bims-mibica 2026-08-09 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–08–09
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

The pivotal role of mitochondrial disorders in cancer development with a special focus on mitochondria-mediated apoptosis.
Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.
Mitochondria with (distinct) personality.
Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
ATHENA promotes the assembly of the ATP synthase-associated macromolecular complex and cancer progression.
Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.
ABHD4-2: a cardiolipin-selective phospholipase of the outer mitochondrial membrane.
Induction of cuproptosis via targeting mitochondrial metabolism using dPTBD with potent therapeutic activity against KRAS-driven cancer.
The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence.
Mannose supports lung cancer metabolism during glycolytic limitation.
Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
A Selective CK1α Degrader Targets Acute Myeloid Leukemia and Spares Normal Hematopoietic Cells.
Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk.
Hyperpolarized [2-13C]Pyruvate Identifies a Mitochondria-Active Hepatocellular Carcinoma Phenotype With Vulnerability to Mitochondrial Inhibition.
Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
A dependency map enhanced with next-generation 3D cancer models.

Cell Mol Biol (Noisy-le-grand). 2026 Apr 30. 72(4): 41-55

The pivotal role of mitochondrial disorders in cancer development with a special focus on mitochondria-mediated apoptosis.

Alexander V Blagov, Nikolay A Orekhov, Ulyana Rozhkova, Stanislav Antonov, Aleksandra Utkina, Alexander N Orekhov.

Emerging evidence indicates that mitochondrial dysfunction is not merely a consequence but a driving force in cancer progression. Unlike normal cells, cancer cells rewire their mitochondrial metabolism to support uncontrolled proliferation, a process that includes aerobic glycolysis, persistent reactive oxygen species production, and adaptation to hypoxic conditions. A common hallmark across many tumors is the suppression of the intrinsic apoptotic pathway, primarily achieved through an imbalance between anti-apoptotic and pro-apoptotic BCL-2 family proteins. This evasion of cell death not only facilitates tumor initiation and metastasis but also contributes to resistance against conventional therapies. Here, we provide an overview of major mitochondrial alterations in cancer, with a detailed focus on how the mitochondrial apoptotic machinery is disabled in malignant cells. We then discuss current therapeutic strategies designed to re-activate mitochondria-mediated apoptosis, including BH3 mimetics, direct activators of pro-apoptotic proteins like BAX, immune checkpoint inhibitors, CAR‑T cell therapy, and mitochondria-targeted nanomedicine. Finally, we address the limitations and safety concerns of existing pro-apoptotic drugs and propose future directions to develop more selective and effective cancer treatments. Understanding the molecular mechanisms that govern mitochondrial apoptosis may open new avenues for inducing tumor cell death while minimizing harm to normal tissues.

DOI: https://doi.org/10.14715/cmb/2026.72.4.6
Mol Cell Biochem. 2026 Aug 07.

Hydroxyhydroquinone as a novel modulator of mitochondrial metabolism with potential to restore CoQ10 homeostasis.

Paulo Roberto Dos Santos, Joseph Rastegar, Mariana Roesch-Ely.

  Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10- 5 mol.L- 1) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.

Keywords:  Coenzyme Q; Hydroxyhydroquinone; Metabolism; Mitochondrial; Ubiquinone

DOI:  https://doi.org/10.1007/s11010-026-05687-8
Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923

Mitochondria with (distinct) personality.

Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.

Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.

DOI: https://doi.org/10.1016/j.molcel.2026.06.044
Elife. 2026 Aug 05. pii: RP106492. [Epub ahead of print]14

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Lindsey N Dzierozynski, Chufan Cai, Leah M Ziolkowski, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

  Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

Keywords:  biochemistry; cancer; cancer biology; chemical biology; diet; human; metabolism; mouse; stress; synthetic lethality; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.106492
Cell Death Differ. 2026 Aug 03.

ATHENA promotes the assembly of the ATP synthase-associated macromolecular complex and cancer progression.

Fang Guo, Xujie Zhao, Xiaohui Yang, Yan Li, Liqiang Duan, Yibi Zhang, Xiaofeng Zhu, Qinong Ye, Yunzhao Chen, Li Ren, Shan Gao.

