bims-mibica 2026-06-28 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–06–28
23 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.
A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
Horizontal mitochondrial transfer and the tug-of-war between cancer cells and immune cells.
Proteolytic coordination of the OXPHOS Life Cycle.
Phenazine Methosulfate Rewires Mitochondrial Redox Circuits to Restore Membrane Potential and ATP Synthesis Under ETC Blockade in Glioblastoma Cells.
Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
Targeting WNK1 suppresses acute myeloid leukemia progression and enhances sensitivity to venetoclax.
Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.
Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
Transcription Factor ATF4 Deletion Reprograms Glucose Metabolism in Clear Cell Renal Cell Carcinoma.
Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer.
The Imipridone ONC206 Inhibits Tumor Growth and Improves Survival in Patient-Derived Xenograft Models of Uveal Melanoma.
Metabolic pathway signatures define prognostic subtypes of lung adenocarcinoma.
Targeting MEK1/2 inhibits mitochondrial respiration and redox homeostasis in resistant rectal cancer.
Metabolic Subtypes Predict Treatment Response in Acute Myeloid Leukemia: A Pilot Study.
Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling.
Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma.
Rewiring of de novo serine synthesis supports tumorigenesis under deficiency of TET2.
The metabolic basis of regulated cell death.
Tumor mitochondrial respiration rather than glycolytic activity predicts recurrence in colorectal cancer: an ex vivo bioenergetic profiling study.

Nat Commun. 2026 Jun 23. pii: 5563. [Epub ahead of print]17(1):

Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.

Laura Pérez Pañeda, Jelena Misic, Tereza Kadavá, Nils-Göran Larsson, Albert J R Heck.

Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F1-TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.

DOI: https://doi.org/10.1038/s41467-026-74730-5
Cell Death Dis. 2026 Jun 25.

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

Lauren Brakefield-Laird, Amit Budhraja, Peter M Hall, Dixie Brewington, Jamila Moore, Josi Lott, Yonghui Ni, Dennis Voronin, Oliver Grant-Chapman, Tresor O Mukiza, Tristen Wright, Yong-Dong Wang, Sandi Radko-Juettner, Shondra M Pruett-Miller, Stanley Pounds, Peter Vogel, Joseph T Opferman.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

DOI: https://doi.org/10.1038/s41419-026-09037-w
Nat Cancer. 2026 Jun;7(6): 944-963

Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.

Xin He, Lei Zhang, Yang Li, Song-Bai Liu, Zheng Li, Haojie Dong, Genevieve E Baker, Le Xuan Truong Nguyen, Wei Chen, Jinhui Wang, Zhilian Jia, Xiyuan Lu, Yi-Chun Lin, Zunsong Hu, Umesh Prasad Yadav, Meng Liu, Lianjun Zhang, Zhenhua Chen, Xiwei Wu, Jianjun Chen, Chun-Wei Chen, Stefano Tiziani, Weidong Hu, Ya-Huei Kuo, Sheng-Li Xue, Yong Zhang, Min Li, Yaoqiu Zhu, Guido Marcucci, Zhaohui Gu, J Jefferson P Perry, Yun Lyna Luo, Ling Li.

De novo purine synthesis is required to maintain tumor growth; however, its impact on therapy resistance remains unclear. Here, through a dynamic BH3-priming-based CRISPR screen, we found that deletion of ADSS2, which encodes the adenylosuccinate synthase 2 enzyme essential for adenosine monophosphate (AMP) synthesis, re-sensitizes drug-resistant acute myeloid leukemia cells to venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing analysis of patient-derived xenograft samples revealed a positive association of high ADSS2 activity in TP53-mutant cells with poor responsiveness to venetoclax. We developed an ADSS2 antagonist, which synergized with BH3 mimetics to promote apoptosis in preclinical models. Mechanistically, sensitization mediated by ADSS2 targeting correlated with downregulated AMP-activated protein kinase activity, which in resistant cells promotes mitophagy to eliminate damaged mitochondria after BH3 mimetic treatment. These data show that AMP synthesis promotes BH3 mimetic resistance and that combining ADSS2 targeting with BH3 mimetics represents a promising anti-cancer approach.

DOI: https://doi.org/10.1038/s43018-026-01184-5
Mol Cell. 2026 Jun 26. pii: S1097-2765(26)00389-8. [Epub ahead of print]

A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.

Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.

