bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2025–09–21
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.
  2. BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.
  3. PDE7A inhibition suppresses triple-negative breast cancer by attenuating de novo pyrimidine biosynthesis.
  4. Autophagy Upregulation in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma Uncovers a Novel Therapeutic Target.
  5. MIF Facilitates Resistance to Androgen Deprivation Therapy by Regulating AMPD2 Expression in Prostate Cancer Cells.
  6. Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.
  7. Modulation of bioenergetic metabolism by PDIA3 inhibition prevents breast cancer cell adhesion to endothelial cells.
  8. Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.
  9. SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.
  10. Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
  11. ELOVL6 activity attenuation induces mutant KRAS degradation.
  12. PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.
  13. Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.
  14. Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.
  15. Targeted ferroptosis induction enhances chemotherapy efficacy in chemoresistant neuroblastoma.
  16. ZFP36 reverses chemoresistance by disrupting lipid droplets accumulation in non-small cell lung cancer.
  17. Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma.
  18. Low-GPX4 drives a sustained drug-tolerant persister state in TNBC by a targetable adaptive FSP1 upregulation.
  19. STYK1 as a targetable vulnerability enhances the efficacy of anti-PD-L1 therapy in pancreatic cancer.
  1. Cancer Med. 2025 Sep;14(18): e71244
    Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.
    Jilsy M J Punnasseril, Abdul Auwal, Vinod Gopalan, Alfred King-Yin Lam, Farhadul Islam.
       BACKGROUND: Cancer metabolism is a field focused on the unique alterations in metabolic pathways that occur in cancer cells, distinguishing them from the metabolic processes in normal cells.
    METHODS: An extensive review of the current literature on the metabolic adaptation of cancer cells was carried out in the current study.
    RESULTS: The rapidly proliferating cells require high levels of molecules, such as glucose, amino acids, lipids, and nucleotides, along with increased energy demand (ATP). These requirements are met through alterations in the processes involving glucose, amino acid, lipid, and nucleotide metabolism. Modifications in glucose metabolism in cancer cells involve changes in glucose uptake, glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. Similarly, alterations in amino acid metabolism in cancer cells relate to upregulated amino acid transport and glutaminolysis. Cancer cells also have increased lipid intake from the extracellular microenvironment, upregulated lipogenesis, and enhanced lipid storage and mobilization from intracellular lipid droplets. These rapidly proliferating cells also achieve their increased demand for nucleotides by changing the expression of enzymes in the salvage and de novo nucleotide pathways. Consequently, these metabolic processes are targets for developing cancer therapeutics. However, it is important to note that the metabolic changes in cancer cells can also contribute to resistance against various cancer therapies.
    CONCLUSION: This review will explore the various ways in which cancer cells reprogram metabolic processes to sustain rapid proliferation and survival. The information presented in this report could help in the therapeutics designed to target them, and the challenges of cancer drug resistance arising from these metabolic adaptations.
    Keywords:  Warburg effect; cancer metabolism; drug resistance; glucose metabolism; nucleotide metabolism; therapeutics
    DOI:  https://doi.org/10.1002/cam4.71244
  2. Nat Metab. 2025 Sep 16.
    BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.
    Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H L Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis.
      Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria-lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells.
    DOI:  https://doi.org/10.1038/s42255-025-01352-4
  3. Cell Rep Med. 2025 Sep 16. pii: S2666-3791(25)00429-X. [Epub ahead of print]6(9): 102356
    PDE7A inhibition suppresses triple-negative breast cancer by attenuating de novo pyrimidine biosynthesis.
    Parmanand Malvi, Suresh Bugide, Roshan Dutta, Kiran Kumar Reddi, Yvonne J K Edwards, Kamaljeet Singh, Romi Gupta, Narendra Wajapeyee.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, associated with poor response to therapies and high mortality. We identify that phosphodiesterase 7A (PDE7A) is overexpressed in the majority of TNBCs, and a higher level of PDE7A associates with poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway, via the transcription factor IRF1, stimulates the expression of PDE7A in TNBC cells. PDE7A inhibition attenuates TNBC growth in both cell culture and mouse models of TNBC. Inhibition of PDE7A suppresses de novo pyrimidine biosynthesis, in part through the downregulation of the enzyme dihydroorotate dehydrogenase (DHODH). DHODH suppression attenuates TNBC tumor growth, mirroring the effects of PDE7A inhibition, and ectopic DHODH expression rescues PDE7A-inhibition-induced tumor suppression. Pharmacological co-targeting of PDE7A and DHODH potently inhibits TNBC tumor growth and metastasis. These findings identify the PDE7A → DHODH →de novo pyrimidine biosynthesis pathway as a key driver of TNBC, offering additional therapeutic opportunities for TNBC patients.