The ATP synthase-associated macromolecular complex plays a crucial role in cellular energy homeostasis. However, the regulation and potential function of this complex remain poorly understood in cancer. Here, we identify a 170-amino acid protein encoded by the lncRNA LINC00528, which we term ATP synthase-associated macromolecular complex enhancing microprotein (ATHENA). Mechanistically, ATHENA localizes to the mitochondrial inner membrane, in which ATHENA directly interacts with ATP synthase subunits (β and γ) and solute carrier proteins, including ANT and PiC, thereby promoting the assembly of these macromolecular complexes, enhancing ATP synthesis, and preserving mitochondrial and cristae architecture. Functionally, ATHENA promotes the proliferation, migration, and invasion of renal cell carcinoma (RCC) cells in vitro and drives RCC tumor growth and metastasis in vivo. Clinically, ATHENA is upregulated in RCC tissues and associated with poorer prognosis in RCC patients. Collectively, our findings identify ATHENA as a previously unrecognized mitochondrial microprotein that facilitates the assembly of ATP synthase-associated macromolecular complex and drives RCC progression.

DOI: https://doi.org/10.1038/s41418-026-01840-4
Cell Metab. 2026 Aug 05. pii: S1550-4131(26)00324-4. [Epub ahead of print]

Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.

Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.

DOI: https://doi.org/10.1016/j.cmet.2026.07.026
J Proteome Res. 2026 Aug 07. 25(8): 3965-3986

Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.

Chiranjit Panja, Aneta Wiesyk, Suchismita Masanta, Katarzyna Niedzwiecka, Emilia Baranowska, Dominik Cysewski, Marta Sipko, Anna Anielska-Mazur, Agata Malinowska, Roza Kucharczyk.

  Protein adenylation (AMPylation) is a post-translational modification in which an adenosine monophosphate (AMP) group is covalently attached to target proteins by AMPylases using ATP as a donor. In metazoans, two conserved AMPylase families are known: FIC-domain proteins and SelO. The yeast Saccharomyces cerevisiae lacks a FIC-domain enzyme; its only known AMPylase is the mitochondrial SelO homologue, Fmp40, involved in redox signaling. We conducted the first comprehensive screen for AMPylated proteins in the mitochondrial proteome of S. cerevisiae analyzing both wild-type and fmp40Δ cells using quantitative mass spectrometry. We identified 124 AMPylated mitochondrial proteins in wild-type and 41 in fmp40Δ mitochondria, suggesting the existence of additional AMPylase(s) in yeast. Among the modified targets, seven ATP synthase subunits were AMPylated, many at sites also phosphorylated, underscoring complex PTM regulation of the enzyme. We demonstrated that substitutions of one such residue, serine 29 in the δ subunit (Atp16), to alanine or glutamic acid, altered ATP synthase activity and oxidative phosphorylation coupling under both fermentative and respiratory conditions. This regulation is crucial for maintaining mitochondrial membrane potential. Our study provides the first catalog of AMPylated mitochondrial proteins in yeast, establishing a foundation for future studies on mitochondrial AMPylation.

Keywords:  AMPylation; ATP synthase; Fmp40; mitochondria; yeast

DOI:  https://doi.org/10.1021/acs.jproteome.5c01273
J Lipid Res. 2026 Aug 06. pii: S0022-2275(26)00149-5. [Epub ahead of print] 101119

ABHD4-2: a cardiolipin-selective phospholipase of the outer mitochondrial membrane.

Raja Narayanasamy, Matthew A Sanders, Huamei Zhang, Marta Moreno-Torres, Vanesa D Ramseyer, Hong-Guang Wei, Nils J Færgeman, Christopher V Kelly, James G Granneman.

