bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2026–05–10
ten papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
  2. MAGMAS Inhibition Enhances Temozolomide Efficacy in Chemotherapy-Resistant Glioblastoma Models.
  3. PinX1 inhibits migrasomes-mediated mitochondrial transfer to confer cisplatin sensitivity in nasopharyngeal carcinoma.
  4. Cigarette smoke induces FASN-dependent fatty acid metabolic rewiring to drive bladder cancer progression.
  5. VGF-Mediated Mitochondrial Remodeling Fuels Lung Adenocarcinoma Brain Metastasis.
  6. HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
  7. The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
  8. Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
  9. FGFR1 drives metabolic adaptation associated with temozolomide resistance in glioblastoma.
  10. DNMT1-DUOXA1 axis discovers a novel methylation-ferroptosis circuit in bicalutamide-resistant prostate cancer.
  1. Mol Cancer Ther. 2026 May 05. OF1-OF13
    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 poly(ADP-ribose) polymerase 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 (OxPhos) 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 The Cancer Genome Atlas and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and resensitized 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 OxPhos and induces ferroptosis, providing a strong rationale for combination strategies with PARPis to overcome drug resistance.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-1157
  2. Cancer Res Commun. 2026 May 06.
    MAGMAS Inhibition Enhances Temozolomide Efficacy in Chemotherapy-Resistant Glioblastoma Models.
    Javier J Lepe, Jennifer D Tran, Naomi Lomeli, Vi P Dang, Valerie C Nguyen, Parthiban Chokkalingam, Sasmita Das, Bhaskar C Das, Daniela A Bota.
      Glioblastoma (GBM, isocitrate dehydrogenase wildtype grade 4 astrocytoma) is the most aggressive and common brain tumor, characterized by increased proliferation, invasiveness, mitochondrial-dependent changes, and necrosis. GBM recurrence is universal despite the standard of care treatment with maximal surgical resection, radiation, and temozolomide (TMZ). Most patients relapse 6 to 9 months following initial diagnosis, and median survival after recurrence is less than a year. Therefore, effective therapeutic strategies are needed to overcome glioma resistance mechanisms and improve long-term outcomes for GBM patients. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS, PAM16) is a nuclear-encoded mitochondrial protein subunit of the translocase of the inner membrane 23 (TIM23) complex that functions as an essential regulator of protein trafficking into the mitochondrial matrix. We previously demonstrated that MAGMAS is overexpressed in GBM, and that the small molecule MAGMAS inhibitor BT9 reduces mitochondrial respiration and is cytotoxic to glioma cells in vitro. Here, we investigated the role of MAGMAS in GBM biology and the effects of MAGMAS inhibition on TMZ-resistant glioma lines and patient-derived glioma stem-like cells (GSCs). We observed elevated PAM16 levels in recurrent GBM, chemoresistant glioma cells, and during metabolic switching processes. Concurrent treatment with BT9 and TMZ significantly increased cell death compared to either drug alone in all glioma lines, irrespective of their TMZ resistance status. Additionally, GBM cells constitutively expressing shPAM16 became sensitized to TMZ both in vitro and in vivo in an intracranial xenograft model. Our findings suggest that targeting MAGMAS holds promise as a novel, effective therapeutic strategy for GBM.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0493
  3. Oncogene. 2026 May 05.
    PinX1 inhibits migrasomes-mediated mitochondrial transfer to confer cisplatin sensitivity in nasopharyngeal carcinoma.
    Juan Zhang, Junqi Wang, Tingfeng Liang, Fang Chen, Zhenchao Zhu, Yong He, Xueyong Hu, Jing Li, Shuaijun Chen, Chaosheng Yu.
