistance remains a major challenge. Metabolic reprogramming supports MM survival and drug resistance, with mitochondria emerging as promising therapeutic targets through their control of OXPHOS and mitochondrial reactive oxygen species (Mito-ROS). Using metabolic flux analyses, flow cytometry, and Western blot analysis, we identified pyruvate as a central metabolic intermediate, which not only enhances mitochondrial respiration and Mito-ROS production, but also the Integrated Stress Response (ISR) pathway. Conversely, metformin, an inhibitor of OXPHOS, was still able to activate the ISR pathway, but rather reduced Bz-induced cytotoxicity by decreasing both protein synthesis, and ROS production. Results were confirmed on primary murine and patient samples. Moreover, analysis of the CoMMpass study revealed that patients with prolonged progression-free survival under PI treatment showed enrichment in OXPHOS-related gene, highlighting the importance of mitochondrial metabolism in regulating MM responses to Bz. These data suggest that targeting pyruvate metabolism to increase ROS production could offer a strategy to enhance Bz activity in MM.

Keywords:  ISR; bortezomib; metformin; multiple myeloma; pyruvate

DOI:  https://doi.org/10.1016/j.canlet.2026.218245
Cell. 2026 Jan 08. pii: S0092-8674(25)01423-0. [Epub ahead of print]189(1): 3-5

When heme is low, copper kills cancer.

Andreas Linkermann.

Heme carries oxygen and is critical for the control of redox reactions. In this issue of Cell, Lewis and Gruber et al. demonstrate how low concentrations of heme destabilize complex IV of the respiratory chain to release copper and kill acute myeloid leukemia cells by cuproptosis.

DOI: https://doi.org/10.1016/j.cell.2025.12.010
J Nucl Med. 2026 Jan 08. pii: jnumed.125.270225. [Epub ahead of print]

Preclinical Comparison of 18F-Labeled Amino Acids Targeting Different Transporter Systems for PET Imaging of Triple-Negative Breast Cancer.

Ugur Akca, Patrick N Song, Dattatray Devalankar, Norio Yasui, Anna G Sorace, Jonathan McConathy.

  Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors and low expression of the human epidermal growth factor receptor 2 gene. Radiolabeled amino acids (AAs) have the ability to specifically target the enhanced AA transport and modified metabolic pathways present in breast cancer cells. The primary objective of this study was to compare the uptake of AA PET tracers targeting different AA transporter systems in 2 mouse models to assess their potential for imaging TNBC. Methods: The AA PET tracers (R)-3-[18F]fluoro-2-methyl-2-(N-methylamino)propanoic acid (18F-MeFAMP, system A transport), (S)-2-amino-3-[1-(2-[18F]fluoroethyl)- 1H-[1,2,3]triazol-4-yl]propanoic acid (18F-AFETP, cationic and neutral transport), and 18F-fluciclovine (system ASC transport) were compared with 18F-FDG in primary tumor orthotopic syngeneic (4T1, n = 10) and patient-derived xenograft (BCM3936, n = 8) models of TNBC. SUV, tumor-to-brain ratios, and tumor-to-muscle ratios were quantified. Quantitative analysis of AA transporter immunohistochemistry was conducted and compared with the imaging results. Results: AA PET tracers demonstrated uptake levels in primary TNBC tumors comparable to those with 18F-FDG, with varying uptake across tracers. All AA tracers demonstrated higher tumor-to-normal tissue ratios than did 18F-FDG across multiple organs. The highest tumor-to-brain ratios were observed for 18F-MeFAMP (4T1 model) and 18F-AFETP (PDX BCM3936 model). 18F-MeFAMP showed the highest tumor-to-muscle ratios in both models, followed by 18F-AFETP and 18F-fluciclovine. Tumor-to-bone and tumor-to-liver ratios consistently favored AA tracers, with 18F-AFETP demonstrating superior tumor-to-liver contrast because of low hepatic uptake. 18F-MeFAMP, 18F-AFETP, and 18F-fluciclovine showed positive but complex correlations between SUV and corresponding AA transporters in immunohistochemical analysis. Conclusion: The AA PET tracers evaluated in this study demonstrated promising imaging properties in TNBC models compared with 18F-FDG, with higher tumor-to-brain ratios and tumor-to-muscle ratios observed across both models. Although these findings highlight the potential of AA tracers for imaging primary tumors and metastases, they also support the continued investigation of AA PET tracers as complementary tools to 18F-FDG to characterize TNBC biology as well as other aggressive cancers.