  Cardiolipin (CL) is a unique dimeric phospholipid essential for mitochondrial integrity and stress signaling. While most CL is present in the inner mitochondrial membranes (IMM), CL can be exposed to the outer mitochondrial membrane (OMM) under specific physiological and pathological conditions; however, the mechanisms regulating its metabolism at the OMM are poorly defined. Based on its striking structural similarity to Cld1p, a yeast CL hydrolase, we hypothesized that α/β-hydrolase domain-containing protein 4 (ABHD4) functions as a mammalian CL hydrolase. We identified two isoforms of mouse ABHD4 arising from alternative splicing: ABHD4-1 localizes to lipid droplets, whereas ABHD4-2 selectively targets mitochondria and is enriched in oxidative tissues. We demonstrate that ABHD4 selectively hydrolyzes CL in vitro, producing monolysocardiolipin (MLCL) and dilysocardiolipin (DLCL). Site-directed mutagenesis identified catalytic serine residues as essential for enzymatic activity in ABHD4 and its Drosophila homolog, Pummelig. In contrast to Cld1p, which resides in the IMM, topological analyses indicate that ABHD4-2 and Pummelig-2 localize to the cytosolic face of the OMM, a conserved orientation that suggests a function distinct from classic acyl chain remodeling of CL. In brown adipocytes, ABHD4-2 overexpression reduces mitochondrial membrane potential in an activity-dependent manner. In silico analyses further reveal conservation of the catalytic triad across yeast, insect, and mammalian orthologs, supporting an evolutionarily conserved role for this enzyme family in CL metabolism. Together, these findings identify ABHD4-2 as an OMM-localized phospholipase with preferential CL hydrolase activity and define an isoform-specific pathway linking CL metabolism to mitochondrial stress responses.

Keywords:  ABHD4-2; Cardiolipin; cardiolipin hydrolase; outer mitochondrial membrane; phospholipase activity

DOI:  https://doi.org/10.1016/j.jlr.2026.101119
Cancer Lett. 2026 Aug 03. pii: S0304-3835(26)00537-9. [Epub ahead of print]658 218773

Induction of cuproptosis via targeting mitochondrial metabolism using dPTBD with potent therapeutic activity against KRAS-driven cancer.

Yichen Sun, Ming Song, Wenwen Ding, Qi Liu, Wenhua Lu, Bingling Luo, Ping Chen, Jing Yang, Yumin Hu, Shijun Wen, Peng Huang.

  Cuproptosis is a type of recently reported cell death characterized by aberrant accumulation of copper ions within cells, leading to mitochondrial stress and protein aggregation. Recent studies suggest that certain cancer cells are particularly susceptible to cuproptosis-inducing agents. However, the genetic determinants of cellular sensitivity to cuproptosis and the therapeutic potential of cuproptosis inducers in cancer treatment remain unclear. Here, we report the discovery of a small molecule, N1,N1-dimethyl-N4-(4-(pyridin-2-yl)thiazol-2-yl)benzene-1,4-diamine (dPTBD), that targets KRAS-driven cancer via a tetracycline-inducible cell-based drug screening. dPTBD exhibited significant antitumor efficacy in KRAS-driven cancers both in vitro and in vivo. Mechanistic studies revealed that dPTBD acted as a copper ionophore, promoting intracellular copper accumulation particularly in the mitochondria, leading to metabolic disruption and cuproptotic cell death. Adding trace amount of copper massively enhanced the cytotoxic effect of dPTBD, resulting in an immediate mitochondrial dysfunction and cuproptosis. In preclinical models, dPTBD, either alone or combined with physiologically tolerable amount of copper, significantly suppressed tumor growth in KRAS-mutant pancreatic and colon cancer xenografts. Taken together, our study reveals that induction of cuproptosis is a new therapeutic strategy for KRAS-driven cancer and identifies dPTBD as a lead compound for future development.

Keywords:  Copper ionophore; Cuproptosis; KRAS; Mitochondria; dPTBD

DOI:  https://doi.org/10.1016/j.canlet.2026.218773
Cell Chem Biol. 2026 Aug 03. pii: S2451-9456(26)00244-8. [Epub ahead of print]

The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence.

Aislinn Gallagher Aldave, Vaishnavi Venugopalan, Gokhan Gunay, Seren Hamsici, Ronaldo Rodrigues Ribeiro, Aoife Costigan, Anna Gabrielyan, Hande Efe-Cicek, Seamus J Martin.

  Cytotoxic chemotherapy is intended to eliminate transformed cells but can also provoke therapy-induced senescence, a persistent and pro-inflammatory cell state that can promote tumor progression. The molecular mechanisms that govern the apoptosis-senescence fate decision remain incompletely understood. Here, we show that the mitochondrial pore-forming proteins BAX and BAK function as a critical checkpoint that restricts entry to therapy-induced senescence. Genetic ablation of BAX and BAK markedly enhanced entry to senescence in response to multiple DNA-damaging agents, whereas loss of the BAX/BAK antagonists Bcl-xL or Mcl-1 suppressed entry to senescence and promoted cell death. Mechanistically, genotoxic stress induced BH3-only proteins, including Noxa, Bid, and Puma, creating a dependence on Bcl-xL and Mcl-1 to restrain BAX/BAK activation and maintain survival. These findings identify the Bcl-2 family network as a central regulator of entry to therapy-induced senescence, a pro-inflammatory cell state that goes beyond the mere avoidance of apoptosis.