  How mitochondrial respiration is tightly regulated by energy demand remains incompletely defined. When mammalian cells switch from glucose to galactose as a carbon source, we observed the enhanced assembly of respiratory chain complexes accompanied by a marked reduction in TMEM141, a mitochondrial inner membrane protein. Loss of TMEM141 increased mitochondrial respiration and promoted complex I assembly, whereas galactose-induced complex I assembly was markedly blunted in TMEM141-deficient cells. TMEM141 interacts with the complex I assembly factor TIMMDC1, limiting its association with complex I subunits. TMEM141 is degraded by the mitochondrial proteases AFG3L2 and YME1L1, and galactose treatment strengthens their interactions. TMEM141 deficiency increases oxidative damage and mtDNA release, leading to activation of the cGAS-STING pathway. In Drosophila, dTMEM141 localizes to mitochondria, modulates mitochondrial activity, and is required for glial cell integrity in the eye. Together, our findings reveal TMEM141 as a negative regulator of complex I assembly that adapts to oxidative phosphorylation (OXPHOS) demands.

Keywords:  Drosophila; OXPHOS; mitochondria; mitochondrial protease; respiration complex

DOI:  https://doi.org/10.1016/j.molcel.2026.06.018
Trends Cancer. 2026 Jun 20. pii: S2405-8033(26)00126-3. [Epub ahead of print]

Horizontal mitochondrial transfer and the tug-of-war between cancer cells and immune cells.

Jaromir Novak, Denisa Hortova, Berwini Endaya, Magdalena Krulova, Michael V Berridge, Jiri Neuzil.

  Horizontal mitochondrial transfer (HMT) is an emerging field of cell biology. Since its discovery, HMT has been extensively studied in the context of cancer due to the essential role of mitochondria in fueling the proliferation of tumor cells. The role of HMT in cancer, however, reaches far beyond a simple mechanism of organelle acquisition. Indeed, several recent studies have demonstrated HMT from cancer to immune cells and vice versa, with a profound impact on antitumor immune responses and potentially on immunotherapy efficacy. In this opinion article, we propose that HMT should receive attention as another modulatable mechanism of the functional tug-of-war between cancer and immune cells, further contributing to the complexity of the tumor microenvironment and likely sculpting the outcome of competition between the two teams of cells.

Keywords:  horizontal mitochondrial transfer; immunotherapy; tumor-infiltrating lymphocytes; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.trecan.2026.05.008
Biochem J. 2026 Jul 08. 483(7): 1253-1280

Proteolytic coordination of the OXPHOS Life Cycle.

Nataliia Nechytailo, Karolina Szczepanowska.

  The mitochondrial oxidative phosphorylation (OXPHOS) system consists of multimeric, highly ordered protein complexes critical for energy production and metabolic wiring in the cell. Recent discoveries in mitochondrial proteolysis, facilitated by advances in proteomic approaches, have transformed the view of mitochondrial proteases from a simple quality-control system into a dynamically coordinated network of enzymes that actively shape the status of the OXPHOS machinery. Mapping OXPHOS-associated proteolytic circuits has uncovered specialized functions of individual proteases and identified key interaction sites. The present review outlines how mitochondrial proteases regulate the OXPHOS life cycle: expression, delivery, assembly, long-term maintenance, and disposal of mitochondrial respiratory complexes. We summarize past findings and highlight emerging concepts, including asynchronous OXPHOS turnover, cofactor-driven proteolysis, and bioenergetics-coupled degradation. Progress in these areas will deepen our understanding of how proteases coordinate the OXPHOS life cycle.

Keywords:  mitochondria; mitochondrial proteases; mitochondrial respiratory complexes; oxidative phosphorylation; regulatory proteolysis; turnover

DOI:  https://doi.org/10.1042/BCJ20250120
Antioxidants (Basel). 2026 Jun 13. pii: 749. [Epub ahead of print]15(6):

Phenazine Methosulfate Rewires Mitochondrial Redox Circuits to Restore Membrane Potential and ATP Synthesis Under ETC Blockade in Glioblastoma Cells.

Andrius Kleinauskas, Marianna Canonaco, Tine Therese Henriksen Raabe, Elin Ryan, Petras Juzenas, Beata Grallert, Aspasia Valiraki, Athanasios Papakyriakou, Theodossis A Theodossiou.

