bims-meract 2026-07-19 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–07–19
twenty-one papers selected by
Andrea Morandi, Università degli Studi di Firenze

YAP1 lactylation confers cisplatin resistance and prognostic value by suppressing ferroptosis via FOSL1 in bladder cancer.
Targeting the CAF-GDF15 axis attenuates AKT-mediated mitochondrial rewiring and chemoradiation resistance in esophageal adenocarcinoma.
SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.
Integration of transcriptomic data reveals lipid metabolic heterogeneity and identifies GSTO1 as a therapeutic target in acute myeloid leukemia.
KRAS on Empty: Lipid Oxidation Blockade Reveals a Metabolic Achilles' Heel in Pancreatic Cancer.
Therapy-resistant lymphomas may want nucleotides, but they just need to grow.
Targeting Purine Metabolism With 6-Mercaptopurine Overcomes Solute Carrier Family 7 Member 2 Deficiency-Induced Cisplatin Resistance in Tongue Squamous Cell Carcinoma.
MAP2K6 reprograms NAD+ metabolism via the HMGA1-NAMPT axis to sensitize ovarian cancer cells to PARP inhibition.
Targeting eIF5A2 hypusination with bikinin sensitizes hepatocellular carcinoma to lenvatinib by suppressing TFEB-mediated autophagy.
Mitochondrial Responses to Conventional and Ultra-high Dose Rate (FLASH) Radiation.
Targeting the NAD+ salvage pathway blocks metabolic recovery and enhances β-lapachone toxicity in NQO1-expressing glioblastoma cells.
PDE5a Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking Through a Non-canonical cGMP-Dependent Pathway.
ENO3-mediated glycolytic reprogramming participates in β-glucan-induced dendritic cells activation and anti-tumor responses.
Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
The spliceosome component SNRPC promotes glioma progression by sustaining mitochondrial function and TNFAIP2 signaling.
Metabolite glues as a means of purine sensing and chemotherapeutic response.
LIG1 Loss in TP53-mutant Triple Negative Breast Cancer Rewires DNA Repair and Confers Sensitivity to PARP-ATR Inhibitor Combinations.
Targeting p300 Reverses Acidic Microenvironment-Induced PARP Inhibitor Resistance.
Proteomic Analysis Reveals AMPKα-Mediated Antiandrogen Resistance via Ferroptosis Suppression in Prostate Cancer.
Targeting of Gpx8-CSF1 axis resets the immune milieu of lung tumor and overcomes resistance to anti-PD-1 therapy.
TIP60 promotes chemoresistance by limiting intracellular platinum accumulation and enhancing removal of cisplatin-DNA adducts.

Cell Rep. 2026 Jul 15. pii: S2211-1247(26)00770-9. [Epub ahead of print]45(7): 117692

YAP1 lactylation confers cisplatin resistance and prognostic value by suppressing ferroptosis via FOSL1 in bladder cancer.

Zheyu Ai, Hao Zhou, Lijuan Jiang, Yuejiao Lang, Zihao Feng, Ziran Dai, Haoqian Feng, Zhenwei Li, Hansen Lin, Jun Lu, Gaowei Huang, Jinchen Luo, Jinhuan Wei, Wei Chen, Junhang Luo, Jingwei He, Anze Yu, Xiaohan Jin, Zhenhua Chen.

  Resistance to cisplatin-based chemotherapy remains a major barrier to effective systemic treatment of bladder cancer, underscoring the need for predictive biomarkers and therapeutic targets. Here, we identify YAP1-K90la as a functional post-translational modification that causally drives cisplatin resistance. Across multi-center clinical cohorts, elevated YAP1-K90la levels were associated with poor therapeutic outcomes and outperformed total YAP1 expression in predicting cisplatin responsiveness. Mechanistically, YAP1-K90la enhances YAP1 nuclear localization and transcriptional activity to induce a FOSL1-dependent program that suppresses ferroptosis and promotes cell survival under cisplatin stress. Notably, AARS1 and SIRT1 function as the "writer" and "eraser" of YAP1-K90la, respectively, with SMURF2-mediated ubiquitination of SIRT1 stabilizing YAP1-K90la and driving resistance. Targeting YAP1-K90la using a cell-penetrating peptide restored ferroptotic vulnerability and sensitized bladder cancer cells to cisplatin. Collectively, these findings reveal the YAP1-K90la/FOSL1 pathway that drives cisplatin resistance and position YAP1-K90la as a clinically actionable biomarker and therapeutic target in bladder cancer.

