bims-meract 2026-09-20 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–09–20
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Therapeutic Co-targeting of Oxidative Phosphorylation and Pyrimidine Synthesis Restores Gemcitabine Response in Pancreatic Ductal Adenocarcinoma.
DHODH inhibition drives albumin-mediated drug resistance through TERF2IP lactylation-activated macropinosome-mitochondria contact.
Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.
Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.
Metabolic plasticity in castration-resistant prostate cancer: reprogramming mechanisms and therapeutic opportunities.
Targeting valine metabolism and ferroptosis to overcome chemoresistance in PDAC.
MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.
Autophagy inhibition sensitizes radiotherapy responses in high-grade mutant IDH1 glioma.
Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.
Metabolic Reprogramming of Cancer Stem Cells: Targeting Lipid Flux and Mitochondrial Plasticity to Overcome Therapeutic Resistance.
Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.
IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.
Targeting USP14 sensitizes glioma to radiotherapy through exacerbated reactive oxygen species accumulation.
Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.
CD36-Pocket Targeting Induces Metabolic Collapse and Disulfidoptosis for Sonodynamic Immunometabolic Therapy of Liver Cancer.
Targeting ferroptosis as a new paradigm for overcoming sorafenib resistance in hepatocellular carcinoma.
PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors.
Cancer-associated fibroblast-derived POSTN as a metabolic "switch" shapes lipid-stressed macrophage polarization in gastric cancer.
HIF1α-KLF4 signaling dictates extra-erythrocyte expression of hemoglobin conferring sorafenib resistance in hepatocellular carcinoma.
Modulation of Ferroptosis Bridges Radiotherapy and Immunotherapy to Improve Cancer Treatment Outcomes.

Transl Res. 2026 Sep 13. pii: S1931-5244(26)00195-7. [Epub ahead of print]

Therapeutic Co-targeting of Oxidative Phosphorylation and Pyrimidine Synthesis Restores Gemcitabine Response in Pancreatic Ductal Adenocarcinoma.

Wenhui Ouyang, Jie Wang, Jie Chen, Zemin Fang, Ting Wei, Jiazi Qian, Shanying Gui.

  Gemcitabine resistance remains a major barrier to effective therapy in pancreatic ductal adenocarcinoma (PDAC), and current combination regimens show potential to overcome this resistance. Here, we identify the mitochondrial ribosomal proteins MRPS22 and MRPL3 as key metabolic gatekeepers that maintain mitochondrial OXPHOS and pyrimidine metabolism, thereby promoting pancreatic cancer cell proliferation and chemoresistance. Across independent cohorts, high MRPS22/MRPL3 expression associates with poorer survival. Depletion of either gene in PDAC curtailed cell proliferation and xenograft growth, which might be due to an impaired mitochondria function, including destabilized respiratory super-complex assembly, diminished ATP production, and increased oxidative stress. Multi-omics profiling revealed a broad reduction of central-carbon intermediates and a pronounced blockade of de novo pyrimidine synthesis at the dihydroorotate dehydrogenase (DHODH) node. MRPS22 depletion hampered nucleotide-pool generation, and exogenous deoxynucleotides partially rescued PDAC cell growth when MRPs were knocked down. Pharmacologic OXPHOS inhibition increased gemcitabine sensitivity, whereas gemcitabine-resistant derivatives exhibited heightened OXPHOS activity and upregulated mitochondrial ribosomal programs. Co-targeting OXPHOS (antimycin A) or DHODH (brequinar) with gemcitabine produced Loewe synergy in vitro and suppressed growth of gemcitabine-resistant xenografts without affecting body weight. Collectively, these findings established MRPS22/MRPL3 as translation-level drivers of PDAC metabolic fitness and nominate OXPHOS/DHODH blockade as a rational combination strategy to overcome gemcitabine resistance.

Keywords:  Chemoresistance; Chemotherapy; Mitochondrial ribosomal protein; Pancreatic ductal adenocarcinoma; Pyrimidine metabolism

DOI:  https://doi.org/10.1016/j.trsl.2026.09.009
Nat Commun. 2026 Aug 14. pii: 9792. [Epub ahead of print]17(1):

DHODH inhibition drives albumin-mediated drug resistance through TERF2IP lactylation-activated macropinosome-mitochondria contact.

Junhu Yuan, Tan Wang, Yarui Ma, Guangyu Li, Chenxi Wang, Mei Liu, Zian Cai, Xiaoyue Wang, Xiaobing Wang, Hongying Wang, Yuchen Jiao.