  Mitochondrial electron transport chain (ETC) dysfunction is a major driver of bioenergetic failure, redox imbalance, and drug toxicity, yet strategies to restore oxidative phosphorylation under ETC blockade remain limited. Redox-active small molecules could, in principle, shuttle electrons from NADH to distal ETC components and oxygen, thereby modulating both respiration and reactive oxygen species (ROS) formation. Here, we show that the enzyme-independent redox cycler phenazine methosulfate (PMS) rewires mitochondrial redox circuits and restores respiration in human glioblastoma cells and cell-free systems under ETC inhibition. At subtoxic concentrations, PMS acutely increased oxygen consumption and mitochondrial superoxide generation via NADH-PMS-O2 redox cycling, while restoring mitochondrial membrane potential and ATP synthesis under ETC blockade, and shifting metabolism away from glycolytic lactate production. This profile is consistent with a protective redox-bypass role, distinct from the pro-apoptotic effects reported following high-dose, prolonged PMS exposure. The PMS-driven restoration of electron flow, mitochondrial membrane potential, and respiratory ATP synthesis under inhibition of Complex I (rotenone), III (antimycin A and myxothiazol), and/or IV (cyanide) is consistent with direct cytochrome c reduction, as demonstrated herein, and engagement of multiple ETC redox centers, including coenzyme Q10. In metformin-treated cells, PMS reversed suppression of respiration and lactate accumulation, outperforming existing redox-bypass strategies. These findings identify PMS-driven redox cycling as a previously unrecognized chemical redox-bypass mechanism that both regenerates mitochondrial bioenergetics and reshapes ROS production, suggesting a potential approach to counteract drug- and toxin-induced mitochondrial dysfunction and to exploit redox vulnerabilities in cancer.

Keywords:  cellular bioenergetics; electron transfer; electron transport chain; mitochondrial dysfunction; mitochondrial redox; phenazine methosulfate

DOI:  https://doi.org/10.3390/antiox15060749
Nature. 2026 Jul;655(8121): 45-46

Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.

Amaia Zabala-Letona, Arkaitz Carracedo.



Keywords:  Biochemistry; Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-026-01802-3
Front Oncol. 2026 ;16 1828240

Targeting WNK1 suppresses acute myeloid leukemia progression and enhances sensitivity to venetoclax.

Fangli Chen, Yuanqin Wang, Zhen Fu, Li Chang, Xuewei Jiang, Zhizhi Zhang, Chongyang Li, Ligen Liu, Li Yang.

   Introduction: The With-No-Lysine (WNK) kinase family plays critical roles in cellular signaling, yet its significance in acute myeloid leukemia (AML) remains unclear.
Methods: We analyzed public databases and primary patient samples for WNK family expression. CRISPR dependency scores were used to assess gene essentiality. The effects of pharmacological WNK1 inhibition (using WNK463 and WNK11) were evaluated on AML cell lines, primary blasts, and mouse xenograft models. Apoptosis was assessed via pro-apoptotic protein expression (Bim, Puma). Transcriptomic analysis identified downstream pathways, and combination studies with venetoclax were performed in vitro.
Results: WNK1, but not other WNK family members, was highly expressed in AML, particularly in adverse subtypes such as FLT3-ITD mutated AML. CRISPR screening confirmed WNK1 as essential for AML cell survival. Pharmacological inhibition of WNK1 suppressed proliferation of AML cells and primary blasts, induced apoptosis through upregulation of Bim and Puma, and impeded tumor growth in xenograft models without significant toxicity. Transcriptomic analysis revealed that WNK1 inhibition downregulated DNA replication pathway genes (MCM5, CHAF1B, GINS2), whose high expression correlates with poor prognosis. Elevated WNK1 expression was associated with resistance to venetoclax. Combining WNK463 with venetoclax produced synergistic anti-leukemic effects in vitro, accompanied by enhanced Bim upregulation.
Discussion: This study identifies WNK1 as a key oncogenic driver in AML and establishes WNK1 inhibition as a promising therapeutic strategy that not only suppresses AML progression but also sensitizes leukemia cells to venetoclax. These findings provide a rationale for novel combination regimens to overcome drug resistance in AML.

Keywords:  DNA replication; WNK1; acute myeloid leukemia; combination therapy; venetoclax

DOI:  https://doi.org/10.3389/fonc.2026.1828240
Cell Death Dis. 2026 Jun 25.

Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.

Yeting Xu, Hongjiang Guo, Shengxi Li, Yucheng Wang, Yinghao Cao, Lin Wang, Qiuxia Chen, Ziyi Qin, Jiaxing Qiu, Yuhan Liu, Yunfan Li, Jiaming Zou, Yingying Wang, Kaihan Zhang, Rui Ju, Lei Guo.

