bims-mibica 2026-04-12 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–04–12
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.
The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.
Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
Targeting BCL-xL in Myeloid Malignancies: From Inhibitors to PROTAC.
PHGDH is a targetable driver of PDAC progression.
Fatty acid scavenging enables cancer escape from KRAS inhibition.
Mitochondrial transfer in acute myeloid leukaemia and multiple myeloma: Mechanisms, consequences and potential therapeutic opportunities.
IDH1 mutation creates a dependency on fatty acid metabolism that underlies sensitivity to cuproptosis in acute myeloid leukemia cells.
Genotype-immunophenotype relationships in NPM1-mutated AML clonal evolution uncovered by single-cell multiomic analysis.

Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.

Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.

  Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.

Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite

DOI:  https://doi.org/10.1016/j.canlet.2026.218488
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123

A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.

Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.

Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis

DOI:  https://doi.org/10.1073/pnas.2535453123
Mol Cancer Ther. 2026 Apr 09.

Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.

Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Kristina D Leslie, Yuqiu Shen, Alan P Lombard, Wei Lou, Pui-Kai Li, Chengfei Liu, Marc Dall'Era, Allen C Gao.

Resistance to PARP inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from TCGA and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and re-sensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts oxidative phosphorylation and induces ferroptosis, providing a strong rationale for combination strategies with PARP inhibitors to overcome drug resistance.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1157
bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]

Rab12 is a regulator of mitophagy and mitochondrial homeostasis.

Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.

Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

DOI: https://doi.org/10.64898/2026.03.29.715103
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00192-9. [Epub ahead of print]

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.

Chao Qin, Zhenhao An, Shu Feng, Wen Fu, Xinchi Xie, Ali Can Savas, Taolin Xie, Charles Brenner, Takeshi Saito, Pinghui Feng.

  Rapid cancer cell proliferation requires extensive macromolecular biosynthesis, yet how distinct anabolic pathways are coordinated remains incompletely understood. Here, we report that the trifunctional carbamoyl-phosphate synthase, aspartate transcarbamoylase, and dihydroorotase (CAD) activates key glycolytic enzymes to support biosynthesis and cancer cell proliferation. When cancer proteomics datasets were queried, a CAD activation signature was identified in diverse tumors. Metabolomics analysis revealed that CAD fuels central carbon metabolism, specifically the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP). Mechanistically, CAD deamidates and activates glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate dehydrogenase (PHGDH), rate-limiting enzymes of the PPP and SSP, respectively, which are fully recapitulated by the glutaminase domain of CAD. Functional interrogation of cancer-associated CAD mutations and human hepatocellular carcinoma tumors predicts the metabolic signature endowed by G6PD and PHGDH deamidation. Simultaneous inhibition of G6PD and PHGDH effectively impeded tumor formation. This work identifies CAD as a central carbon metabolism signaling node and a potential therapeutic target.

Keywords:  CAD; Cancer metabolism; G6PD; PHGDH; central carbon metabolism; deamidation; pyrimidine synthesis; the pentose phosphate pathway; the serine synthesis pathway

DOI:  https://doi.org/10.1016/j.molcel.2026.03.016
Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6
Nat Metab. 2026 Apr 07.

Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.

Jennifer A Brain, Anna-Lena B G Vigil, Kristian Davidsen, Ayaha Itokawa, Abby C Jurasin, Hannah J Kerbyson, Maximilian Kobiesa, Madeleine L Hart, Sang Jun Yoon, Peter Bellotti, Juan Pablo Maianti, Gina M DeNicola, Lucas B Sullivan.

Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.

DOI: https://doi.org/10.1038/s42255-026-01499-8
Sci Rep. 2026 Apr 10.

Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.

Lidia de Bari, Mariano Francesco Caratozzolo, Giuseppe Petrosillo, Miriana Calò, Cinzia Antognelli, Tatiana Armeni, Andrea Scirè, Miklós Péter Kalapos.