Macropinocytosis enables cancer cells to scavenge extracellular nutrients and contributes to tumor progression, but its role in chemoresistance remains poorly characterized. Through CRISPR-Cas9 and small-molecule screens, we identify inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis, as an inducer of macropinocytosis. Mechanistically, DHODH inhibition triggers metabolic reprogramming toward glycolysis and lactate accumulation. This metabolic shift promotes lysine 208 lactylation of telomeric repeat-binding factor 2-interacting protein (TERF2IP), unveiling its moonlighting function in transcriptional activation of epiregulin, which activates EGFR signaling to promote macropinocytosis. Macropinosomes contact mitochondria, enabling albumin translocation into the mitochondrial intermembrane space where it interacts with DHODH, diminishing inhibitor binding and restoring DHODH activity. This adaptive response contributes to drug resistance in vitro and in vivo, and co-administration of DHODH inhibitors with macropinocytosis blockers or EGFR inhibitors enhances anti-tumor efficacy. Our findings reveal a previously unknown metabolic stress-induced macropinocytosis pathway and provide a rationale for combination therapy to enhance DHODH inhibitor efficacy in cancer treatment.

DOI: https://doi.org/10.1038/s41467-026-75872-2
PLoS Biol. 2026 Sep 18. 24(9): e3003555

Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.

Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero.

Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the (LAT1)-4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1-4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.

DOI: https://doi.org/10.1371/journal.pbio.3003555
JCI Insight. 2026 Sep 15. pii: e205218. [Epub ahead of print]

Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.

Silvia Romero-Murillo, Irene Peris, Anna Maria Lucianò, Nerea Marcotegui, Carmen Vicente, Brian Tran, Kelsey Barrie, Caitlin M O'Connor, Andrea Torres-López, Maria C Mateos, Maria L Cayuela, Victoriano Mulero, Joaquín Fernández-Irigoyen, Enrique Santamaría, Maria D Odero, Goutham Narla.

  Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the pro-apoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.

Keywords:  Cell biology; Drug therapy; Hematology; Phosphoprotein phosphatases; Tumor suppressors

DOI:  https://doi.org/10.1172/jci.insight.205218
Cell Signal. 2026 Sep 12. pii: S0898-6568(26)00544-9. [Epub ahead of print]149 112885

Metabolic plasticity in castration-resistant prostate cancer: reprogramming mechanisms and therapeutic opportunities.

Yanzhi Lou, Zhengda Lou, Luo He, Junfeng Luo.

  Prostate cancer (PCa) is one of the most common malignant tumors, and most patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Metabolic plasticity, which allows cancer cells to reprogram glucose, lipid, and glutamine utilization, plays a key role. This metabolic adaptation meets the bioenergetic and biosynthetic needs of tumor cells, and it can interact with the androgen receptor (AR) signaling pathway bidirectionally to evade immune surveillance via metabolic reprogramming. Current treatments include single metabolic node inhibition and AR-guided combination therapy. However, due to intratumoral metabolic heterogeneity, compensatory pathway activation, and systemic metabolic toxicity of drugs, there is a need to explore new intervention targets and strategies. This article comprehensively discusses the metabolic network, regulatory mechanism, and current challenges of CRPC in order to provide a theoretical basis for clinical prevention and treatment.

Keywords:  Castration-resistant prostate cancer; Metabolic plasticity; Metabolic reprogramming; Prostate cancer; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.cellsig.2026.112885
Nat Cancer. 2026 Sep 14.

Targeting valine metabolism and ferroptosis to overcome chemoresistance in PDAC.

DOI: https://doi.org/10.1038/s43018-026-01235-x
Nat Cancer. 2026 Sep 11.

MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.

Peixiang Zheng, Yanni Lin, Meiyin Zhang, Zhiyuan Tang, Wenxing Qin, Min Xiao, Xue Sun, Yuli Shen, Zhiqiang Hu, Shuo Ru, Yuran Duan, Bofei Dong, Ting Wen, Mengdie Li, Hong Wu, Yueru Hou, Guimei Ji, Zheng Wang, Xiaohong Wu, Qimin Zhou, Xiaoguang Liu, Gaopeng Li, Yuhao Wang, Shengzhong Duan, Yang Luo, Bo Chu, Xu Qian, Zhimin Lu, Yuan Ding, Chuan Xu, Xu Qian, Tong Liu, Daqian Xu.

Limited efficacy of neoadjuvant chemotherapy (NAC) in pancreatic ductal adenocarcinoma (PDAC) underscores the need for novel combination strategies and a deeper understanding of metabolic determinants of chemoresistance. Here we identify methylmalonate semialdehyde dehydrogenase (MMSDH), a valine catabolism enzyme, as a driver of gemcitabine (GC) resistance. Hypoxia induces GCN5-mediated lactylation of MMSDH at K113. Lactylated MMSDH interacts with acyl-CoA synthetase long-chain family member 4 (ACSL4), generating propionyl-CoA to facilitate KAT8-mediated ACSL4 K606 propionylation. This modification enhances ACSL4-HSC70 binding, promoting its degradation through chaperone-mediated autophagy. Critically, this MMSDH-mediated ACSL4 propionylation correlates with low ACSL4 levels and poor NAC response in recipients. Combining dietary valine restriction with GC synergistically induces ferroptosis and suppresses tumor growth. Blocking MMSDH-K113la disrupts this axis, potentiating GC-induced ferroptosis and inhibiting tumor progression. These findings reveal a previously unknown mechanism of ferroptosis evasion through valine metabolism and ACSL4 regulation, nominating the GCN5-MMSDH-ACSL4 axis as a therapeutic target to enhance PDAC chemosensitivity.