Pancreatic ductal adenocarcinoma (PDAC) exhibits hyperactive mitochondrial metabolism, yet how this rewiring spatially restricts the availability of metabolites for oncogenic signaling and drives systemic metabolic dysregulation in PDAC remains unknown. Here, we identify enhanced mitochondrial α-ketoglutarate (α-KG) sequestration as a key metabolic vulnerability in PDAC. Using multi-omics, preclinical models, and clinical correlation analyses, we identified elevated mitochondrial metabolic gene expression in PDAC. Moreover, higher expression of dihydrolipoamide succinyltransferase (DLST) correlates with poorer PDAC prognosis, suggesting the role of mitochondrial α-KG sequestration in PDAC progression. Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression. Consequently, prolonged CTO exposure downregulated multiple metabolic pathways (glycolysis, pentose phosphate pathway, fatty acid synthesis) regulated by c-Myc/HIF-1α, and significantly delayed PDAC progression in vitro and in vivo. Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level.

DOI: https://doi.org/10.1038/s41419-026-09016-1
bioRxiv. 2026 Jun 10. pii: 2026.06.09.731211. [Epub ahead of print]

Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.

Bo J Price, Sai Sangeetha Balasubramaniam, Adam L Hughes.

Cells undergoing metabolic transitions rapidly remodel mitochondria through coordinated expansion and reorganization of the mitochondrial proteome. How the outer mitochondrial membrane (OMM) accommodates acute increases in newly synthesized proteins before organelle adaptation is complete remains poorly understood. Here we show that mitochondrial-derived compartments (MDCs), multilamellar domains that form from the OMM and selectively sequester OMM-associated cargo, arise during metabolic perturbations associated with acute mitochondrial biogenesis, including glucose restriction, carbon-source switching, and salt stress. In these situations, MDC formation requires the energy-sensing kinase Snf1 and derepression of the transcriptional repressor Mig1, linking MDC induction to transcriptional programs that increase mitochondrial protein expression. Activation of mitochondrial biogenesis in the absence of metabolic changes is sufficient to trigger MDCs, whereas disruption of mitochondrial protein targeting and import prevents MDC formation and causes mislocalization of outer membrane cargos. Together, these findings, combined with previous observations that MDCs are induced by hydrophobic protein overexpression, mistargeting, and metabolic perturbations, support an emerging model in which MDCs function as adaptive outer-membrane remodeling domains that buffer outer membrane protein load during mitochondrial adaptation.

DOI: https://doi.org/10.64898/2026.06.09.731211
Cancers (Basel). 2026 Jun 16. pii: 1953. [Epub ahead of print]18(12):

Transcription Factor ATF4 Deletion Reprograms Glucose Metabolism in Clear Cell Renal Cell Carcinoma.

Yuling Chi, Qiuying Chen, Eduardo Mere Del Aguila, Steven S Gross, John A Wagner, Shannon M Reilly, David M Nanus, Lorraine J Gudas.

  Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Human ccRCCs have increased glycolytic metabolism and decreased mitochondrial oxidative metabolism relative to normal kidneys. Our research using human RCC4 ccRCC cells and a murine model of ccRCC, TRACK (TRAnsgenic model/Cancer/Kidney), in which a triple-mutant (P402A, P564A, N803A) human HIF1α is selectively expressed in proximal tubule cells (PTCs), revealed highly induced ATF4, a stress-responsive transcription factor. We then investigated the role of ATF4 in the metabolic changes in ccRCC. Methods: We performed comprehensive analysis of the ccRCC Cancer Genomics Atlas (TCGA) data. We deleted ATF4 in PTCs of TRACK mice and human RCC4 cells. We conducted genome-wide transcriptomic and untargeted metabolomic studies of cortices of WT and CGERA∆T (TRACK mice with PTC-specific ATF4-knockout (KO)) mice and performed glucose isotopologue tracing in parental and ATF4 KO RCC4 cells. Results: Analysis of TCGA data showed increased mRNAs of enzymes in glycolysis and reduced mRNAs of enzymes in the TCA cycle. Transcriptomic and metabolomic studies demonstrated that ATF4 deletion suppressed glycolysis and enhanced TCA cycle metabolism in CGERA∆T versus WT cortices. Glucose isotopologue tracing showed that ATF4 deletion altered glycolysis pathway metabolite levels and shifted glucose metabolism towards the TCA cycle, evidenced by increased intracellular [13C2]citrate in RCC4-ATF4 KO cells. Using the Seahorse XFe96 analyzer we also showed reduced glycolytic capacity and reserve in RCC4-ATF4 KO cells. Conclusions: Collectively, our results demonstrate that ATF4 regulates glycolysis in ccRCC, supporting ATF4 as a therapeutic target.