      Chemotherapy resistance is a major factor contributing to the failure of nasopharyngeal carcinoma (NPC) treatment. Migrasomes can export damaged mitochondria out of the cell, and the timely removal of damaged mitochondria is key to cancer cell resistance. However, whether migrasomes regulate tumor resistance remains unknown. Here, we elucidated the role and mechanism of migrasomes in chemoresistance of NPC. We found that the formation of migrasomes was increased in cisplatin-resistant NPC cells, and inhibiting migrasome formation reduced cisplatin resistance. PinX1 was lowly expressed in tumor tissues of patients with high migrasome scores. Upstream mechanism analyses showed that TP53 was effectively bound to the promoter of PinX1, thereby enhancing its transcriptional activity. Knockdown of PinX1 facilitated migrasome formation via its telomerase inhibitory domain 252-328aa region binding to Rab11a, which relied on serine residues at the N-terminal 25aa site for promoting migrasome formation. Mechanistically, PinX1 recruited RanBP2 to induce the SUMOylation of Rab11a, leading to the degradation of Rab11a at the K207 site. Furthermore, PinX1 reduced cancer cell energy metabolism by inhibiting the export of damaged mitochondria via migrasomes. Collectively, TP53-activated PinX1 recruits RanBP2 to Rab11a, triggering Rab11a K207 SUMOylation and degradation, leading to impaired migrasome formation and mitochondrial transfer, and ultimately suppresses cisplatin resistance in NPC. Our study provides a new target for clinical reversal of chemotherapy resistance in patients with NPC.
    DOI:  https://doi.org/10.1038/s41388-026-03741-9
  4. Cancer Lett. 2026 May 04. pii: S0304-3835(26)00325-3. [Epub ahead of print] 218562
    Cigarette smoke induces FASN-dependent fatty acid metabolic rewiring to drive bladder cancer progression.
    Chandra Sekhar Amara, Danthasinghe Waduge Badrajee Piyarathna, Abu Hena Mostafa Kamal, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, MinJae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri.
      Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via FASN. Genetic and pharmacological inhibition of FASN significantly reduced tumor growth in a Chicken embryo Chorio-allantoic Membrane model exposed to smoke. FASN inhibitors such as TVB-2640, currently in clinical trials, may represent an effective therapeutic strategy for smokers with bladder cancer exhibiting high FASN levels.
    Keywords:  Bladder Cancer; Cigarette Smoke; DNA damage and repair; FASN; Fatty acid metabolism
    DOI:  https://doi.org/10.1016/j.canlet.2026.218562
  5. Cancer Res. 2026 May 04. 86(9): 2104-2125
    VGF-Mediated Mitochondrial Remodeling Fuels Lung Adenocarcinoma Brain Metastasis.
    Yibei Wang, Xinyue Sheng, Yi Yang, Chen Liu, Shubao Wang, Ruixi Guo, Yue Gu, Ming Chen, Hongyan Zhang, Jingjing Du, Xiaoxue Qin, Ziwei Miao, Pengfei Wu, Xiujuan Qu, Bo Li.
      Lung adenocarcinoma cells exhibit a marked propensity for brain metastasis, in which they face unique metabolic challenges imposed by the microenvironment. The mechanisms that enable lung adenocarcinoma cells to adapt to these constraints represent potential therapeutic targets. In this study, we identified the neuropeptide VGF as a clinically relevant driver of brain metastatic progression. VGF expression was markedly upregulated in lung adenocarcinoma brain metastases, and elevated VGF expression was associated with an increased risk of brain metastasis and poor survival outcomes. Moreover, brain-derived signals induced VGF expression in lung adenocarcinoma cells, promoting cell survival and proliferation through enhanced mitochondrial oxidative phosphorylation and ATP production. Mechanistically, the N-terminal domain of VGF-a nonclassically secreted peptide-interacted with the hydrolase domain of ABHD12B to suppress cardiolipin degradation, leading to increased cardiolipin levels, stabilization of mitochondrial membranes, and a shift toward mitochondrial fusion over excessive fission. These changes helped meet the heightened energetic demands of metastatic cells in the brain. Genetic deletion of the VGF N-terminal domain disrupted mitochondrial fusion, impaired oxidative metabolism, and significantly reduced brain colonization in mouse models of brain metastasis. Together, these findings uncover a role for VGF and establish the VGF-ABHD12B-cardiolipin axis as a critical mechanism underlying metabolic adaptation in lung adenocarcinoma brain metastases, highlighting the potential of this pathway as a therapeutic target for intervention.
    SIGNIFICANCE: The N-terminal domain of VGF is required for sustaining mitochondrial fusion and oxidative phosphorylation to support metabolic adaptation in lung cancer brain metastases, underscoring a potentially targetable mechanism to impair brain colonization.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2712
  6. Elife. 2026 May 06. pii: RP104079. [Epub ahead of print]14
    HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.