    Keywords:  DHODH; PDE7A; phosphodiesterases; pyrimidine biosynthesis; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102356
  4. Res Sq. 2025 Sep 11. pii: rs.3.rs-7483444. [Epub ahead of print]
    Autophagy Upregulation in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma Uncovers a Novel Therapeutic Target.
    Maria Castro, Felipe Núñez, Kaushik Banerjee, Anzar Mujeeb, Ava Mauser, Claire Tronrud, Ziwen Zhu, Sadhakshi Raghuram, Maya Sheth, Jorge Armando Pena Agudelo, Julio Zelaya, Ayman Taher, Padma Kadiyala, Stephen Carney, Maria Garcia-Fabiani, Andrea Comba, Mahmoud Alghamri, Brandon McClellan, Zeribe Nwosu, Hanna Hong, Peter Sajjakulnukit, Tingting Qin, Maureen Sartor, Mats Ljungman, Joshua Welch, Shi-Yuan Cheng, Pedro Lowenstein, Joerg Lahann, Costas Lyssiotis.
      Mutant isocitrate dehydrogenase 1 (mIDH1) catalyzes 2-hydroxyglutarate production which leads to epigenetic reprogramming. RNA-seq, scRNA-seq, and ChIP-seq analysis revealed that human and mouse mIDH1 gliomas exhibit downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated autophagy-related GOs. Decreased mitochondrial metabolism was accompanied by decreased glycolysis, rendering autophagy a source of energy in mIDH1 gliomas. Human and mouse mIDH1 glioma cells exhibited increased expression of autophagy-related proteins and enhanced LC3 I/II conversion, indicating augmented autophagy. Inhibiting autophagy in vivo by administration of synthetic protein nanoparticles encapsulating siRNA targeting Atg7 sensitized mIDH1 glioma cells to radiation, resulting in tumor regression, long-term survival, and immunological memory. This work uncovered 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 mouse models. Thus, autophagy inhibition emerges as an attractive therapeutic target for mIDH1 gliomas.
    DOI:  https://doi.org/10.21203/rs.3.rs-7483444/v1
  5. Prostate. 2025 Sep 19.
    MIF Facilitates Resistance to Androgen Deprivation Therapy by Regulating AMPD2 Expression in Prostate Cancer Cells.
    Changying Li, Chenchen He, Jiancheng Pan, Yuhong Feng, Dawei Tian, Jinhuan Meng, Zhi Qi, Changlin Li, Kuo Yang.
       OBJECTIVE: Androgen deprivation therapy (ADT) was the frontline treatment for patients with prostate cancer ineligible for radical prostatectomy. However, the development of resistance to ADT significantly limits its clinical efficacy.
    METHODS: Using a genome-wide CRISPR/Cas9 knockout (GeCKO) library screen combined with single-cell RNA sequencing (scRNA-seq) analysis, we identified key genes involved in ADT resistance.
    RESULTS: Macrophage migration inhibitory factor (MIF) was identified as a critical mediator of ADT resistance. Inhibition of MIF significantly overcomes ADT resistance. Moreover, we found that the androgen receptor (AR), but not its splice variant AR-V7, negatively regulates MIF expression. Consequently, inhibition of the AR signaling pathway via ADT results in the upregulation of MIF expression. Elevated expression of MIF promotes prostate cancer cell proliferation by upregulating AMPD2 expression.
    CONCLUSIONS: Our findings demonstrate that ADT induces MIF upregulation, which in turn drives prostate cancer cell proliferation via upregulating AMPD2 expression, eventually contributing to the development of resistance to ADT.