Keywords:  CP: cancer; CP: metabolism; YAP1; bladder cancer; cisplatin resistance; ferroptosis; lactylation

DOI:  https://doi.org/10.1016/j.celrep.2026.117692
J Exp Clin Cancer Res. 2026 Jul 17. pii: 164. [Epub ahead of print]45(1):

Targeting the CAF-GDF15 axis attenuates AKT-mediated mitochondrial rewiring and chemoradiation resistance in esophageal adenocarcinoma.

Ningbo Fan, Pinwei Deng, Zhefang Wang, Feng Ju, Lisa Raatz, Oscar Velazquez Camacho, Axel M Hillmer, Margarete Odenthal, Phuong-Hien Nguyen, Zicheng Lyu, Felix Popp, Seung-Hun Chon, Maarten F Bijlsma, Romy Ros, Hanneke W M van Laarhoven, Alexander Quaas, Jörg Wischhusen, Yue Zhao, Christiane J Bruns.

   BACKGROUND: Therapeutic resistance in esophageal adenocarcinoma (EAC) remains poorly understood at the level of tumor-stroma interactions. We investigated whether cancer-associated fibroblast (CAF)-derived signaling contributes to chemoradiation resistance and adverse clinical outcomes in EAC, with a focus on the functional role of GDF15 within the CAF-secreted program.
METHODS: Serum GDF15 levels were analyzed in EAC patients before and after neoadjuvant chemoradiotherapy according to the CROSS regimen, with prognostic relevance validated in an independent cohort and public datasets. Primary EAC CAFs, EAC cell lines, and patient-derived organoids (PDOs) were used to model tumor-stroma crosstalk in 2D and 3D co-culture systems. Compartment-specific transcriptomic and proteomic profiling identified CAF-regulated pathways. Genetic depletion and antibody-mediated neutralization of GDF15 were used to assess its functional contribution, followed by evaluation of chemoradiation sensitivity, mitochondrial function, oxidative phosphorylation dependency, and AKT pathway activation.
RESULTS: Serum GDF15 levels increased significantly following CROSS treatment, and elevated post-treatment GDF15 independently predicted poor overall survival in EAC patients. CAFs enhanced resistance to chemotherapy and radiotherapy in EAC cells and PDOs, accompanied by increased GDF15 secretion. Compartment-specific transcriptomic analysis and ELISA supported CAFs as a major source of inducible GDF15 during tumor-stroma interaction. Genetic depletion of GDF15 reduced treatment resistance, whereas recombinant GDF15 partially restored chemoresistance in GDF15-depleted models. GDF15 neutralization attenuated CAF-associated cisplatin tolerance. Mechanistically, GDF15 contributed to AKT activation and mitochondrial respiratory adaptation, including enhanced oxidative phosphorylation. Pharmacological attenuation of oxidative phosphorylation further sensitized EAC cells to cisplatin, particularly under CAF co-culture conditions.
CONCLUSIONS: Our study identifies CAF-derived GDF15 as a clinically relevant and functionally targetable component of a broader CAF-secreted resistance program in EAC. GDF15 contributes to AKT-associated mitochondrial adaptation and tumor cell tolerance to chemoradiation, while elevated post-CROSS serum GDF15 serves as a prognostic biomarker. These findings support further investigation of GDF15-directed and mitochondria-targeted strategies to overcome CAF-associated treatment resistance in esophageal adenocarcinoma.