Keywords:  ATF4; clear cell renal cell carcinoma (ccRCC); glycolysis; metabolomics; mitochondrial oxidative phosphorylation

DOI:  https://doi.org/10.3390/cancers18121953
Oncol Res. 2026 ;34(7): 21

Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer.

Jinhui Che, Zhiyuan Chen, Feng Zhang, Shuo Zhu, Shengya Cao, Ou Li, Rong Li, Jun Zheng, Yubin Liu.

  Objective: Advanced liver cancer, a highly lethal and increasingly prevalent malignancy, frequently develops sorafenib resistance, with aberrant mitochondrial dynamics and metabolism implicated in its pathogenesis. This study aimed to investigate their interplay and assess combination therapies against sorafenib-resistant liver cancer. Methods: Mitochondrial morphology was assessed using immunofluorescent staining. Besides, the mitochondrial metabolic profile was evaluated by measuring the oxygen consumption rate, glucose uptake, and lactate production. Dynamin-related protein 1 (Drp1) expression was determined through immunohistochemical staining, western blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting, colony formation, and cell cycle assays were conducted to evaluate in vitro cell growth. Furthermore, time-lapse cell motility and Transwell assays were employed to assess cell migration and invasion capacities, respectively. Orthotopic xenograft models were utilized to demonstrate the therapeutic effects of the combined administration of the oxidative phosphorylation (OXPHOS) inhibitor IACS-010759 and the Drp1 inhibitor mdivi-1. Result: Importantly, our findings revealed that Drp1-mediated mitochondrial fission and the metabolic switch from OXPHOS to aerobic glycolysis were dominant in sorafenib-resistant liver cancer cells and strongly correlated with tumor prognosis (hazard ratio = 3.899, 95% confidence interval: 1.167-13.022, p = 0.027). Drp1 knockdown or inhibition impaired the invasive and metastatic capabilities of these cancer cells but promoted cell cycle progression and cellular growth, attributed to a metabolic shift from aerobic glycolysis to OXPHOS. Notably, the combined administration of the OXPHOS inhibitor IACS-010759 with mdivi-1 significantly attenuated tumor progression in sorafenib-resistant liver cancer, affecting both proliferation and metastasis. Conclusion: The results of this study collectively indicate that mitochondrial dynamics regulate metabolism in sorafenib-resistant liver cancer, which displays an aggressive hybrid metabolic phenotype. Accordingly, the combined targeting of mitochondrial dynamics and metabolism may represent an effective strategy to overcome sorafenib resistance in liver cancer.

Keywords:  IACS-010759; Sorafenib-resistant hepatocellular carcinoma; glucose metabolism; mdivi-1; mitochondrial dynamics

DOI:  https://doi.org/10.32604/or.2026.067443
Cancers (Basel). 2026 Jun 10. pii: 1895. [Epub ahead of print]18(12):

The Imipridone ONC206 Inhibits Tumor Growth and Improves Survival in Patient-Derived Xenograft Models of Uveal Melanoma.

Mir Mustafa Ali, Md Alauddin, Iqbal Mahmud, Aron Joon, Aalim B Momin, Jacob R Cortez, Huiqin Chen, Lin Tan, Waikin Chan, Rachel William Anantha, Danielle L Stolley, Diana Shamsutdinova, Kurt Evans, Funda Merric-Bernstam, Meenhard Herlyn, Monzy Thomas, Yeqing Chen, Michael A Davies, Chandrani Chattopadhyay.

  Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM.

Keywords:  PDX; autophagy; imipridones; lipidomics; liver metastasis; oxidative phosphorylation; uveal melanoma (UM)

DOI:  https://doi.org/10.3390/cancers18121895
Discov Oncol. 2026 Jun 23.

Metabolic pathway signatures define prognostic subtypes of lung adenocarcinoma.

Doris Kafita, Zitha Mukwamba, Vanity Mapulanga, Adon Chawe, Musalula Sinkala.