Keywords:  AFETP; MeFAMP; breast cancer; fluciclovine; radiolabeled amino acids

DOI:  https://doi.org/10.2967/jnumed.125.270225
bioRxiv. 2025 Dec 23. pii: 2025.12.22.696122. [Epub ahead of print]

Cardiolipin Remodeling as a Regulatory Switch in Osteogenesis: Insights from Multimodal Metabolic Imaging and Molecular Profiling.

Maria Iftesum, Praveen Kumar Guttula, Kirti Agrawal, Subhrajyoti S Kundu, Sreyashi Das, Fabrizio Donnarumma, Ram Devireddy, Manas Ranjan Gartia.

Cardiolipin (CL), a mitochondria-specific phospholipid, plays a fundamental role in respiratory chain organization and bioenergetic efficiency, yet its contribution to osteogenic differentiation is poorly defined. Here, we used a multimodal approach integrating untargeted LC-MS lipidomics, Raman spectroscopy, fluorescence lifetime imaging microscopy (FLIM), and structural imaging to investigate CL remodeling during human adipose-derived stem cell differentiation. Lipidomics revealed a selective enrichment of highly unsaturated CL species, accompanied by transcriptional upregulation of the cardiolipin biosynthetic and remodeling enzymes CDS1/2, PGS1, CRLS1, TAZ, and HADHA. Lipidomics also revealed a time-dependent increase in membrane-associated lipids including phosphatidylcholine (PC), serine, and phosphatidylinositol (PI). These lipids were implicated in supporting mitochondrial membrane expansion, oxidative phosphorylation, and signaling processes critical for osteoblast maturation. Spatial imaging techniques confirmed cardiolipin accumulation and redistribution in differentiated cells, while Raman-based direct classical least squares (DCLS) analysis provided label-free mapping of lipid species. Gene Ontology (GO) enrichment and protein-protein interaction network analysis further identified biological pathways related to bone remodeling, cardiolipin metabolism, and osteoblast-specific signaling. Fluorescence Lifetime Imaging Microscopy (FLIM) data revealed a metabolic shift from glycolysis to oxidative phosphorylation during differentiation, supported by structural and gene expression evidence. These changes temporally coincided with matrix mineralization and collagen organization, linking CL metabolism to both cellular bioenergetics and extracellular matrix production. Our findings identify cardiolipin remodeling as a metabolic checkpoint in osteogenesis and suggest that targeted modulation of CL pathways may provide new therapeutic strategies for enhancing bone regeneration.

DOI: https://doi.org/10.64898/2025.12.22.696122
Nat Commun. 2026 Jan 08.

Molecular mechanism of exchange coupling in CLC chloride/proton antiporters.

Deniz Aydin, Chih-Ta Chien, Jürgen Kreiter, Amy R Nava, Jasmina M Portasikova, Lukas Fojtik, Briana L Sobecks, Catalina Mosquera, Petr Man, Ron O Dror, Wah Chiu, Merritt Maduke.

The ubiquitous CLC membrane transporters are unique in their ability to exchange anions for cations. Despite extensive study, there is no mechanistic model that fully explains their 2:1 Cl‒/H+ stoichiometric exchange mechanism. Here, we provide such a model. Using differential hydrogen-deuterium exchange mass spectrometry, cryo-EM structure determination, and molecular dynamics simulations, we uncovered conformational dynamics in CLC-ec1, a bacterial CLC homolog that has served as a paradigm for this family of transporters. Simulations based on a cryo-EM structure at pH 3 revealed critical steps in the transport mechanism, including release of Cl‒ ions to the extracellular side, opening of the inner gate, and water wires that facilitate H+ transport. Surprisingly, these water wires occurred independently of Cl‒ binding, prompting us to reassess the relationship between Cl‒ binding and Cl‒/H+ coupling. Using isothermal titration calorimetry and quantitative flux assays on mutants with reduced Cl‒ binding affinity, we conclude that, while Cl‒ binding is necessary for coupling, even weak binding can support Cl‒/H+ coupling. By integrating our findings with existing literature, we establish a complete and efficient CLC 2:1 Cl‒/H+ exchange mechanism.