    Keywords:  MIF; androgen deprivation therapy; prostate cancer; purine metabolism; resistance
    DOI:  https://doi.org/10.1002/pros.70053
  6. Blood. 2025 Sep 19. pii: blood.2024027496. [Epub ahead of print]
    Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.
    Flor Navarro, Teresa Lozano, Andrea Fuentes-García, Inés Sánchez-Moreno, Marta Larrayoz, Pedro Justicia, Beatriz Perucha, Maialen Martinez-Tabar, Rebeca Martinez-Turrillas, Noelia Casares, Celia Martín-Otal, Marta Gorraiz, Erin W Meermeier, Marta Chesi, Douglas Lake, Paul Leif Bergsagel, Eva Santamaría, Maria Erendira Calleja-Cervantes, Patxi San Martín-Úriz, Lorea Jordana-Urriza, Xabier Agirre, Sandra Hervas-Stubbs, Juan Roberto Rodriguez-Madoz, Jose A Martínez-Climent, Felipe Prosper, Juan J Lasarte.
      Glutamine-dependence of cancer cells reduces local glutamine availability, which hinders anti-tumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of CAR T-cell therapies in cancer patients. We have seen that antigen-specific T cells are unable to proliferate or produce IFN-γ in response to antigen stimulation when glutamine concentration is limited. Using multiple myeloma (MM) as a glutamine-dependent disease model, we found that murine CAR-T cells selectively targeting BCMA in MM cells were sensitive to glutamine deprivation. However, CAR-T cells engineered to increase glutamine uptake by expression of the glutamine transporter Asct2 exhibited enhanced proliferation and responsiveness to antigen stimulation, increased production of IFN-γ, and heightened cytotoxic activity, even under conditions of low glutamine concentration. Mechanistically, Asct2 overexpression reprogrammed CART cell metabolic fitness of CART cells by upregulating the mTORC1 gene signature, modifying the Solute Carrier transporter (SLC) repertoire, and improving both basal oxygen consumption rate and glycolytic function thereby enhancing CART cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of BCMA-CART cells in syngeneic and genetically-engineered mouse models of MM, which prolonged mouse survival. In patients, reduced expression of Asct2 by MM cells predicted poor outcome to combined immunotherapy and BCMA-CAR T-cell therapy. Our results indicate that reprogramming glutamine metabolism may enhance anti-tumor CAR T-cell functionality in MM. This approach may also be effective for other cancers that depend on glutamine as a key energy source and metabolic hallmark.
    DOI:  https://doi.org/10.1182/blood.2024027496
  7. Biochem Pharmacol. 2025 Sep 17. pii: S0006-2952(25)00609-4. [Epub ahead of print] 117344
    Modulation of bioenergetic metabolism by PDIA3 inhibition prevents breast cancer cell adhesion to endothelial cells.
    Marta Stojak, Kamila Wojnar-Lason, Anna Kurpinska, Patrycja Kaczara, Filip Fedak, Joanna Suraj-Prażmowska, Martyna Stachowicz-Suhs, Joanna Rossowska, Magdalena Milczarek, Ivars Kalviņš, Joanna Wietrzyk, Stefan Chlopicki.
      Increased expression of protein disulphide isomerase (PDI), particularly PDIA3, is associated with breast cancer cell aggressiveness. However, it has not been explored whether PDIA3 modulates cancer cell phenotypes by altering cancer cell metabolism. Here, we investigated the effects of C-3399, a novel PDIA3 inhibitor, on the adhesion of breast cancer cells to the extracellular matrix (ECM) and pulmonary microvascular endothelial cells (hLMVEC). Additionally, we explored whether the anti-adhesive effect of PDIA3 inhibition by C-3399 could be mediated by changes in cellular bioenergetics. We found that PDIA3 inhibition modifies adhesive interactions of two human breast cancer lines, representing the luminal (MCF-7) and basal (MDA-MB-231) subtypes, to ECM and hLMVEC. We confirmed that the anti-adhesive effect of C-3399 was due to the inhibition of PDIA3, as the effect was lost in cancer cells with silenced PDIA3. MCF-7 and MDA-MB-231 cells displayed distinct metabolic profiles, with higher levels of tricarboxylic acid (TCA) cycle metabolites in MCF-7. Interestingly, the anti-adhesive effect of PDIA3 inhibition was associated with the downregulation of TCA metabolites (maleate, fumarate, alpha-ketoglutarate, isocitrate) and increased lactate production, particularly in MCF-7 cells. Treatment with mitochondrial respiration inhibitors phenocopied the anti-adhesive effect in MCF-7 but had weaker effects in MDA-MB-231 cells. Quantification of C-3399 and its major metabolite (C-3399-B) revealed the extracellular metabolism of the active compound. In conclusion, the inhibition of extracellular PDIA3 represents a novel approach by which to inhibit the mitochondrial bioenergetic metabolism of cancer cells and limit adhesion signalling among breast cancer cells, the ECM, and the pulmonary endothelium.