Keywords:  Cancer-associated fibroblasts; Esophageal adenocarcinoma; GDF15; Mitochondrion; Organoids; Treatment resistance

DOI:  https://doi.org/10.1186/s13046-026-03776-6
J Clin Invest. 2026 Jul 15. pii: e199709. [Epub ahead of print]136(14):

SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.

Haojun Yang, Vincenzo Andrea Zingaro, Kevin Boardman, Ashish Noronha, Ekin Guney, Lingru Xue, Saishma Hoigebazar, Isabelle Liu, Sohit Miglani, Siyu Chen, Hieu Vu, Kwun Wah Wen, Hao G Nguyen, Hani Goodarzi, Ralph J DeBerardinis, Davide Ruggero.

  Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. A similar mechanism occurred after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrated that dipeptides containing essential amino acids activated the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored resistant lymphoma sensitivity to 6MP. Strikingly, resistant lymphomas, but not primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, in culture and in vivo. We extended these findings in human lymphoma biopsies, which revealed increased SLC15A3 expression following antimetabolite therapy. Together, our study uncovered a metabolic adaptation that fuels cancer resistance to nucleotide deficiency and positions the mTORC1 inhibitor, rapamycin, as a potential therapeutic strategy for transforming the management of chemotherapy-resistant lymphomas.

Keywords:  Drug therapy; Hematology; Lymphomas; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI199709
Front Immunol. 2026 ;17 1815163

Integration of transcriptomic data reveals lipid metabolic heterogeneity and identifies GSTO1 as a therapeutic target in acute myeloid leukemia.

Fangmin Zhong, Zihao Wang, Jialin Huang, Linfeng Jin, Fangyi Yao, Xiaozhong Wang.

   Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor prognosis and significant heterogeneity. Lipid metabolic reprogramming is a key hallmark of cancer, yet its systemic characterization and clinical relevance in AML remain largely unexplored.
Methods: Multi-omics data were integrated, including one single-cell RNA-seq dataset and bulk transcriptomes from nine AML cohorts. Lipid metabolism activity was assessed using GSVA. Consensus clustering based on lipid metabolism pathways identified molecular subtypes. A lipid metabolism-related prognostic signature (LMRS) was constructed via machine learning algorithms and validated across nine independent cohorts. Functional validation was performed in AML cell lines using GSTO1 inhibition.
Results: Single-cell analysis revealed significant upregulation of lipid metabolism pathways in AML malignant cells, particularly in progenitor-like subpopulations. Three lipid metabolism-based subtypes (C1-C3) were identified, with the C3 subtype exhibiting the highest metabolic activity, an immunosuppressive microenvironment, and the worst prognosis. A robust nine-gene LMRS model was developed, which effectively stratified patients into high- and low-risk groups with distinct survival outcomes. LMRS demonstrated superior predictive accuracy over existing models, was independently prognostic, and correlated with chemotherapy and immunotherapy resistance. Inhibition of GSTO1 significantly induced apoptosis and ROS production in AML cells.
Conclusion: This study comprehensively defines lipid metabolic heterogeneity in AML, establishes a clinically applicable prognostic signature, and underscores lipid metabolism as a key driver of AML progression and immunosuppression. Targeting lipid metabolism, particularly through GSTO1 inhibition, represents a promising therapeutic strategy.

Keywords:  GSTO1; acute myeloid leukemia; immunotherapy; lipid metabolism; prognostic signature; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1815163
Cancer Res. 2026 Jul 15. 86(14): 3374-3376

KRAS on Empty: Lipid Oxidation Blockade Reveals a Metabolic Achilles' Heel in Pancreatic Cancer.