DOI: https://doi.org/10.1038/s41467-025-68098-1
Cancer Diagn Progn. 2026 Jan-Feb;6(1):6(1): 31-39

Methionine Restriction Must Be Continuously Maintained to Selectively Inhibit Cancer Cells Co-cultured With Normal Cells.

Byung Mo Kang, Qinghong Han, Shukuan Li, Jin Soo Kim, Kohei Mizuta, Yohei Asano, Yuta Miyashi, Michael Bouvet, Robert M Hoffman.

   Background/Aim: Methionine addiction (Hoffman effect) is a fundamental and general cancer hallmark targetable by methionine restriction, using methionine-depleted media or diet, or recombinant methioninase (rMETase). Our previous studies showed differential sensitivity of HCT-116 colon-cancer cells and Hs27 normal fibroblasts to rMETase in co-culture. The present study aimed to demonstrate the rescue conditions of cancer cells by methionine replenishment in the co-cultures of HCT-116 and Hs27 cells after rMETase treatment.
Materials and Methods: Equal numbers of HCT-116 colon-cancer cells and Hs27 normal fibroblasts were co-cultured in 6-well plates in Dulbecco's modified Eagle's medium (DMEM). Two days after seeding, co-cultures were treated with rMETase at the HCT-116 IC50 (0.46 U/ml) or left untreated as controls. Growth of each cell type in co-culture was evaluated by phase-contrast microscopy on days 2, 4, 6, 8, 10, and 12 after treatment to assess the response to rMETase. On day 12, the existing medium in all wells was replaced with fresh DMEM containing methionine (methionine replenishment). Regrowth of HCT-116 and Hs27 was then assessed by phase-contrast microscopy 3, 6, and 9 days later.
Results: In the untreated control group, HCT-116 cancer cells rapidly proliferated, and progressively overtook the Hs27 fibroblasts and predominated by day 12. In the rMETase-treated group, viable HCT-116 cells progressively decreased and were almost undetectable by day 12, whereas Hs27 cells remained viable throughout the observation period. After day-12 replenishment of methionine, previously rMETase-treated co-cultures showed reappearance of viable HCT-116 cells by day 3 and dominance over Hs27 cells by day 9.
Conclusion: Continuous treatment with rMETase is necessary to maintain inhibition of cancer cells and normal-cell dominance in co-culture with cancer cells. These results have clinical implications indicating that methionine restriction must be continually maintained to inhibit cancer.

Keywords:  Cancer cells; Hoffman effect; co-culture; methionine addiction; methionine rescue; normal fibroblasts; recombinant methioninase; selective cancer efficacy

DOI:  https://doi.org/10.21873/cdp.10504
bioRxiv. 2025 Dec 31. pii: 2025.12.31.697091. [Epub ahead of print]

Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.

Sneha P Rath, Zhu Li, Arkajit Guha, Fangcong Dong, Ruma Banerjee, Vamsi K Mootha.

Of the ∼1100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including the vitamin B12 chaperone MMADHC and cytosolic B12-dependent methionine synthase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.
Significance Statement: Humans have only two vitamin B12-dependent enzymes - mitochondrial MMUT and cytosolic MTR - and both require a common B12 chaperone MMADHC. We discover that MMADHC is a low abundant, short-lived protein that is continuously imported and degraded by energized mitochondria. Upon collapse of the mitochondrial proton motive force, MMADHC accumulates in the cytosol and increases the levels and activity of MTR, critical for one-carbon metabolism. This PMF-dependent regulation of MMADHC stability and localization is important for understanding cofactor rationing and spatiotemporal compartmentalization of B12 metabolism.

DOI: https://doi.org/10.64898/2025.12.31.697091
Ann Med. 2026 Dec;58(1): 2603016

The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions.

Damian Dyńka, Łukasz Rodzeń, Mateusz Rodzeń, Dorota Łojko, Hanna Karakuła-Juchnowicz, Georgia Ede, Żaneta Grzywacz, Katarzyna Antosik, Shebani Sethi, David Unwin.