    Keywords:  Adhesion; Breast cancer cells; Cellular bioenergetics; Endothelial cells; PDIA3
    DOI:  https://doi.org/10.1016/j.bcp.2025.117344
  8. Mol Oncol. 2025 Sep 16.
    Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.
    Shuangshuang Wu, Jianlei Zhao, Aaban Asfar Azmi, Avanti Gupte, Jenna Thibodeau, Shuang Liu, Jinli Yang, Guan Wang, Holly Edwards, Lisa A Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Julie Boerner, Maik Hüttemann, Jay Yang, Yue Wang, Jeffrey W Taub, Yubin Ge.
      Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.
    Keywords:  AZD4573; acute myeloid leukemia; azacitidine; venetoclax
    DOI:  https://doi.org/10.1002/1878-0261.70124
  9. Adv Sci (Weinh). 2025 Sep 17. e10811
    SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.
    Dai-Wei Hu, Chih-Hao Huang, Yu-Hao He, Ya-Ling Wei, Shu-Wei Hu, Fang-Ju Cheng, Thanh Kieu Huynh, Bo-Rong Chen, Bo-Wei Wang, Li-Chi Kuan, Der-Yen Lee, Ming-Hsin Yeh, Ya-Jen Chang, Liang-Chih Liu, Mien-Chie Hung, Wei-Chien Huang.
      Early-onset breast cancer (EOBC), diagnosed before the age of 45, is associated with poor therapeutic outcomes and limited survival, yet the underlying mechanisms remain poorly defined. Identifying environmental risk factors and actionable therapeutic targets is an urgent clinical need. Notably, the largest survival gap between younger and older patients occurs in luminal breast cancer, implicating potential endocrine disruption. Here, an association is identified between elevated levels of di(2-ethylhexyl)phthalate (DEHP) in hair, a widely used endocrine-disrupting plasticizer, and earlier age at diagnosis of breast cancer. Mechanistically, DEHP exposure promotes tumor initiation by enhancing cancer stemness through mitochondrial fusion and glutamine-driven oxidative phosphorylation. DEHP upregulates the glutamine transporter SLC6A14 to enhance glutamine uptake, while suppressing mitochondrial fission factor (MFF), which exacerbates mitochondrial fusion. High SLC6A14 expression correlates with cancer stemness signatures and earlier onset in patient cohorts. Inhibition of SLC6A14 reduces stemness, impairs tumor growth, and sensitizes tumors to chemotherapy. Collectively, the findings uncover a novel environmental-metabolic axis linking plasticizer exposure to EOBC and establish SLC6A14 as a promising metabolic vulnerability. These results provide a strong preclinical rationale for targeting SLC6A14 in young breast cancer patients and offer new insights into mitigating the oncogenic impact of environmental pollutants.
    Keywords:  SLC6A14; cancer stemness; early‐onset breast cancer; mitochondria dynamics; plasticizer
    DOI:  https://doi.org/10.1002/advs.202510811
  10. Trends Immunol. 2025 Sep 16. pii: S1471-4906(25)00215-7. [Epub ahead of print]
    Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
    Ana Belén Plata-Gómez, Weixin Chen, Ping-Chih Ho, Guang Sheng Ling.