DOI: https://doi.org/10.1038/s43018-026-01236-w
Nat Commun. 2026 Sep 18. pii: 9740. [Epub ahead of print]17(1):

Autophagy inhibition sensitizes radiotherapy responses in high-grade mutant IDH1 glioma.

Felipe J Núñez, Kaushik Banerjee, Anzar A Mujeeb, Ava Mauser, Claire E Tronrud, Ziwen Zhu, Sadhakshi Raghuram, Maya R Sheth, Jorge Armando Pena Agudelo, Julio Zelaya, Ayman Taher, Padma Kadiyala, Stephen V Carney, Maria B Garcia-Fabiani, Andrea Comba, Mahmoud S Alghamri, Brandon L McClellan, Adam Klaiss, Zeribe C Nwosu, Hanna S Hong, Peter Sajjakulnukit, Tingting Qin, Maureen A Sartor, Mats Ljungman, Joshua D Welch, Shi-Yuan Cheng, Pedro R Lowenstein, Joerg Lahann, Costas A Lyssiotis, Maria G Castro.

Mutant isocitrate dehydrogenase 1 (mIDH1) catalyzes 2-hydroxyglutarate (2HG) production which leads to epigenetic reprogramming in astrocytomas with tumor protein p53 (TP53)/α-thalassemia/mental retardation, X-linked (ATRX) loss. RNA-sequencing, single-cell RNA-sequencing, and Chromatin Immunoprecipitation sequencing (ChIP-seq) followed by bioinformatics analysis shows that human and mouse mIDH1 gliomas exhibit downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated autophagy-related GOs. Decreased mitochondrial metabolism is accompanied by decreased glycolysis, rendering autophagy as a source of energy in mIDH1 gliomas. Mutant IDH1 glioma cells exhibit increased expression of autophagy-related proteins and enhanced microtubule-associated protein 1 light chain 3 (LC3) I/II conversion, indicating augmented autophagy. Inhibiting autophagy in vivo by administration of synthetic protein nanoparticles (SPNPs) encapsulating autophagy related gene 7 (ATG7) silencing RNA sensitizes mIDH1 glioma cells to radiation, resulting in tumor regression, long-term survival, and immunological memory. This work uncovers autophagy as a critical pathway for survival in mIDH1 gliomas and its inhibition elicits radiosensitivity in vitro in human and mouse mIDH1 glioma cells, and in vivo in mIDH1 models.

DOI: https://doi.org/10.1038/s41467-026-77320-7
Nat Commun. 2026 Aug 20. pii: 9957. [Epub ahead of print]17(1):

Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.

Chiara Pecorari, Mojca Bratina, Evelyn Gonzalez, Salvatore Rizza, Letizia Incampo, Lina Vardouli, Paola Giglio, Elena Maresca, Zsófia Márta Sztupinszki, Marcus Montanares Kildegaard Nielsen, Perrine Verdys, Mario Presti, Maria Pires Pacheco, Yuya Qiu, Samuel D Mador, Trine Skov Petersen, Julie Lund Petersen, Yonglun Luo, Emmanuelle Bignon, Zoltan Szallasi, Marco Donia, Jonathan S Stamler, Simone Cardaci, Thomas Sauter, Giuseppe Filomeni.

Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system-the major pathway for MGO detoxification-restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC.

DOI: https://doi.org/10.1038/s41467-026-76938-x
Cancer Med. 2026 Sep;15(9): e72275

Metabolic Reprogramming of Cancer Stem Cells: Targeting Lipid Flux and Mitochondrial Plasticity to Overcome Therapeutic Resistance.

Daniel Ejim Uti, Esther Ugo Alum, Josephine E Egbung, Zuhair M Mohammedsaleh, Manpreet Kaur, Kranti Kiran Reddy Ealla.