  Metabolic reprogramming is a core hallmark of cancer, yet how it contributes to the clinical heterogeneity of lung adenocarcinoma (LUAD) remains poorly understood. Here, by applying unsupervised clustering to the metabolic transcriptomes of 510 LUAD tumours, we identify two robust and prognostically significant subtypes. We show that these subtypes have divergent clinical outcomes, with subtype-1 patients exhibiting significantly longer overall and disease-specific survival compared to the more aggressive subtype-2. This clinical distinction is underpinned by fundamentally different metabolic architectures: the aggressive subtype-2 is characterized by the upregulation of central carbon metabolism, including the citric acid cycle and respiratory electron transport, whereas the less aggressive subtype-1 shows a distinct enrichment for choline catabolism. Consistent with this, Cox regression analysis reveals that high expression of the TCA cycle enzyme OGDH is a top predictor of increased disease risk, while the glycolytic enzyme PGK1 is associated with a decreased risk. Our findings establish a direct link between transcriptional metabolic states and patient survival in LUAD, defining a framework for prognostic stratification and identifying subtype-specific metabolic vulnerabilities for therapeutic targeting.

Keywords:  Bioinformatics; Choline metabolism; Citric acid cycle; Lung adenocarcinoma; Machine learning; Metabolic reprogramming; Prognosis; Survival analysis; Transcriptome; Tumour subtyping

DOI:  https://doi.org/10.1007/s12672-026-05480-5
J Bioenerg Biomembr. 2026 Jun 23. pii: 33. [Epub ahead of print]58(1):

Targeting MEK1/2 inhibits mitochondrial respiration and redox homeostasis in resistant rectal cancer.

Hu Chenghao, Wu Feng, Chen Chunli, Cai Ting, Li Haixia, Hu Guangyue, Liu Xuefeng, Ma JinLu.

  Chemo-resistance is a major challenge in rectal cancer treatment. This study investigates the therapeutic potential of MEK inhibitors, cobimetinib and trametinib, in 5-fluorouracil (5-FU)-resistant rectal cancer cells. High-throughput drug screening identified these inhibitors as top candidates based on their selective drug sensitivity scores (sDSS). Both drugs exhibited dose-dependent cytotoxicity against rectal cancer cells while sparing normal epithelial cells and showed synergistic interactions with 5-FU. MEK inhibition disrupted redox homeostasis, increasing reactive oxygen species (ROS) and oxidative damage markers, including protein carbonyl and malondialdehyde (MDA), while also decreasing mitochondrial respiration, as evidenced by reduced oxygen consumption rates (OCR). Apoptotic induction was significantly reduced in mitochondrial respiration-deficient p⁰ cells, supporting the role of mitochondrial respiration in MEK inhibitor activity. Genetic MEK1/2 knockdown mimicked these effects, confirming MEK1/2 as a key regulator of oxidative stress and mitochondrial respiration. In vivo, cobimetinib and trametinib suppressed tumor growth in a chemo-resistant colorectal cancer xenograft model without significant toxicity, inducing oxidative stress and decreasing mitochondrial respiration. These findings highlight MEK inhibitors as promising candidates for overcoming chemo-resistance in rectal cancer by targeting oxidative stress and mitochondrial respiration.

Keywords:  5-FU resistance; MEK inhibition; Mitochondrial respiration; Oxidative stress; Rectal cancer

DOI:  https://doi.org/10.1007/s10863-026-10116-y
Blood Lymphat Cancer. 2026 ;16 612305

Metabolic Subtypes Predict Treatment Response in Acute Myeloid Leukemia: A Pilot Study.

Changjian Yan, Yan Huang, Qing Cai, Xiang Li, Qinwen Yang, Gang Feng, Huilin Yang, Yanxin Chen, Jianda Hu.

   Introduction: To establish a dynamic metabolic subtyping system for acute myeloid leukemia (AML) based on longitudinal metabolomics and multi-omics integration, and to evaluate its ability to predict treatment response.
Methods: We enrolled 29 AML patients and performed untargeted metabolomics on pre‑ and post-treatment serum samples. Based on finite cyclic combinations of metabolic pathways, pre-treatment patients were classified into G1 (glycolysis/gluconeogenesis/TCA cycle) and G2 (fatty acid/folate biosynthesis). Post‑treatment patients were categorized into TG1 (α-linolenic acid metabolism, pantothenate/CoA biosynthesis) and TG2 (purine metabolism, cysteine/methionine metabolism). Baseline transcriptome data were integrated and validated in three external cohorts (Beat2, GSE6891, GSE37642; total n=994). Single cell and spatial transcriptomics were used to investigate cellular heterogeneity and resistance mechanisms.
Results: The complete remission (CR) rate was significantly higher in G2 (71%) than in G1 (29%). After treatment, TG2 showed an 83% CR rate versus 17% in TG1. All patients transitioning from G2 to TG2 achieved CR (100%), whereas those from G1 to TG2 maintained poor response. Baseline metabolic subtype was an independent predictor of treatment response (p<0.05). To explore candidate cellular niches linking G1 metabolic features to chemotherapy resistance, we further integrated single-cell and spatial transcriptomic analyses. The results revealed co-localization of CA2-high immature erythrocytes and neutrophils in non-CR patients.
Discussion: Dynamic metabolic subtyping (G1/G2, TG1/TG2) strongly correlates with AML treatment response. The co-localization of CA2-high immature erythrocytes and neutrophils in the bone marrow microenvironment of non-CR patients provides a candidate cellular and microenvironmental correlate of the G1 metabolic phenotype, suggesting a mechanistic link between systemic metabolic reprogramming and chemotherapy resistance. Collectively, these findings highlight the potential of combining dynamic metabolic subtyping with identified microenvironmental features to guide precision therapy.