      Mitochondrial lipid metabolism plays a pivotal role in tumor immunosurveillance and immune evasion. This review explores how mitochondrial regulation shapes immune cell metabolism within the tumor microenvironment (TME), focusing on the antitumor effects of the mitochondrial-fueled immune response and the detrimental impact of impaired mitochondrial function on immune cell cytotoxicity. Although current studies support this dual role, critical gaps remain, including how immune cells adapt differently to the lipid-rich TME, and how therapies can target lipid metabolism without harming immune memory. By synthesizing current findings and highlighting these uncertainties, this review highlights mitochondrial lipid metabolism as a promising therapeutic axis in cancer immunotherapy.
    Keywords:  immunometabolism; lipid metabolism; mitochondria; tumor metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.it.2025.08.005
  11. Nat Chem Biol. 2025 Sep 15.
    ELOVL6 activity attenuation induces mutant KRAS degradation.
    Xiyue Hu, Ranjit Singh Atwal, Sophie Xiao, Sharif U Ahmed, Zongjie Wang, Chenlin Zhao, Hansen Wang, Shana O Kelley.
      KRAS is one of the most frequently mutated oncogenes in cancer. Targeting mutant KRAS directly has been challenging because of minor structural changes caused by mutations. Despite recent success in targeting KRAS-G12C, targeted therapy for another hotspot mutant, KRAS-G12V, has not been described. We used CRISPR-Cas9 genome-wide knockout screens to identify genes that specifically modulate mutant KRAS harboring the G12V substitution. Our top hit, a fatty acid elongase (ELOVL6), showed remarkable selectivity in diminishing KRAS-G12V protein expression and aberrant oncogenic signaling associated with mutant KRAS. Our studies reveal that ELOVL6 can be targeted to control the production of phospholipids exploited by KRAS mutants for function-targeted and trigger-targeted degradation of the protein. Our results demonstrate the basis for a first-in-class small-molecule inhibitor to selectively clear KRAS-G12V from cancer cells.
    DOI:  https://doi.org/10.1038/s41589-025-01998-x
  12. Oncogene. 2025 Sep 16.
    PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer.
    Jia Peng, Qiongsi Zhang, Xiongjian Rao, Derek B Allison, Yifan Kong, Ruixin Wang, Jinghui Liu, Yanquan Zhang, Wendy Katz, Zhiguo Li, Xiaoqi Liu.
      Although the involvement of polo-like kinase 1 (PLK1) in metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis has been previously described, the underlying molecular mechanism remains unclear. Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate into acetyl-CoA, the starting material for the tricarboxylic acid (TCA) cycle. In a companion study by Zhang et al., we demonstrated that PLK1 phosphorylation of PDHA1 at threonine 57 (PDHA1-T57) drives its protein degradation via mitophagy activation. Using a stable-isotope resolved metabolomics (SIRM) approach, we now show that PLK1 phosphorylation of PDHA1-T57 results in metabolic reprogramming from OXPHOS to glycolysis. Notably, cells mimicking PDHA1-T57 phosphorylation rely more on the aspartate-malate shuttle than on glucose-derived pyruvate to sustain the TCA cycle. This metabolic shift was also observed in mouse embryonic fibroblasts (MEFs) and transgenic mice conditionally expressing the PDHA1-T57D variant, highlighting the role of PLK1 in metabolic reprogramming in vivo. It is well-established that pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation of PDH leads to its inactivation and that dichloroacetic acid (DCA), a PDK inhibitor, has been investigated in preclinical and early clinical studies as a potential therapeutic agent for lung cancer. We demonstrated that DCA combined with Onvansertib, a PLK1 inhibitor, synergistically inhibits lung tumor growth by enhancing mitochondrial ROS, inhibiting glycolysis, and inducing apoptosis. This study aims to elucidate how PLK1-associated activity drives the metabolic reprogramming from OXPHOS to glycolysis during cellular transformation, thereby contributing to lung carcinogenesis. Our results provide support for a clinical trial to evaluate the efficacy of Onvansertib plus DCA in treating lung cancer.
    DOI:  https://doi.org/10.1038/s41388-025-03571-1
  13. bioRxiv. 2025 Sep 08. pii: 2025.09.04.673818. [Epub ahead of print]
    Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.
    Colin Sheehan, Lyndon Hu, Guillaume Cognet, Grace Croley, Thao Trang Nguyen, Anika Thomas-Toth, Darby Agovino, Patrick B Jonker, Mumina Sadullozoda, Leah M Ziolkowski, James K Martin, Alica K Beutel, Ranya Dano, Mohammed A Khan, Christopher J Halbrook, Kay F Macleod, Christopher R Weber, James L LaBelle, Alexander Muir.