  Cancer stem cells (CSCs) are increasingly recognized as metabolically plastic subpopulations within malignant tissues that drive tumor initiation, metastatic dissemination, and relapse after therapy. Although traditional models of cancer metabolism have emphasized aerobic glycolysis, CSCs rarely exhibit a single, clearly defined bioenergetic phenotype. Rather, they dynamically remodel glucose utilization, oxidative phosphorylation, redox regulation, de novo fatty acid synthesis, lipid uptake, lipid sequestration, and fatty acid oxidation in response to hypoxic conditions, nutrient restriction, stromal interactions, and therapeutic perturbations. This review focuses on two interconnected aspects of metabolic flexibility: lipid flux and mitochondrial plasticity. We examine how de novo lipogenesis, CD36-mediated fatty acid uptake, fatty acid-binding protein trafficking, cholesterol biosynthesis, and lipid-droplet turnover contribute to stemness, membrane remodeling, metastatic potential, and resistance to cytotoxic agents. We also examine how mitochondrial dynamics, including fusion, fission, mitophagy, and biogenesis, together with reactive oxygen species buffering and shifts in oxidative phosphorylation, facilitate CSC survival during chemotherapy, radiotherapy, targeted therapy, and immune-mediated cytotoxicity. Particular emphasis is placed on the integration of fatty acid oxidation to respiratory metabolism, on the epigenetic consequences associated with the acetyl-CoA availability, and the metabolic crosstalk linking CSCs to adipocytes, fibroblasts, mesenchymal cells, and immune cell populations in the tumor microenvironment. Finally, we evaluate therapeutic strategies involving inhibitors of fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), carnitine palmitoyltransferase-1 (CPT1), and OXPHOS. We also discuss combination therapies, nanotechnology-based drug delivery, and emerging artificial intelligence (AI)-guided approaches. Taken together, current evidence identifies the lipid-mitochondrial axis as a critical systems-level driver of therapeutic resistance and a promising target for improving long-term cancer control.

Keywords:  cancer stem cells; lipid metabolism; metabolic plasticity; mitochondrial dynamics; therapeutic resistance

DOI:  https://doi.org/10.1002/cam4.72275
Cancer Drug Resist. 2026 ;9 30

Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.

Melis Poyraz, Buse Sari, Jérôme Ambroise, Melanie Spears, Martin Michaelis, Jindrich Cinatl, Romain Boidot, Kristian Serafimov, Olivier Feron, François P Duhoux, Manon Desgres, Cyril Corbet.

  Aim: Resistance to neoadjuvant chemotherapy remains a major challenge in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). Although anthracyclines and taxanes constitute the standard sequential regimen, the metabolic adaptations accompanying resistance to these agents remain poorly defined. We investigated whether chemoresistance is associated with shared or drug-specific metabolic alterations. Methods: Parental MCF-7 and ZR-75-1 cells and their anthracycline-, and taxane-resistant derivatives, were characterized through multi-omics, Seahorse-based metabolic flux, and pharmacological inhibition analyses, alongside validation in patient transcriptomic datasets. Results: Chemoresistant cells displayed reduced drug sensitivity and improved recovery following treatment withdrawal. Transcriptomic profiling revealed extensive yet largely distinct gene expression changes among resistant models, whereas metabolomics showed limited divergence. Functional studies demonstrated concurrent reductions in mitochondrial respiration and glycolytic capacity, indicating a low-bioenergetic phenotype without compensatory metabolic rewiring. Lipidomic changes were heterogeneous and model-dependent. Despite this overall metabolic constraint, spermidine and spermine levels were increased across all resistant models, whereas upregulation of the polyamine-related genes ATP13A4 and SAT1 was specific to anthracycline-resistant cells. Chemoresistant phenotypes conferred reduced sensitivity to mitochondrial inhibitors. In contrast, sensitivity to polyamine pathway inhibition varied across models. Clinical datasets corroborated key experimental features, showing increased ATP binding cassette subfamily B member 1 (ABCB1) expression and significant post-treatment suppression of oxidative phosphorylation and glycolysis signatures. Polyamine pathway enrichment trends were less uniform, reflecting clinical heterogeneity. Conclusion: Chemoresistance in HR+/HER2- BC is characterized by heterogeneous transcriptional remodeling but relative metabolic constraint. Clinical dataset validation confirms post-chemotherapy bioenergetic suppression, while polyamine alterations represent context-dependent adaptations rather than universal vulnerabilities.

Keywords:  Breast cancer; HR+/HER2- disease; anthracycline; chemoresistance; metabolic plasticity; neoadjuvant chemotherapy; polyamine metabolism; taxane

DOI:  https://doi.org/10.20517/cdr.2026.57
Blood. 2026 Sep 17. pii: blood.2026034181. [Epub ahead of print]

IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells.

Aykut Demir, Maximilian Mönnig, Nesrine Aroua, Eleni Besiridou, Valentin Schmidt, Kristina Müller, Simon Renders, Fabian Schulte, Alireza Pouya, Alexander Waclawiczek, Aino-Maija Leppä, Karolin Stumpf, Markus Sohn, Dominic Depke, Patrick Wuchter, Darja Karpova, Elisa Donato, Halvard Bonig, Carolin Andresen, Michael Büttner, Gernot Poschet, Daniel Hübschmann, Nicola Zamboni, Tim Sauer, Andreas Trumpp, Carsten Müller-Tidow, Simon Raffel.