   BACKGROUND: The ketogenic diet (KD), initially developed for the treatment of neurological disorders, has gained increasing attention for its potential role in the management of various metabolic diseases. Alongside its expanding clinical use, concerns have emerged regarding its safety, tolerability, and suitability in specific patient populations. This review summarises key contraindications, clinical situations requiring caution, relevant drug interactions, and commonly reported adverse effects associated with KD.
DISCUSSION: Rare absolute contraindications include selected inborn errors of metabolism affecting pyruvate carboxylase activity, carnitine transport or utilisation, fatty acid oxidation pathways, as well as porphyria. Relative contraindications encompass acute pancreatitis, advanced hepatic or renal disease, familial hypercholesterolaemia, and other conditions that may be aggravated by KD-induced metabolic changes, including concomitant use of propofol. Particular caution is warranted in patients with type 1 or type 2 diabetes receiving specific glucose-lowering therapies, pharmacologically treated hypertension, gallbladder disease or prior cholecystectomy, electrolyte disturbances, cardiac arrhythmias, pregnancy or lactation, underweight status, intense physical activity, significant psychosocial stress, or postoperative recovery.Clinically relevant interactions with medications are reviewed, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, insulin and sulphonylurea derivatives, antiepileptic drugs, diuretics, lipophilic drugs, and corticosteroids. The most frequently reported adverse effects range from transient "keto flu" symptoms (fatigue, headache, nausea) to gastrointestinal disturbances, polyuria, and hypoglycaemia.
CONCLUSIONS: KD demonstrates therapeutic potential in the management of a broad range of metabolic and neurological diseases; however, it is not an intervention suitable for all clinical situations. Awareness of existing contraindications, conditions requiring particular caution, and potential drug interactions enables a more responsible, individualised, and safe approach to patient selection and clinical management. In this context, the present paper provides a concise yet comprehensive synthesis to support clinicians and researchers in the rational and effective application of the ketogenic diet in both clinical practice and scientific research.

Keywords:  Ketogenic diet (KD); absolute contraindications; diseases; drug interactions; relative contraindications; side effects

DOI:  https://doi.org/10.1080/07853890.2025.2603016
Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00534-0. [Epub ahead of print]38(1): 5-6

On the mechanisms of ultra-processed diet effects.

Romain Barrès, Stephen J Simpson, Marcelo A Nóbrega, Jessica M Preston.

DOI: https://doi.org/10.1016/j.cmet.2025.12.003
Anal Chim Acta. 2026 Jan 22. pii: S0003-2670(25)01380-7. [Epub ahead of print]1384 344986

Visualization of de novo synthesized nascent purine and pyrimidine using carbon isotope imaging and spectral tracing (CIIST) in single microbial cell.

Jiro Karlo, Tejas Ajit Mhaiskar, Hrishikesh Ravindra Karande, S P Singh.

   BACKGROUND: Nitrogenous bases, namely purine and pyrimidine, and their derivatives are key metabolites for the growth and division of cells as they are an integral part of biomolecules that store genetic information, involved in protein synthesis, as energy carrier molecules, and many other metabolic processes. Purine and pyrimidine can either be synthesized (de novo pathway), recycled, and/or acquired exogenously (salvage pathway). These nitrogenous bases can be analysed with high sensitivity using mass spectrometry-based methods, which are inherently destructive. Therefore, there remains a challenge for imaging of nascent purine and pyrimidine nitrogenous bases distribution at the single-cell level.
RESULTS: Here, we report a novel single-cell Raman imaging framework, "carbon isotope imaging and spectral tracing (CIIST)" for mapping nascent nitrogenous bases in prokaryotic and eukaryotic microbial systems. This method helps in visualising the turnover of nascent purine and pyrimidine nitrogenous bases at the subcellular level over time. The enrichment of carbon isotope (carbon-12 or carbon-13) in the nitrogenous base pool generates Raman peaks at distinct positions, and targeting these CIIST can be used for generating spatial maps for quasi-quantitative imaging of nitrogenous base turnover in cells.
SIGNIFICANCE: Overall findings provide the prospective utility of the CIIST technique as a highly effective non-destructive tool for multiplex and spatial biomolecular analysis of nitrogenous base metabolism at the single-cell level.

Keywords:  Bioimaging; Biosensing; Carbon-13; Metabolic mapping; Metabolomics; Nitrogenous bases; Purine; Pyrimidine; Raman imaging

DOI:  https://doi.org/10.1016/j.aca.2025.344986
Nature. 2026 Jan 05.

Daily briefing: The human cells in our bodies that aren't genetically ours.

Flora Graham.

DOI: https://doi.org/10.1038/d41586-026-00043-8