Deborah de la Caridad Delgado Herrera, Christina M Ferrer.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, driven by its aggressive biology and high metastatic incidence at diagnosis. With a 5-year survival rate of just 8%, PDAC remains one of the most lethal cancers. Mutant KRAS, present in more than 90% of cases, serves as a key driver of tumorigenesis and metabolic reprogramming. In this issue of Cancer Research, Thakur and colleagues uncover a novel metabolic adaptation that PDAC cells use to survive therapeutic stress. Their integrated metabolomic and lipidomic analyses show that ERK inhibition-targeting a key KRAS pathway effector-not only disrupts glycolysis and glutamine metabolism but also triggers a compensatory increase in fatty acid oxidation (FAO). This shift occurs through lipophagy, a lysosome-mediated lipid degradation process, rather than cytosolic lipolysis. Mechanistically, ERK inhibition promotes the nuclear translocation of TFEB, which drives the upregulation of FAO and lipophagy genes. This metabolic reprogramming enables PDAC cells to survive KRAS pathway blockade. Importantly, cotargeting FAO alongside ERK or KRAS inhibitors elicits a potent synergistic antitumor effect in vivo. This dual-target strategy holds promise for overcoming PDAC resistance to KRAS-targeted therapies, laying the groundwork for novel combination treatments. See related article by Thakur et al., p. 3519.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1877
J Clin Invest. 2026 Jul 15. pii: e208384. [Epub ahead of print]136(14):

Therapy-resistant lymphomas may want nucleotides, but they just need to grow.

Carlos Carmona-Fontaine.

Malignant cells must rapidly synthesize nucleotides to grow and proliferate. Antimetabolite chemotherapies throw a wrench in this process by administering decoy molecules resembling nucleotide precursors that cells cannot use, such as 6-mercaptopurine (6MP) and methotrexate. While this approach remains an essential tool in the treatment of lymphoblastic leukemias and B cell non-Hodgkin lymphomas, approximately 1 in 3 patients will eventually develop therapy-resistant malignancies. In this issue of the JCI, Yang et al. investigated the metabolic adaptations that enable therapy-resistant tumors to grow in the presence of these drugs. Using their previously described mouse model of MYC-driven large B cell lymphoma, they identified that increased expression of the vesicular oligopeptide and histidine transporter SLC15A3 drives dipeptide accumulation in therapy-resistant cells. In lieu of finding other ways to make more nucleotides, these adaptations force cell growth by boosting mTOR signaling. This cunning adaptation, however, is also a vulnerability that can be targeted clinically.

DOI: https://doi.org/10.1172/JCI208384
Oral Dis. 2026 Jul 15.

Targeting Purine Metabolism With 6-Mercaptopurine Overcomes Solute Carrier Family 7 Member 2 Deficiency-Induced Cisplatin Resistance in Tongue Squamous Cell Carcinoma.

Yu-Lu Mao, Ben-Yuan Mao, Yu-Long Ouyang, Yi Zhang, Ping Cheng, Hong-Chao Feng.

   BACKGROUND: Cisplatin resistance remains a major clinical obstacle in the treatment of tongue squamous cell carcinoma (TSCC). Solute carrier family 7 member 2 (SLC7A2) is a key cationic amino acid transporter, yet its functional significance in TSCC drug resistance has not been explored.
METHODS: We established cisplatin-resistant TSCC cell lines and performed integrated proteomics and metabolomics. SLC7A2 function was assessed via gain-of-function and loss-of-function assays combined with CCK-8, Transwell, wound healing, flow cytometry, Western blot, and RT-qPCR.
RESULTS: SLC7A2 was markedly downregulated in both TSCC tissues and cisplatin-resistant cells. Multi-omics analysis revealed significant perturbations in purine metabolism, identifying 6-mercaptopurine (6-MP) as a critical metabolite. SLC7A2 overexpression or combined Cis+6-MP treatment synergistically suppressed proliferation, migration, and invasion while promoting apoptosis. Mechanistically, SLC7A2 expression correlated with p53 signaling activity: SLC7A2 knockdown increased MDM2 expression and induced cisplatin resistance, while SLC7A2 overexpression or Cis+6-MP treatment reversed these effects. Pharmacological inhibition of p53 with PFT-α sensitized cells to cisplatin, whereas p53 activation with Nutlin-3a partially reversed resistance in a p53-dependent manner.
CONCLUSION: This study identifies SLC7A2 as a regulator of cisplatin response in TSCC, acting through the p53 signaling network. It also highlights 6-MP as a sensitizer, offering a combination strategy to overcome chemoresistance.