Targeting metabolic dependencies of leukemic stem cells (LSC) may open avenues to improve outcomes of patients suffering from acute myeloid leukemia (AML). LSCs rely heavily on an active tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation whereas healthy hematopoietic stem and progenitor cells (HSPCs) possess more metabolic flexibility. Here, we identify the TCA cycle enzyme isocitrate dehydrogenase 3 (IDH3) as a critical and selective regulator of LSC maintenance. IDH3 is more abundant in LSCs compared to healthy HSPCs, and TCA cycle activity correlates with inferior clinical outcomes of AML patients. Knockdown of IDH3A, the catalytic subunit of the complex, impairs colony-forming potential and bone marrow organoid as well as in vivo engraftment of AML, while sparing healthy hematopoiesis. Mechanistically, IDH3A downregulation reduces TCA cycle flux and leads to accumulation of intracellular citrate, impairing both glycolysis and oxidative phosphorylation. The resulting bioenergetic crisis activates AMPK and suppresses mTORC1, leading to reduced translational activity and an imbalance of anti-apoptotic proteins. Consequently, IDH3A-KD cells show enhanced susceptibility to BCL2 inhibition by venetoclax in vitro and in vivo. In a clinical cohort, LSCs from patients resistant to venetoclax/azacitidine (Ven/Aza) exhibit transcriptomic programs indicative of active TCA cycle and glycolysis. We demonstrate that downregulation of IDH3A activity and subsequent citrate accumulation directly affect these pathways and shift AML stem cells towards a metabolic state of increased vulnerability. In summary, we establish IDH3 as a metabolic rheostat in LSCs and suggest targeting the IDH3A-citrate axis to overcome Ven/Aza resistance of AML patients.

DOI: https://doi.org/10.1182/blood.2026034181
Med Gas Res. 2027 01 01. 17(1): 79-88

Targeting USP14 sensitizes glioma to radiotherapy through exacerbated reactive oxygen species accumulation.

Xinyu Liu, Lichen Shen, Yijun Lu, Zimeng Wang, Shuanghu Yuan, Hongcang Gu, Junchao Qian.

  Radiotherapy is one of the most effective treatments for glioma, but therapeutic efficacy is strongly limited due to intrinsic radioresistance, which is closely linked to reactive oxygen species. This research was designed to elucidate the role and underlying mechanisms of the deubiquitinase ubiquitin-specific protease 14 (USP14) in reactive oxygen species Accumulation and radioresistance of glioma. Bioinformatics analysis demonstrated that upregulation of USP14 was associated with tumor progression, high levels of USP14 in glioma patients were correlated with a significantly poorer prognosis. Cytological experimental results demonstrated that radiotherapy could induce increased USP14 expression. Inhibition of USP14 disrupted intracellular protein homeostasis, leading to upregulation of endoplasmic reticulum stress-related proteins thereby exacerbating endoplasmic reticulum stress. This stress response further induced substantial reactive oxygen species generation and DNA damage accumulation, ultimately synergistically enhancing the tumoricidal effect of radiotherapy. In vivo, the combined application of b-AP15 (a USP14 inhibitor) and radiotherapy elicited potent antitumor effects, marked by significant suppression of tumor growth and increased apoptotic cell death. In summary, we reveal a new regulatory axis by which USP14 governs glioma radiosensitivity through reactive oxygen species-mediated DNA damage and apoptosis, providing a promising therapeutic target and strategy for reversing clinical radioresistance.

Keywords:  DNA damage; USP14; apoptosis; deubiquitinating enzyme; endoplasmic reticulum stress; glioma; glioma radioresistance; radiosensitization; radiotherapy; reactive oxygen species

DOI:  https://doi.org/10.4103/mgr.MEDGASRES-D-26-00027
Nat Commun. 2026 Aug 15. pii: 9805. [Epub ahead of print]17(1):

Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.

Ya Chun Yu, Yulseung Sung, Seonghun Lim, Jeong Ah Kwon, Min Ju Lee, Hyeong Yun Kim, Sunghoon Kim, Kuglae Kim, Do Sik Min, Hee Chan Yoo, Jung Min Han.

Trained immunity enables innate immune cells to acquire memory-like responses, offering a strategy to enhance antitumor immunity. However, the metabolic‒epigenetic mechanisms underlying this process remain poorly defined. Here, we show that lipopolysaccharide-induced macrophage training is encoded by a mitochondrial metabolic checkpoint. Integrated transcriptomic, metabolomic, and epigenomic profiling reveals that TLR4-NF-κB signaling represses SLC1A5_var, a mitochondrial glutamine transporter, limiting glutaminolysis and reducing α-ketoglutarate availability. This metabolic restriction limits removal of the activating histone mark histone H3 lysine 4 trimethylation by KDM5B, thereby maintaining inflammatory gene accessibility. Functionally, pharmacological inhibition or myeloid-specific knockdown of SLC1A5_var potentiates macrophage training and improves tumor control in murine cancer models, whereas enforced SLC1A5_var expression or α-ketoglutarate supplementation abrogates these effects. These findings define an SLC1A5_var-α-ketoglutarate-KDM5B metabolic-epigenetic axis that programs macrophage trained immunity and illustrate how targeted metabolic restriction can be leveraged to enhance innate immune responses against cancer.