    Sara M Frangos, Henver S Brunetta, Dongdong Wang, Maria Joy Therese Jabile, Leslie M Jeffries, Grace Mencfeld, David W L Ma, William J Muller, Cezar M Khursigara, Kelsey H Fisher-Wellman, Jim Petrik, Gregory R Steinberg, Graham P Holloway.
      It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I-IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.
    Keywords:  HER2; bioenergetics; cancer biology; cancer metabolism; cell biology; mitochondria; mouse; proteomics; transcriptomics
    DOI:  https://doi.org/10.7554/eLife.104079
  7. Cancer Lett. 2026 Apr 30. pii: S0304-3835(26)00320-4. [Epub ahead of print] 218557
    The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
    Xiaofeng Kang, Guanglin Lei, Xiaobo Hou, Yimeng Du, Minghao Xu, Chunyuan Xue, Donghui Liu, Songhao Jia, Jingbo Shan, Chuanhao Tang, Xiaojie Xu, An Xu.
      Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial function to stemness remain largely elusive. Integrating bulk and single-cell transcriptomics, we identified Butyrophilin Subfamily 3 Member A3 (BTN3A3) as a novel oncogene driving HCC stemness. BTN3A3 depletion markedly reduced sphere formation, stemness-related gene expression, and the percentage of CD90+/EpCAM+ cancer stem cells. Rescue experiments confirmed that BTN3A3 promotes HCC cell proliferation, migration, and invasion. Furthermore, BTN3A3 depletion sensitized HCC cells to sorafenib by inducing ROS accumulation and apoptosis. Mechanistically, mass spectrometry and Co-IP identified TOMM22 as a key mitochondrial interactor of BTN3A3. Crucially, sorafenib stress actively promotes BTN3A3 mitochondrial translocation, where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency led to TOMM22 depletion, mitochondrial fragmentation, and impaired oxidative phosphorylation (OXPHOS) and ATP production. Importantly, silencing TOMM22 reversed BTN3A3-mediated stemness and sorafenib resistance. In vivo orthotopic xenograft models and patient-derived organoids (PDOs) further validated that BTN3A3 correlates with stemness and malignant tumor growth. Utilizing 5E08, a pan-BTN3 monoclonal antibody, markedly suppressed tumor growth and concurrently downregulated TOMM22 expression in vivo. In conclusion, our study unveils a previously unrecognized non-immunological role for BTN3A3 in mitochondrial reprogramming. We demonstrate that BTN3A3 drives HCC stemness and drug resistance by preventing TOMM22 ubiquitination to maintain mitochondrial homeostasis. These findings position BTN3A3 as a promising therapeutic target, with the pan-BTN3 monoclonal antibody 5E08 offering a potential strategy to overcome stemness-driven malignancy and resistance in HCC patients.
    Keywords:  BTN3A3; Cancer stemness; Hepatocellular carcinoma; Sorafenib resistance; TOMM22
    DOI:  https://doi.org/10.1016/j.canlet.2026.218557
  8. Nat Commun. 2026 May 09.
    Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
    Mingxi Lin, Zhexu Wen, Cheng Zeng, Yizi Jin, Teng Zhou, Yuxin Yan, Shenglin Huang, Xin Hu, Xiaoxiang Guan, Xichun Hu, Jian Zhang.
      Triple-negative breast cancer (TNBC) brain metastases (BrMs) remain a therapeutic challenge. We depict the discrepancies between primary tumors and BrMs, and examine patient-matched cerebrospinal fluid and plasma to provide detailed profiles of BrMs' metabolic microenvironment. High-throughput in vivo loss of function CRISPR screens identify NDUFB9 (NADH: Ubiquinone Oxidoreductase Subunit B9) as a brain-specific metabolic vulnerability. NDUFB9-knockout selectively inhibits the BrMs outgrowth without affecting extracranial metastases. Mechanistically, TNBC cells exhibit an imbalance between aspartate upstream supply and downstream biosynthetic demand. NDUFB9-knockout disrupts mitochondrial complex I and reduces intracellular aspartate, but this alone is insufficient to inhibit TNBC proliferation. Instead, the lower asparagine concentration in the brain microenvironment induces compensatory upregulation of asparagine synthetase, which further diverts aspartate toward asparagine biosynthesis. This dual-hit mechanism exhausts the aspartate pool and restricts nucleotide biosynthesis, thereby selectively suppressing BrM outgrowth. Our findings uncover a therapeutic strategy for TNBC BrMs.