Keywords:  acute myeloid leukemia; metabolic reprogramming; metabolomics; subtyping; treatment response

DOI:  https://doi.org/10.2147/BLCTT.S612305
Nat Med. 2026 Jun 25.

Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling.

Déborah Suissa, Marine Fidelle, Ella Reich, Thao-Nguyen Pham, Simon Thomas, Johannes R Björk, Peng Liu, Liwei Zhao, Koji Kitaoka, Eléonore Piard, Isabelle Lebhar, Ai-Ling Tian, Cassandra Thelemaque, Carolina Alves Costa Silva, Eric Deutsch, Yohann Loriot, Nicola Segata, Gianmarco Piccinno, Geke A P Hospers, Saman Maleki Vareki, Michael S Silverman, John G Lenehan, Véronique Bataille, David Boulate, Tatiana Kuznetsova, Rinse K Weersma, Meriem Messaoudene, Sylvère Durand, Carlijn M van der Aalst, Harry J de Koning, Beatrice Schuler-Thurner, I Jolanda M de Vries, Edmond Rafie, Renée Maria Saliby, Marc Machaalani, Sebastian Haferkamp, Bastian Schilling, Serena Porcari, Chiara Ciccarese, Roberto Iacovelli, Chiara Cremolini, Toni K Choueiri, Arielle Elkrief, Guido Kroemer, Lucie Heinzerling, Kenji Chamoto, Gianluca Ianiro, Bertrand Routy, Lisa Derosa, Nikos Paragios, Laurence Zitvogel.

Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.

DOI: https://doi.org/10.1038/s41591-026-04481-9
Nat Cell Biol. 2026 Jun 26.

Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.

DOI: https://doi.org/10.1038/s41556-026-02008-5
Nat Commun. 2026 Jun 26.

Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma.

Vashisht Gopal Y N, Evelyn de Groot, Kaley Loftin, Barbara Knighton, Debora Ledesma, Courtney Hudgens, Diana Shamsutdinova, Mehboob Ali, Zhenlin Ju, Min Xiao, Toshitha Kannan, Gregory Fontenot, Michael S Nakazawa, Monzy Thomas, Khalida Wani, Clifford Stephan, Phyu P Aung, Lawrence N Kwong, Janos Roszik, Rehan Akbani, Andrew Kossenkov, Vito W Rebecca, Ryan J Sullivan, Meenhard Herlyn, Michael A Davies.

There are currently no effective targeted therapies for BRAF-mutant metastatic melanoma patients with acquired resistance to approved BRAF and MEK inhibitors (BRAFi and MEKi), and very few ongoing clinical trials. Anti-apoptotic BCL2 family proteins promote de novo resistance to several therapies, including single-agent BRAFi in BRAF-mutant melanomas. In this study, in vivo testing of a large collection of patient-derived xenograft (PDX) models from melanoma patients with acquired resistance to BRAFi or BRAFi+MEKi shows that combining BCL2 inhibitors (BCL2i; navitoclax or venetoclax) with BRAFi+MEKi induces tumor regressions in a subset of these PDXs. High basal BCL2 predicts response whereas high basal MCL1 predicts resistance to this strategy. MCL1 overexpression studies functionally validate its role in resistance. Further, combining BRAFi+MEKi with an MCL1 inhibitor (MCL1i) counteracts resistance and interestingly decreases MCL1i-associated markers of cardiotoxicity. Together these studies identify potential personalized strategies to improve outcomes in this challenging patient population.

DOI: https://doi.org/10.1038/s41467-026-74691-9
Br J Cancer. 2026 Jun 26.