Keywords:  BAK; BAX; Bcl-2 family; DNA damage; apoptosis; cell death; chemotherapy; mitochondria; senescence; senolysis

DOI:  https://doi.org/10.1016/j.chembiol.2026.07.002
EMBO Rep. 2026 Aug 07.

Mannose supports lung cancer metabolism during glycolytic limitation.

Theresa Haitzmann, Niklas B Thompson, Hardik Shah, Katharina Schindlmaier, Joseph Jelwan, Thomas O Eichmann, Nia G Hammond, Maia G Clare, Robert B Cameron, Brandon Faubert, Katharina Leithner.

Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. 13C6-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.

DOI: https://doi.org/10.1038/s44319-026-00874-6
Nat Cell Biol. 2026 Aug 06.

Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.

Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.

Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.

DOI: https://doi.org/10.1038/s41556-026-02025-4
Cancer Res. 2026 Aug 03.

A Selective CK1α Degrader Targets Acute Myeloid Leukemia and Spares Normal Hematopoietic Cells.

Bo-Reum Kim, Hyemin Kim, Hoon Choi, Daehun Kwag, Yoon-Ju Kim, Hyunsong Son, Sohyun Park, Jisu Park, Hadong Kim, Woosuk Choi, Seunghoon Lee, Hee-Je Kim, Hyunseok Kang, Hyunsun Jo, Byung-Sik Cho.

Casein kinase 1⍺ (CK1⍺) is a multifunctional serine/threonine kinase, serving as an upstream regulator of the p53 pathway and a potential therapeutic target for acute myeloid leukemia (AML). Small-molecule degraders show preclinical promise in AML by selectively degrading target proteins. Here, we developed and evaluated PinA1, a molecular glue degrader targeting CK1⍺, in preclinical AML models. PinA1 preferentially degraded CK1⍺ at nanomolar concentrations, resulting in enhanced p53 expression, cell-cycle arrest, and apoptosis in TP53 wild-type AML cell lines but not in TP53 mutated cells. PinA1 also induced CK1⍺ degradation and p53-dependent apoptosis in primary AML cells with wild-type TP53. Notably, PinA1 had minimal effects on the viability of human peripheral blood and bone marrow mononuclear cells, including CD34+ cells, with limited activation of the p53 pathway. In both cell lines and primary AML cells, PinA1 enhanced apoptosis when combined with targeted agents, including FLT3, BCL-2, or MDM2 inhibitors. PinA1 demonstrated robust anti-leukemic efficacy as a monotherapy and exhibited synergistic effects when combined with targeted agents in xenografts derived from human AML cell lines and primary AML cells. In conclusion, PinA1 degrades CK1⍺, activates the p53 pathway, and induces cell-cycle arrest and apoptosis in TP53 wild-type AML cells. The robust anti-leukemic efficacy of PinA1, both as monotherapy and further in combination with targeted agents, along with its minimal toxicity to normal hematopoietic cells, underscores its potential for future clinical applications.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3629
Nat Cell Biol. 2026 Aug 06.

Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk.

DOI: https://doi.org/10.1038/s41556-026-02032-5
NMR Biomed. 2026 Sep;39(9): e70360

Hyperpolarized [2-13C]Pyruvate Identifies a Mitochondria-Active Hepatocellular Carcinoma Phenotype With Vulnerability to Mitochondrial Inhibition.

Qianhui Dou, Sophia M Mirrione, Karen Dos Santos, Samuel R Calos, Aaron K Grant, Yi-Fen Yen, Leo L Tsai.