DOI: https://doi.org/10.1038/s41467-026-76757-0
Small. 2026 Sep 15. e75339

CD36-Pocket Targeting Induces Metabolic Collapse and Disulfidoptosis for Sonodynamic Immunometabolic Therapy of Liver Cancer.

Liang Zhang, Mengxin He, Yao Lu, Shuai Lu, Jianmin Ding, Hong Ji, Jun Kang, CongHui Han, Jun Yan.

  Obesity-driven lipid accumulation in hepatocellular carcinoma (HCC) establishes a coupled metabolic-immunosuppressive niche that fuels tumor progression and undermines anti-tumor immunity. Through multiplexed immunofluorescence profiling of clinical HCC tissues stratified by visceral adiposity, we explicitly map this lipid-immunosuppressive landscape and demonstrate that fatty acid translocase CD36 overexpression directly correlates with FoxP3+ Treg infiltration and CD8+ T cell exclusion, defining a clinically actionable immunometabolic vulnerability. To therapeutically exploit this vulnerability, we engineer an AI-designed, structure-guided CD36-occluding nanoplatform (LAIBP) with intrinsic ultrasound-responsive sonodynamic capability. Mechanistically, LAIBP selectively blockades CD36-mediated exogenous lipid influx to impose metabolic vulnerability; subsequent ultrasound activation triggers a spatiotemporally controlled oxidative burst, driving disulfidoptosis-like cell death through NADPH depletion, redox imbalance, and cytoskeletal collapse in the lipid-replete tumor microenvironment. Transcriptomic analysis and protein-level validation indicate coordinated metabolic, redox, and immune-associated changes, with G protein-coupled receptor (GPCR)-associated phosphatidylinositol 3-kinase (PI3K)/ serine/threonine-protein kinase (Akt)/ Serine/threonine-protein kinase mTOR signaling and the cystine/glutamate transporter (SLC7A11) - phospholipid hydroperoxide glutathione peroxidase(GPX4) axis emerging as pathways associated with the observed metabolic-redox response. In obesity-associated implanted HCC mouse models, LAIBP combined with ultrasound irradiation suppresses tumor growth, reduces intratumoral lipid accumulation, and is associated with remodeling of the tumor immune microenvironment. Collectively, this work supports a clinically grounded rationale and a nanotherapeutic framework for further immunometabolic investigation in obesity-associated HCC. CONCLUSION: The LAIBP nanoplatform, via the integrated paradigm of "metabolic entry blockade + redox homeostasis disruption + exogenous trigger amplification", induces metabolic collapse and disulfidoptosis-like damage in HCC cells and is associated with remodeling of the antitumor immune microenvironment. This work supports a candidate sonodynamic, immunometabolism-associated strategy for obesity-associated HCC.

Keywords:  CD36; disulfidoptosis; hepatocellular carcinoma; immunometabolic therapy; lipid metabolic reprogramming; nanoplatform; obesity‑associated HCC; sonodynamic therapy

DOI:  https://doi.org/10.1002/smll.75339
Biochim Biophys Acta Rev Cancer. 2026 Sep 15. pii: S0304-419X(26)00187-3. [Epub ahead of print] 189715

Targeting ferroptosis as a new paradigm for overcoming sorafenib resistance in hepatocellular carcinoma.

Wenxuan Zhang, Wenhan Geng, Yumei Fan, Pengxiu Cao, Ke Tan.

  Hepatocellular carcinoma (HCC), the most prevalent primary liver malignancy, is characterized by a rising global incidence, dismal prognosis, and high mortality rates attributed to its complex etiology and therapeutic resistance. Sorafenib, the first approved systemic therapy for advanced HCC, is limited by the rapid emergence of resistance, with approximately 60% of patients developing resistance within 6 months of treatment. This challenge highlights the urgent need to elucidate underlying mechanisms driving treatment failure. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been recognized as a critical player in cancer biology. Accumulating evidence indicates that dysregulation of ferroptotic pathways, including persistent activation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling, lipid metabolic reprogramming, reinforcement of the cystine/glutamate antiporter System Xc- and glutathione peroxidase 4 (GPX4) antioxidant axis, and iron metabolic dysregulation, is closely associated with sorafenib resistance. Importantly, these observations shift the focus from classical apoptosis-based resistance models to ferroptosis as an actionable vulnerability. In this review, we integrate current knowledge on the interplay between sorafenib and ferroptosis, highlighting how ferroptotic dysregulation contributes to therapeutic resistance. By elucidating these mechanisms, we further propose rational strategies to overcome sorafenib resistance by targeting ferroptosis pathways, such as modulating NRF2 activity, rewiring lipid metabolism, or enhancing iron-dependent oxidative stress. Overall, incorporating ferroptosis into the HCC resistance framework offers a promising avenue to improve sorafenib efficacy and patient outcomes.