    DOI:  https://doi.org/10.1038/s41467-026-72927-2
  9. Cancer Lett. 2026 May 04. pii: S0304-3835(26)00328-9. [Epub ahead of print] 218565
    FGFR1 drives metabolic adaptation associated with temozolomide resistance in glioblastoma.
    Laura Zarzuela, Ignacio G López-Cepero, Kevin M Rattigan, Ana Reina-Bando, Jorge Martín-Montalvo, Jesús M Sierra-Párraga, Elena Sánchez-Escabias, Macarena Morillo-Huesca, Sara S Oltra, María Ceballos-Chávez, Vivian Capilla-González, Gema Moreno-Bueno, Piedad Del Socorro Murdoch, José C Reyes, G Vignir Helgason, Mercedes Tomé, Raúl V Durán.
      Therapy resistance is a major limitation in therapeutic efficacy for glioblastoma (GBM) patients, positioning GBM among the deadliest tumor types. In this work, we have dissected resistance mechanisms in GBM, which resulted in the identification of FGFR1 pathway as a major controller of the signaling and metabolic rewiring associated to temozolomide (TMZ) resistance. Hence, in FGFR1-positive, p53 WT GBM cells, FGFR1 controls a p53-mediated cell cycle arrest to allow DNA repair in response to TMZ. FGFR1 also regulates a complete metabolic rewiring promoting lipid catabolism and preventing lipid peroxidation. Indeed, FGFR1 inhibition completely abolishes this signaling and metabolic reprograming, restoring sensitivity to TMZ. Our results also indicated a correlation of FGFR1 with poor prognosis in GBM patients, and validated the dual treatment with TMZ and FGFR1 inhibitors as an efficient strategy to induce tumor cell death in FGFR1-positive, p53 WT pre-clinical animal GBM models. These data position FGFR1 as a promising candidate for future clinical evaluation to limit therapy resistance to TMZ in FGFR1-positive GBM patients.
    Keywords:  FGFR1; GBM; Lipidomics; Metabolic reprograming; TMZ; Therapy resistance
    DOI:  https://doi.org/10.1016/j.canlet.2026.218565
  10. Redox Biol. 2026 Apr 25. pii: S2213-2317(26)00186-2. [Epub ahead of print]94 104188
    DNMT1-DUOXA1 axis discovers a novel methylation-ferroptosis circuit in bicalutamide-resistant prostate cancer.
    Shunyao Xia, Yan Sun, Ziwen Ye, Haixing Jia, Zan Liu, Youcheng Xiu.
      Prostate cancer, a prevalent malignancy in the male reproductive system, poses significant therapeutic challenges due to the development of resistance to androgen deprivation therapies such as bicalutamide. While current research predominantly focuses on androgen receptor (AR)-dependent mechanisms of resistance, non-AR-dependent pathways remain poorly understood. Here, we report a novel non-AR-dependent mechanism of bicalutamide resistance centered on DUOXA1, a maturation factor for dual oxidases (DUOX) that catalyzes hydrogen peroxide (H2O2) production. Our analysis of RNA sequencing data from bicalutamide-resistant and sensitive prostate cancer cells revealed DUOXA1 as a significantly downregulated gene in resistant cells. We demonstrate that hypoxia in the prostate cancer microenvironment enhances HIF1α transcriptional activity, leading to increased DNMT1 expression. DNMT1, an epigenetic modifier, mediates the methylation of the DUOXA1 promoter, thereby silencing its expression. This epigenetic silencing of DUOXA1 inhibits ferroptosis, a form of regulated cell death characterized by iron metabolism disruption and lipid peroxidation, thereby promoting bicalutamide resistance. Our findings indicate that DUOXA1 can enhance bicalutamide resistance by promoting ferroptosis through ROS generation. This study not only provides mechanistic insights into the role of DUOXA1 in bicalutamide resistance but also highlights the HIF1α-DNMT1-DUOXA1 axis as a critical regulator of resistance. Our work suggests potential therapeutic strategies to overcome resistance through epigenetic modulation and activation of DUOXA1, offering a novel perspective on the molecular mechanisms of bicalutamide resistance and paving the way for the development of improved treatment approaches for advanced prostate cancer.
    Keywords:  Bicalutamide; DUOXA1; Epigenetic modification; Ferroptosis; Prostate cancer
    DOI:  https://doi.org/10.1016/j.redox.2026.104188
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