      Cytotoxic chemotherapy remains the standard-of-care treatment for patients with pancreatic ductal adenocarcinoma (PDAC). However, chemotherapy only has modest effects at improving patient survival due to primary or rapidly acquired chemoresistance. The biological underpinnings of PDAC therapy resistance are incompletely defined, but the tumor microenvironment is known to be a major contributor to chemoresistance. We have found chemoresistance is imprinted on PDAC cells by the tumor microenvironment and persists for a period of days after PDAC cells are removed from tumors. However, PDAC chemoresistance is lost upon long term culture in standard laboratory conditions. Interestingly, culture of PDAC cells in Tumor Interstitial Fluid Medium (TIFM), a culture medium we developed to recapitulate the nutrient availability of the tumor microenvironment, maintains PDAC cells in a chemo- and targeted therapy resistant state even after long term culture ex vivo . These findings suggest that microenvironmental metabolic stress keeps PDAC cells in a physiologically relevant, therapy resistant cell state that standard culture models fail to maintain. Using TIFM culture, we sought to understand how PDAC cells in this state resist therapeutic challenge. We found that chemo- and targeted therapies largely retain on-target activity within TIFM medium but fail to activate cell death, enabling a "chemotolerant" cell state, which is also observed in PDAC tumors. This chemotolerant state is driven by suppression of apoptotic priming and can be overcome by targeting the anti-apoptotic regulator BCL-XL. Taken together, these findings suggest that reprogramming of cell death mechanisms by the PDAC nutrient microenvironment is a key contributor to therapy resistance in this disease.
    DOI:  https://doi.org/10.1101/2025.09.04.673818
  14. bioRxiv. 2025 Sep 11. pii: 2025.09.10.675369. [Epub ahead of print]
    Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.
    Gokhan Unlu, Alon Millet, Khando Wangdu, Romain Donné, Ranya Erdal, Nicole L DelGaudio, Beste Uygur, Vyom Shah, Kevin Cho, Antonia Fecke, Feyza Cansiz, Zeynep Cagla Tarcan, Michael Isay-Del Viscio, Ece Kilic, Isabel Kurth, Henrik Molina, Albert Sickmann, Olca Basturk, Gary Patti, Semir Beyaz, Karl W Smith, Amaia Lujambio, Alpaslan Tasdogan, Sohail F Tavazoie, Kıvanç Birsoy.
      Although oncogenic alterations influence tumor metabolism, how they impose distinct metabolic programs within a shared tissue context remains poorly defined. Here, we developed a rapid mitochondrial profiling platform to compare metabolites and proteins in genetic models of primary liver cancer (PLC). Analyses of six genetically distinct PLCs revealed that mitochondrial energy metabolism is largely dictated by oncogene identity. Kras -driven tumors required creatine metabolism to buffer energy demands during early tumorigenesis, whereas c-MYC -driven tumors relied on oxidative phosphorylation. Among c-MYC -driven PLCs, Pten -deficient tumors accumulated mitochondrial phosphoethanolamine, a precursor for phosphatidylethanolamine (PE) synthesis. Inhibition of PE synthesis selectively impaired the growth of Pten -deficient tumors and extended survival, in part through enhanced infiltration of CD8⁺ T cells and sensitization to TNFα-mediated cytotoxicity. Mechanistically, loss of PE elevated surface TNF receptor 2 (TNFR2), promoting TNFα signaling and pro-inflammatory response. These findings uncover genotype-specific mitochondrial metabolic liabilities and establish PE synthesis as a tumor-intrinsic mechanism of immune evasion in PLC.
    DOI:  https://doi.org/10.1101/2025.09.10.675369
  15. NPJ Precis Oncol. 2025 Sep 16. 9(1): 311
    Targeted ferroptosis induction enhances chemotherapy efficacy in chemoresistant neuroblastoma.
    Adriana Mañas, Alexandra Seger, Aleksandra Adamska, Kyriaki Smyrilli, Joachim T Siaw, Katarzyna Radke, Erick A Muciño-Olmos, Oscar C Bedoya-Reina, Javanshir Esfandyari, Kristina Aaltonen, Daniel Bexell.