Keywords:  Ferroptosis; Lipid peroxidation; NRF2; Sorafenib resistance; iron metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2026.189715
Cell Rep. 2026 Sep 17. pii: S2211-1247(26)01094-6. [Epub ahead of print]45(10): 118016

PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors.

Mariachiara Gani, Francesca Agostini, Luca Secco, Lavinia De Pino, Raffaella Picco, Danilo Licastro, Vanessa Tolotto, Francesca D'Este, Himanshi Choudhary, Annalisa Ferino, Valentina Rapozzi, Leonard Barasa, Yuhei Ohta, Hidehiko Nakagawa, Riccardo Sgarra, Paul R Thompson, Luigi E Xodo, Eros Di Giorgio.

  KRAS(ON) and KRAS(OFF) inhibitors have improved the treatment of KRAS-driven tumors, yet resistance remains a major challenge. Here, we identify PADI1 and PADI3 as negative prognostic markers in KRAS-mutant colorectal and pancreatic cancers. KRAS-driven metabolic rewiring sustains their expression through an enhancer within the PADI1 locus. Although KRAS inhibition suppresses PADI1/3 expression in sensitive cells, resistant models maintain elevated PADI1/3 expression and accumulate intracellular calcium, sustaining PADI-dependent adaptive survival. Pharmacological inhibition of PADIs synergizes with KRAS(ON) and KRAS(OFF) inhibitors in two- and three-dimensional cancer models, restores sensitivity in resistant cells, and enhances antitumor activity in vivo. Integrated transcriptomic and proteomic analyses identify HSPA9/Mortalin as a critical citrullinated effector. PADI3-mediated citrullination enhances Mortalin ATPase activity and ATP/ADP cycling, whereas loss of citrullination correlates with apoptosis. Disruption of this adaptive circuitry triggers mitochondrial dysfunction, caspase activation, and non-lytic apoptosis without detectable DAMP release, revealing a therapeutic vulnerability of KRAS-driven tumors.

Keywords:  CP: cancer; KRAS; KRAS(OFF); KRAS(ON); Mortalin; PADI1; PADI3; citrullination; colorectal cancer; pancreatic ductal adenocarcinoma; zoldonrasib

DOI:  https://doi.org/10.1016/j.celrep.2026.118016
Redox Biol. 2026 Sep 09. pii: S2213-2317(26)00388-5. [Epub ahead of print]97 104389

Cancer-associated fibroblast-derived POSTN as a metabolic "switch" shapes lipid-stressed macrophage polarization in gastric cancer.

Qin Ding, Ziteng Li, Ruiwen Liu, Wanjing Feng, Jiayi Wei, Chengye Liu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Shenglin Huang, Xiaodong Zhu.

   BACKGROUND: Cancer-associated fibroblasts (CAFs) foster an immunosuppressive tumor microenvironment (TME) and confer resistance to immune checkpoint blockade (ICB) in gastric cancer (GC). However, the mechanisms by which specific CAF subsets regulate metabolic crosstalk and immune evasion remain poorly defined.
METHODS: We integrated bulk and single-cell RNA-sequencing data, spatial transcriptomics, and clinical cohorts of GC patients treated with immunotherapy. Functional validation was performed using in vitro co-culture systems, multiple murine models, and lipid nanoparticle (LNP)-encapsulated siRNA targeting Postn.
RESULTS: We identified POSTN + CAFs as a key subset enriched in ICB non-responders and associated with poor prognosis. Mechanistically, POSTN secreted by CAFs engaged integrin β1 (ITGB1) on tumor cells and macrophages, activating the PI3K/AKT/mTOR signaling axis and upregulating PPARγ. This signaling cascade drove lipid metabolic reprogramming, characterized by increased lipid accumulation and oxidative stress, and promoted the polarization of macrophages toward an immunosuppressive, lipid-stressed M2 phenotype. Targeting POSTN signaling with LNP-formulated siPostn attenuated tumor growth, suppressed lipid metabolism, and reduced M2 macrophage infiltration in the TME.
CONCLUSION: This work reveals that POSTN + CAFs establish an immunosuppressive TME and are associated with ICB non-response in GC by remodeling lipid metabolism through the ITGB1-PI3K/AKT/mTOR-PPARγ axis, a finding that underscores the therapeutic value of intervening in this specific CAF-macrophage metabolic crosstalk.