Rewiring of de novo serine synthesis supports tumorigenesis under deficiency of TET2.

Ke Zheng, Keqiang Rao, Xiaoxu Lu, Miaomiao Yang, Hui Wu, Zhilong Ai, Jing He.

BACKGROUND: Ten-eleven translocation 2 (TET2) is initially identified as a mammalian DNA dioxygenase to orchestrate expression of numerous genes and diverse interplays of physiological and pathological processes. Beyond its canonical role, the moonlight functions of TET2 have been gradually uncovered.
METHODS: RNA-seq, qPCR and western blot are employed to validate expression of genes. ChIP and RIP analyses are conducted to test the enrichment of genes. Stable isotope labelled glucose is utilized to analyze the metabolic flux. Xenograft analysis is performed to explore growth of tumour in vivo.
RESULTS: TET2 binds to and oxidizes mRNA 5-methylcytosine (m5C) of the transcription factors ATF3 and ATF4, thereby enhancing mRNAs degradation. Deficiency of TET2 rewires de novo serine synthesis and the viability of hepatocellular carcinoma (HCC) cells. Both ATF3 and ATF4 are required to sustain transcription of de novo serine synthesis enzymes and the associated metabolic reprogramming under TET2 loss. Ultimately, ATF3 collaborates with ATF4 to contribute to growth of tumours lack of TET2. Deficiency of TET2 sensitizes HCC tumours to serine restriction.
CONCLUSIONS: Our findings not only elucidate a heretofore unrecognized mechanism of transcriptional suppression of de novo serine synthesis enzymes, but also propose a targetable vulnerability of HCC tumours.

DOI: https://doi.org/10.1038/s41416-026-03526-7
Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]

The metabolic basis of regulated cell death.

Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.

Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.

DOI: https://doi.org/10.1016/j.cmet.2026.06.001
BMC Gastroenterol. 2026 Jun 25.

Tumor mitochondrial respiration rather than glycolytic activity predicts recurrence in colorectal cancer: an ex vivo bioenergetic profiling study.

Wei-En Hou, Chun-Wei Chen, Yu-De Chu, Yang-Hsiang Lin, Jy-Ming Chiang, Siew-Na Lim, Wey-Ran Lin.

   BACKGROUND: Metabolic reprogramming is a recognized hallmark of colorectal cancer (CRC), yet whether intratumoral bioenergetic capacity directly influences clinical outcomes remains unclear. In particular, the relative prognostic contributions of mitochondrial respiration and glycolytic activity to postoperative recurrence have not been systematically evaluated. This study aimed to determine whether tumor oxygen consumption rate (OCR) or extracellular acidification rate (ECAR), measured ex vivo by Seahorse bioenergetic assays, is associated with recurrence-free survival (RFS) and overall survival (OS) in patients with resected CRC.
METHODS: In a single-center prospective cohort of 104 patients who underwent surgical resection for CRC between 2012 and 2017, paired tumor and adjacent normal mucosal specimens were analyzed using the Seahorse XF24 analyzer to quantify basal OCR and ECAR. Tumors were stratified by cohort median values and by receiver operating characteristic (ROC)-derived cutoffs optimized for recurrence prediction. Associations with RFS and OS were assessed using Kaplan-Meier analysis and Cox proportional hazards regression, adjusting for clinicopathological covariates.
RESULTS: Over a median follow-up of 69 months, tumor OCR was significantly lower than that of adjacent normal mucosa (p < 0.001), whereas ECAR did not differ between paired tissues. OCR and ECAR were positively correlated within tumors (R² = 0.268, p < 0.001). In multivariate Cox regression, higher tumor OCR was independently associated with shorter RFS, both as a continuous variable (hazard ratio 1.455 per 1000-unit increase, p = 0.010) and when dichotomized by median or ROC-derived cutoffs (all p < 0.05). ROC analysis demonstrated moderate discriminatory ability for OCR (area under the curve 0.650), whereas ECAR showed no prognostic value. No bioenergetic parameter was significantly associated with OS.
CONCLUSIONS: Intratumoral mitochondrial respiratory capacity, rather than glycolytic activity, independently predicts recurrence in resected CRC. These findings suggest that tumor OCR may serve as a functional metabolic biomarker for recurrence risk stratification, warranting prospective validation in independent cohorts.

Keywords:  Colorectal cancer; Extracellular acidification rate; Mitochondrial respiration; Oxygen consumption rate; Recurrence-free survival

DOI:  https://doi.org/10.1186/s12876-026-05045-4