Hepatocellular carcinoma (HCC) exhibits metabolic heterogeneity that is not fully characterized by glycolysis-focused spectroscopic profiling. This study investigated whether in vitro hyperpolarized (HP) [2-13C]pyruvate NMR spectroscopy can identify a mitochondria-active HCC phenotype and assess its association with sensitivity to mitochondrial metabolic inhibition. HP [2-13C]pyruvate NMR spectroscopy was used to evaluate mitochondrial metabolism in McA-RH7777 HCC cells, with N1S1 cells serving as a glycolysis-dominant reference. Cell viability following treatment with the glutaminase inhibitor BPTES and the mitochondrial metabolic inhibitor CPI-613 was assessed by MTT assay, and metabolic changes following CPI-613 treatment were further evaluated using HP [2-13C]pyruvate. HP [2-13C]pyruvate demonstrated enhanced pyruvate-to-glutamate conversion in McA-RH7777 cells, whereas N1S1 showed minimal glutamate labeling. CPI-613 treatment resulted in a dose-dependent reduction in cell viability, while BPTES produced limited effects. Although pyruvate-to-glutamate conversion did not significantly decrease following CPI-613 treatment, pyruvate-to-lactate conversion increased, indicating metabolic adaptation. These findings demonstrate that HP [2-13C]pyruvate enables functional identification of a mitochondria-active HCC phenotype characterized by enhanced pyruvate-to-glutamate conversion. This approach may facilitate metabolic subtype classification, help identify tumors susceptible to mitochondrial metabolic inhibition, and enable non-invasive monitoring of treatment-induced metabolic adaptation.

DOI: https://doi.org/10.1002/nbm.70360
Nat Metab. 2026 Aug 05.

Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.

Anke Vandekeere, Juan Fernández-García, Yiming Peng-Winkler, Miguel Martín Pérez, Ming Liu, Sara Isabel Fernandes, Janine Theile, Philipp Willnow, Sanne Verheul, Gitte Zels, Anirudh Pabba, Christine Desmedt, Cornelis Verhoef, Patricia Altea-Manzano, Salvador Aznar Benitah, Ilaria Elia, Ilaria Malanchi, Sarah-Maria Fendt.

Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.

DOI: https://doi.org/10.1038/s42255-026-01582-0
Nature. 2026 Aug 05.

A dependency map enhanced with next-generation 3D cancer models.

James V Neiswender, Samuel Maffa, Lisa Brenan, Dina ElHarouni, Yejie Yun, Isabella Boyle, Kirsty Wienand, Haider Inam, Tate Bertea, Ashley Anderson, Megan Wong, Matias Enriquez, Evan Lenz, Beatriz Villafranca, Nora Shanks, Mary Hager, Nia Lloyd, Hannah Shadmany, Sarah J Wie, Harry Liang, Konnor Yunghans, Xiaomeng Zhang, Lauren Golden, Hannah Harris, Serena Day, Philip Montgomery, Samantha Stokes, Ross M Giglio, Cynthia Hajal, James R Whittle, Guadalupe Garcia, Caitlin E Mills, Mehdi Touat, Kristine Pelton, Hongyu Li, Prem Sai Prabhakar, Sonja Herter, Zoe Hoffmann Kamrat, Dan Gui, Julien Dilly, Chen Khuan Wong, Jimmy A Guo, Sangita Pal, Yossef Baidi, Ryan Johnston, Daniel D Brown, Sonam Bhatia, Peter S Winter, Srivatsan Raghavan, Rameen Beroukhim, Eva Colas, David L Spector, Adam J Bass, Peter K Sorger, Yu Chen, Sarah J Hill, Steffi Oesterreich, Adrian V Lee, Himisha Beltran, Jesse S Boehm, Yuen-Yi Tseng, David E Root, William C Hahn, Andrew J Aguirre, Catarina D Campbell, Keith L Ligon, Joshua M Dempster, Tsukasa Shibue, Francisca Vazquez.

Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over 1,300 cell lines have led to the discovery of new therapeutic strategies across multiple tumour types2. However, mapping cancer vulnerabilities using traditional cell lines has limitations, including insufficient cancer subtype representation and the impact of culture conditions on perturbation responses. Here we perform 147 genome-scale CRISPR screens and multi-omic characterizations of next-generation (NextGen) cancer models (organoids and spheroids) across 10 cancer types. This strategy enables the expansion of DepMap to cover new genomic and molecular subtypes and to identify new biomarker-associated vulnerabilities. These new models also preserve transcriptional programs that are silenced in traditional cell lines and facilitate the discovery of specific gene dependencies associated with these programs. Comparisons of traditional and NextGen cancer models enable further identification of distinct effects of growth format and culture medium on gene essentiality. The integrated dataset combines data from both model types to offer a valuable, expansive resource for exploring cancer vulnerabilities and is accessible via the DepMap portal.

DOI: https://doi.org/10.1038/s41586-026-10843-7