Keywords:  Fatty acid metabolism; Gastric cancer; Immunotherapy response; Lipid-stressed macrophage; POSTN

DOI:  https://doi.org/10.1016/j.redox.2026.104389
Signal Transduct Target Ther. 2026 Sep 16. pii: 383. [Epub ahead of print]11(1):

HIF1α-KLF4 signaling dictates extra-erythrocyte expression of hemoglobin conferring sorafenib resistance in hepatocellular carcinoma.

Bo Zhang, Feichang Liu, Xinyue Gao, Yichao Zhu, Tong Chen, Jiahui Hao, Yuexian Wei, Zhuoran Sun, Ruigang Yang, Yalan Yang, He Ren, Yutong Li, Chunxiao Yu, Tianyi Ren, Yinuo Huang, Hong Jiang, Gerry Melino, Li Ma, Hongyan Huang, Qiang Sun.

Cancer cells must deal with excessive reactive oxygen species (ROS) to survive severe hypoxia and anticancer therapy; however, anti-ROS mechanisms other than the well-known NFE2L2/NRF2 signaling pathway are poorly recognized. Here, we report a ROS scavenging mechanism mediated by HIF1α-KLF4-induced hemoglobin extraerythrocytically expressed in hepatocellular carcinoma (HCC). We found that the ROS pathway was aberrantly activated in HCC and was associated with hemoglobin upregulation, which independently predicts poor outcomes. Network analysis further identified heme binding as the top ROS-associated functional module, suggesting a previously unrecognized role of hemoglobin in maintaining redox homeostasis in HCC. Hemoglobin expression in cancer cells is transcriptionally controlled by HIF1α via KLF4 but not HIF2α or the recently identified KDM5A-KLF1 signaling. The upregulated hemoglobin counteracts the detrimental effects of oxidative stress by scavenging ROS, promoting sorafenib resistance, which could be effectively reversed by interfering with hemoglobin expression, leading to tumor suppression. Both in vitro and in vivo experiments consistently supported the functional importance of hemoglobin in regulating oxidative stress adaptation and therapeutic response. Overall, a previously unrecognized mechanism was identified for cancer cell survival under oxidative stress, where HIF1α-KLF4 signaling induces hemoglobin to scavenge ROS produced during hypoxia and anticancer therapy, providing a promising target of synthetic lethality for cancer therapeutics.

DOI: https://doi.org/10.1038/s41392-026-02971-3
Cancer Lett. 2026 Sep 15. pii: S0304-3835(26)00572-0. [Epub ahead of print] 218808

Modulation of Ferroptosis Bridges Radiotherapy and Immunotherapy to Improve Cancer Treatment Outcomes.

Hong-Xiang Zhao, Xue Gao, Ru Xie, Miaoqing Zhao.

  Programmed cell death evasion fuels malignant progression and undermines therapeutic efficacy across diverse neoplasms. Ferroptosis, an iron-driven membrane lipid oxidation that culminates in catastrophic membrane integrity loss, has emerged as a metabolically distinct liability amenable to therapeutic exploitation through radiotherapy and immunotherapy combinations. Ionizing radiation overwhelms cellular antioxidant buffering capacities within the tumour microenvironment, shifting the redox balance toward peroxidative membrane injury and bypassing resistance mechanisms active in treatment refractory tumours. Ferroptotic corpses release alarmins and lipid peroxidation products, triggering immunogenic cell death that reshapes immune surveillance, draws in antigen presenting cells, and reduces activation barriers for immune checkpoint inhibitors and adoptive cellular therapies. At the same time, radiotherapy triggered metabolic reprogramming of the tumour microenvironment marked by glutamine dependence, lipid peroxidation accumulation, and cystine limitation aligns with immunomodulatory effects to strengthen anti-tumour immunity. This Review deconstructs the enzymatic cascades and metabolic checkpoints that govern ferroptotic vulnerability, mapping how radiation induced metabolic rewiring links cytotoxic and immune stimulatory therapeutic goals. We examine whether ferroptosis serves as a central node connecting radiotherapy and immunotherapy, assessing preclinical data on radio immunotherapy combination strategies that leverage this dual functionality. Translational barriers remain. Constrained therapeutic windows, lack of validated pharmacodynamic markers, and unclear toxicological consequences in normal tissues require careful evaluation prior to clinical application. We outline a conceptual framework for deploying ferroptosis as a mechanistic bridge between radiotherapy and immunotherapy, suggesting that its targeted induction under tumour specific metabolic conditions could reshape multimodal treatment strategies and enhance cancer treatment outcomes beyond the marginal gains achievable with single agent approaches.

Keywords:  Ferroptosis; immunotherapy; metabolic reprogramming; radiotherapy; tumour microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2026.218808