      Neuroblastoma (NB) is an aggressive pediatric solid tumor which often develops chemoresistance. Ferroptosis is a potential vulnerability in NB, but its interplay with chemoresistance and standard-of-care chemotherapy is not known. Here, we report that key antioxidant pathways are enriched in refractory NB, and that ferroptosis can be induced in NB through various mechanisms of action (MOA) in vitro and in vivo. We observed that NB standard-of-care chemotherapy can interfere with certain ferroptosis-inducing mechanisms, particularly those targeting GPX4, and that the combination of ferroptosis-inducing drugs with current clinical therapy should be based on MOA. Our work also shows that a combination of chemotherapy and the thioredoxin reductase inhibitor Auranofin counteracted some of the anti-ferroptotic effects of chemotherapy and the combination outperformed chemotherapy alone, resulting in increased survival in a chemoresistant NB patient-derived xenograft model. The combination of Auranofin and chemotherapy decreased the population of immature mesenchymal-like NB cells in vivo and exerted its effect through ferritinophagy, lysosome accumulation and iron overload. Thus, upon careful selection of the MOA, the inclusion of ferroptosis-inducing agents within a clinically relevant treatment protocol is feasible and can outperform standard-of-care chemotherapy in high-risk NB.
    DOI:  https://doi.org/10.1038/s41698-025-01090-6
  16. Cell Signal. 2025 Sep 12. pii: S0898-6568(25)00534-0. [Epub ahead of print]136 112119
    ZFP36 reverses chemoresistance by disrupting lipid droplets accumulation in non-small cell lung cancer.
    Zhe Wang, Peng Hou, Yang Wu, Jiaojiao Dai, Ping Zhao, Xiaoxun Cheng, Zhengze Hu, Lingling Zhang, Jinghan Hua.
      Acquired chemoresistance is a major factor contributing to non-small cell lung cancer (NSCLC) therapy failure, and there is no effective intervention target. Recent evidence suggests that disrupting the altered lipid metabolism could sensitize cancer cells to chemotherapy treatments. Here, we demonstrate that zinc finger protein 36 (ZFP36) downregulation promotes the accumulation of lipid droplets (LDs) through the ZFP36-mediated fatty acid synthase (FASN) mRNA decay process, contributing to NSCLC progression and the acquisition of chemoresistance. We advocate that enhancing the suppressive role of ZFP36 on LDs accumulation to treat chemoresistant NSCLC, based on its novel regulatory mechanism in chemoresistance.
    Keywords:  Chemoresistance; FASN; LDs; NSCLC; ZFP36
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112119
  17. Blood. 2025 Sep 12. pii: blood.2025029950. [Epub ahead of print]
    Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma.
    Zhibo Yan, Zhannan Han, Yihui Wang, Maja Beus, Yu Zhang, Alfredo Picado, Carrow I Wells, Jian Wu, Loren B Weidenhammer, Karla M Pires, Elizabeth A Leibold, Liang Liu, David M Gooden, Ivan Spasojevic, Erik Soderblom, Yubin Kang, Lawrence H Boise, Timothy M Willson, Mikhail A Nikiforov.
      The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is often associated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified STK17B kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in MM patients and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified two major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2) and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, pro-ferropototic transferrin receptor and anti-ferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.
    DOI:  https://doi.org/10.1182/blood.2025029950
  18. Redox Biol. 2025 Sep 11. pii: S2213-2317(25)00377-5. [Epub ahead of print]87 103864
    Low-GPX4 drives a sustained drug-tolerant persister state in TNBC by a targetable adaptive FSP1 upregulation.
    Nazia Chaudhary, Dibita Mandal, Bhagya Shree Choudhary, Sushmita Patra, Darshan Jain, Pritam Poonia, Shagufa Shaikh, Siddhi Tekalkar, Shivani Malvankar, Anusha Shivashankar, Eeshrita Jog, Leena Pilankar, Rahul Thorat, Vaishali V Kailje, Sonal Khanna, Subhakankha Manna, Bushra K Khan, Anjana Jadhav, Kedar Sharma, Soundharya Ramu, Sarthak Sahoo, Mohit Kumar Jolly, Sorab N Dalal, Sanju Sinha, Nishanth Ulhas Nair, Eytan Ruppin, Fabienne Lamballe, Flavio Maina, Nandini Verma.