  Although metformin (MET), the well-known antidiabetic drug, exhibits clear antineoplastic effects and is reported to target mitochondria, several issues are still open in this regard, thus limiting its utilization as an anticancer drug alone or in combination with other molecules. Here a functional investigation was carried out to reveal how MET impacted on mitochondrial functions and cell energy metabolism in human cultured clear cell renal carcinoma cells (ccRCCs), in which the anticancer effect of MET is already known. The in vitro effect of increasing MET concentrations on cell viability, necrosis and apoptosis of ccRCCs was checked and compared to normal immortalized HK2 cells. At the same time, the effect of MET on mitochondrial functions, ATP synthesis via oxidative phosphorylation, cellular ATP level, L-lactate (L-LAC) production and export, glucose consumption and key mitochondrial and cytosolic enzyme activities was also investigated in cancer cells. MET affected ccRCC viability and impaired mitochondrial respiration, membrane potential generation and ATP production by targeting complex I (CI), III and IV of the respiratory chain at a concentration near to the IC50 value (25 mM). Importantly, we first identified a significant inhibition of the adenine nucleotide translocator (ANT) activity in response to MET treatment. Notably, the sensitivity of ANT and CI activity to increasing MET concentrations differed markedly, the former being considerably inhibited already at a low, near-clinically relevant concentrations, while the latter only at concentrations ≥ 1 mM. The drug also induced a glycolytic shift in ccRCCs and increased the activity of the mitochondrial flavoenzymes succinate dehydrogenase (SDH) and D-lactate dehydrogenase (D-LDH), and of the key enzymes of the pay-off phase of glycolysis, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK) and pyruvate kinase (PK). Nevertheless, cellular ATP level dropped markedly, and the intracellular L-LAC amount was almost doubled in the presence of MET. Interestingly, MET-induced glycolytic shift showed a drug concentration dependence similar to that seen for CI inhibition, suggesting not ANT but rather CI inhibition may be the trigger for metabolic rewiring. These findings give new insights into MET mechanisms of action which may potentially improve its application and outcome in cancer as well as in other pathologies.

Keywords:  Adenine nucleotide translocator; Clear cell renal cell carcinoma; Glycolysis; Metformin; Mitochondrial respiratory chain complexes; Oxidative phosphorylation

DOI:  https://doi.org/10.1038/s41598-026-48200-3
Cell Commun Signal. 2026 Apr 06.

Small but mighty: mitochondrial DNA at the centre of retrograde signalling.

Eve Harding, Veronica Bazzani, Carlo Vascotto.



Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial-derived Peptides; Mitochondrial-derived non-coding RNAs; Retrograde signalling

DOI:  https://doi.org/10.1186/s12964-026-02858-4
J Cell Mol Med. 2026 Apr;30(7): e71036

Targeting BCL-xL in Myeloid Malignancies: From Inhibitors to PROTAC.

Daniela Cilloni, Alessandro Ferrando, Francesco Frassoni.

  Restoring apoptosis in malignant cells represents a central goal of anticancer therapy. Tumour cells often escape cell death by overexpressing anti-apoptotic members of the BCL-2 protein family, particularly BCL-2, BCL-xL, and MCL1. These proteins inhibit the intrinsic mitochondrial apoptotic pathway through intricate interactions with pro-apoptotic partners and direct modulation of the mitochondrial outer membrane. Their pivotal role in cell survival has established them as attractive therapeutic targets. Over the past two decades, significant efforts have been devoted to developing selective small-molecule inhibitors capable of neutralising these proteins and reactivating apoptosis. A first milestone was the discovery of ABT-263 (navitoclax), a dual BCL-2/BCL-xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL-2 inhibitor, marked a major breakthrough, demonstrating potent pro-apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL-2 family members remains challenging, largely due to the structural characteristics of the BH3-binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL-xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.

Keywords:  BCL‐2; BCL‐2 inhibitors; BCL‐xL; PROTAC

DOI:  https://doi.org/10.1111/jcmm.71036
bioRxiv. 2026 Mar 14. pii: 2026.03.11.711147. [Epub ahead of print]

PHGDH is a targetable driver of PDAC progression.

Yumi Kim, Le Jin Sun, Meredith Long, Samantha Caldwell, H Carlo Maurer, Kenneth P Olive, Florian Karreth, Gina M DeNicola.

Pancreatic ductal adenocarcinoma (PDAC) arises in a nutrient-deprived microenvironment through progressive stages from pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. While serine metabolism supports tumor growth across multiple cancer types, the stage-specific role of de novo serine synthesis in PDAC evolution remains undefined. Here, we show that expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of serine biosynthesis, increases progressively from PanIN to invasive PDAC in human and mouse specimens. Using genetically engineered mouse models with inducible PHGDH knockdown, we found that PHGDH loss delayed PDAC development. Unexpectedly, PHGDH-deficient tumors did not increase reliance on exogenous serine, and dietary serine/glycine manipulation had no effect on tumor development. Instead, stable isotope tracing and metabolomic profiling revealed that PHGDH loss suppressed mTOR signaling, reduced expression of the glutamine transporter ASCT2, and impaired glutamine uptake and utilization. Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant. These findings reveal an unanticipated connection between serine biosynthesis and glutamine metabolism in PDAC and identify a therapeutic vulnerability that may be exploited through combined metabolic targeting.
Statement of significance: PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.

DOI: https://doi.org/10.64898/2026.03.11.711147
bioRxiv. 2026 Apr 03. pii: 2026.04.01.715565. [Epub ahead of print]

Fatty acid scavenging enables cancer escape from KRAS inhibition.

Zihang Yuan, Bo Lin, Chunlan Wang, Yingying Miao, Da Zhang, Ziru Meng, Gangqi Wang, Andrew M Lowy, Michael Karin, Fei Yang, Beicheng Sun, Hua Su.