      Metastatic relapses in Triple-Negative Breast Cancer (TNBC) patients with residual disease pose a significant clinical challenge. In this study, we longitudinally modelled cellular state transition from dormant drug-tolerant persister (DDTP) to proliferative (PDTP) cell state across TNBC subtypes. We identified specific molecular and phenotypic alterations that characterize the DTP states in TNBC cells that are maintained upon re-gaining proliferation. We found that Basal-Like proliferative DTPs stably acquired mesenchymal traits, while luminal androgen receptor-positive TNBC DTPs undergo partial Epithelial-to-Mesenchymal Transition (EMT). TNBC DTP cells exhibit reduced expression of glutathione peroxidase-4 (GPX4), conferring susceptibility to ferroptosis inducers. Mechanistically, GPX4 downregulation promotes EMT in TNBC, supported by an inverse correlation between GPX4 and EMT marker vimentin (VIM) expression that also serves as a predictor of survival in TNBC patients undergoing chemotherapy. The genetic, pharmacological, or chemotherapy-induced suppression of GPX4 in TNBC cells leads to robust upregulation of ferroptosis suppressor protein-1 (FSP1). The clinical significance of these findings is established by a strong predictive value of FSP1high/VIMhigh signature for worst survival and incomplete pathological response in chemotherapy-treated TNBC patients. Further, targeting FSP1 re-sensitizes cells to chemotherapy, while combined inhibition of FSP1 and GPX4 is selectively lethal in proliferative DTP TNBC cells by inducing ferroptosis.
    Keywords:  Combination therapy; Drug-tolerant persister cells; EMT; FSP1; GPX4; TNBC
    DOI:  https://doi.org/10.1016/j.redox.2025.103864
  19. J Gastroenterol. 2025 Sep 19.
    STYK1 as a targetable vulnerability enhances the efficacy of anti-PD-L1 therapy in pancreatic cancer.
    Xiao Wang, Yueqin Zhang, Anan Li, Chuanzan Zhou, Sen Xu, Zongting Gu, Wei Wang, Peng Nan, Ran Tao.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. Immunotherapy, though effective in various tumors, has limited efficacy in PDAC due to immune tolerance. Thus, identifying new targets to enhance immunotherapy response is crucial.
    METHODS: This study used bioinformatics analysis and public database data to identify STYK1 as a potential PDAC biomarker. We analyzed STYK1 expression in PDAC tissues, its link to patient prognosis and immune cell infiltration. In vitro experiments assessed the impact of STYK1 knockdown on PDAC cell proliferation, migration, and invasion. Immunohistochemical analysis was performed on 79 PDAC tissue samples to evaluate CD8+ T cell infiltration. In vivo studies examined the effects of STYK1 knockdown on tumor growth, T cell infiltration and activation, especially with anti-PD-L1 antibodies. We also investigated the molecular mechanisms of STYK1's regulation of T cell infiltration, focusing on its association with CCL20 and its role beyond the PD-1/PD-L1 pathway.
    RESULTS: Elevated STYK1 expression in PDAC tissue is associated with poor prognosis and reduced CD8+ T cell infiltration. STYK1 knockdown inhibits PDAC cell proliferation, migration, and invasion in vitro. In vivo, it decreases tumor growth and, when combined with anti-PD-L1 antibody treatment, significantly enhances T cell infiltration and activation without affecting PD-L1 expression. STYK1 regulates T cell infiltration via CCL20, independently of the PD-1/PD-L1 signaling pathway.
    CONCLUSIONS: STYK1 is a potential predictive biomarker for immunotherapy response in PDAC, as its regulation of T cell infiltration via CCL20, independent of the PD-1/PD-L1 pathway, may provide a strategy to potentially augment immunotherapy efficacy, pending mechanistic confirmation.
    Keywords:  Bioinformatics; Immune infiltration; Immunotherapy; Pancreatic cancer; STYK1
    DOI:  https://doi.org/10.1007/s00535-025-02291-3
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