Although inhibitors of oncogenic KRAS have shown clinical efficacy 1 , resistance to KRAS inhibition is common 2 , and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3Kα signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3Kγ-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3Kγ signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.

DOI: https://doi.org/10.64898/2026.04.01.715565
FEBS J. 2026 Apr 10.

Mitochondrial transfer in acute myeloid leukaemia and multiple myeloma: Mechanisms, consequences and potential therapeutic opportunities.

Ebubechukwu Nwarunma, Mark T S Williams.

  Haematological malignancies, such as acute myeloid leukaemia (AML) and multiple myeloma (MM), which develop from malignant transformations within the bone marrow, represent the most critical unmet needs in the haemato-oncology field. Sub-optimal clinical outcomes in patients with AML and MM are often driven by resistance to chemotherapy. It is well established that cells within the bone marrow microenvironment (BMME) support the proliferation and survival of these blood cancer cells. One of the mechanisms by which these BMME-resident cells support the malignant cells is through horizontal mitochondrial transfer (HMT), a mechanism well documented as occurring under steady-state conditions as well as in many cancers. Recent research implicates mitochondrial transfer in BMME-driven chemoresistance in AML and MM. In this review, we critically analyse current understanding of the role of HMT in supporting the survival and proliferation of AML and MM cells, as well as driving resistance to cytotoxic effects of chemotherapy. We further elucidate various mechanisms, molecular triggers, functional consequences, and therapeutic implications for HMT in AML and MM. Our review also highlights unanswered questions within the HMT field and provides a theoretical basis for further study, giving direction on what is important in translating this knowledge into effective future therapeutic strategies.

Keywords:  Horizontal mitochondrial transfer (HMT); Multiple myeloma (MM); acute myeloid leukaemia (AML); bone marrow microenvironment (BMME); chemoresistance

DOI:  https://doi.org/10.1111/febs.70544
Int J Med Sci. 2026 ;23(4): 1243-1256

IDH1 mutation creates a dependency on fatty acid metabolism that underlies sensitivity to cuproptosis in acute myeloid leukemia cells.

Xuening Zhang, Dayuan Zheng, Tong Chu, Dongfan Yang, Kuanyun Zhang, Shaokui Liang, Lu Yang, Wenzhe Ma.

  Acute myeloid leukemia (AML) harboring IDH1 mutations presents unique metabolic vulnerabilities that remain incompletely addressed by current targeted therapies. In this study, we demonstrate that IDH1-mutant AML cells are markedly more sensitive to cuproptosis induced by the copper ionophore elesclomol (ES), compared to their wild-type counterparts. While ES impairs mitochondrial function in both cell types, transcriptomic profiling reveals that ES treatment induces a global downregulation of lipid metabolism pathways. Functional assays further show that IDH1-mutant cells rely more heavily on exogenous fatty acids and exhibit impaired de novo lipogenesis. Under lipid-deprived conditions, ES-induced cytotoxicity is significantly enhanced, suggesting a synthetic-lethal interaction between cuproptosis and fatty acid metabolic deficiency. In vivo experiments confirm that ES more effectively suppresses tumor growth in IDH1-mutant xenografts. These findings uncover a copper-dependent metabolic vulnerability and provide a rationale for exploiting cuproptosis as a therapeutic strategy in IDH1-mutant AML.

Keywords:  acute myeloid leukemia; cuproptosis; fatty acid; isocitrate dehydrogenase 1 mutation

DOI:  https://doi.org/10.7150/ijms.127886
Blood. 2026 Apr 08. pii: blood.2025030772. [Epub ahead of print]

Genotype-immunophenotype relationships in NPM1-mutated AML clonal evolution uncovered by single-cell multiomic analysis.

Morgan Drucker, Darren Lee, Michael S Bowman, Xuan Zhang, Bailee Nicole Kain, Deedra Nicolet, Roopsha Bandopadhyay, Varsha Singh, Zhe Wang, Richard M Stone, Caner Saygin, Krzysztof Mrózek, Andrew J Carroll, Daniel T Starczynowski, Ross L Levine, John C Byrd, Nathan Salomonis, Sarah J Skuli, H Leighton Grimes, Ann-Kathrin Eisfeld, Robert L Bowman, Linde A Miles.

Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single-cell molecular profiling and immunophenotyping on 43 samples from 32 NPM1-mutated AML patients at different timepoints in disease progression. Here we show that diagnosis and relapse AML samples display similar clonal architecture patterns, but signaling mutations drive increased clonal complexity, specifically at relapse that correlates with overall survival. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on front-line AML therapy identified dynamic clonal and immunophenotypic changes consistent with the genotype-immunophenotype relationships we identified.

DOI: https://doi.org/10.1182/blood.2025030772