Keywords:  6‐mercaptopurine; SLC7A2; amino acid metabolism; cisplatin resistance; tongue squamous cell carcinoma

DOI:  https://doi.org/10.1111/odi.70401
Cell Death Dis. 2026 Jul 17.

MAP2K6 reprograms NAD+ metabolism via the HMGA1-NAMPT axis to sensitize ovarian cancer cells to PARP inhibition.

Ming Wen, Zhuohang Chen, Dongdong Zhan, Mingwei Liu, Shuran Tan, Fang Zhu, Siyu Yang, Jinru Xie, Yu Zhang, Jianjian Li, Lunquan Sun, Rong Tan.

PARP inhibitors (PARPi) selectively target cancers with homologous recombination deficiency (HRD), yet emerging evidence suggests that additional determinants beyond BRCA/HRD status modulate PARPi response. Here, by integrating unbiased proteomic profiling with systematic drug-response phenotyping across 11 ovarian cancer cell lines, we identify MAP2K6 as a previously unrecognized regulator of PARP1 activation and an important determinant of PARP inhibitor sensitivity in BRCA-wild-type ovarian cancer. MAP2K6 promotes global PARP1-mediated PARylation and enhances cellular responsiveness to the PARP inhibitor olaparib both in vitro and in vivo. Mechanistically, MAP2K6 can phosphorylate and activate HMGA1, which in turn transcriptionally upregulates NAMPT, resulting in increased intracellular NAD+ levels, and sustained PARP1 activation. Genetic depletion of HMGA1 or NAMPT abolishes MAP2K6-driven PARylation and PARPi sensitization, whereas loss of MAP2K6 reduces NAD+ levels, attenuates PARP1 activation, and confers resistance to PARPi. We propose that MAP2K6 promotes PARP inhibitor sensitivity by coupling metabolic control of NAD+ supply to PARP1 activation, thereby potentially helping extend the therapeutic scope of PARP inhibition beyond homologous recombination-deficient ovarian cancer.

DOI: https://doi.org/10.1038/s41419-026-09104-2
Hum Cell. 2026 Jul 18. pii: 110. [Epub ahead of print]39(8):

Targeting eIF5A2 hypusination with bikinin sensitizes hepatocellular carcinoma to lenvatinib by suppressing TFEB-mediated autophagy.

Shuqian Wang, Qingyun Zhou, Qiaomei Lin, Shufen Zhang, Ying Cai, Fangnan Wu, Fangyuan Kuang, Lianghui Wang, Shangzhi Xie, Jiahua Lan, Li Zheng, Guodong Xu, Chuxiao Shao, Wei Chen, Chaoyong Tu.

  Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a multikinase inhibitor, necessitating the development of novel therapeutic strategies. Here, we identify bikinin as a potent eIF5A2 inhibitor through structure-based virtual screening (> 100,000 compounds) and demonstrate its synergistic effect with lenvatinib in HCC cells. Mechanistically, bikinin suppresses deoxyhypusine synthase (DHS)-mediated hypusination of eIF5A2, thereby downregulating the expression of transcription factor EB (TFEB). Furthermore, while DHS knockdown enhanced the sensitivity of HCC cells to lenvatinib, the addition of bikinin treatment provided no further significant sensitization. We also observed that the combination of bikinin and lenvatinib significantly promoted apoptosis and suppressed proliferation in HCC cells. Although TFEB overexpression conferred resistance to lenvatinib and activated autophagy, these effects were reversed by co-treatment with bikinin, which restored lenvatinib sensitivity and inhibited autophagic flux. Bikinin disrupts TFEB-driven autophagy, as evidenced by reduced LC3-II conversion, p62 accumulation, and decreased autophagosome formation. In in vivo experiments, the combination therapy with lenvatinib and bikinin achieved marked tumor regression, accompanied by suppressed Ki-67 expression and elevated TUNEL positivity. Finally, RNA-seq data identified TFEB downregulation as a critical mediator of this therapeutic sensitization. Our work unveils a novel therapeutic axis wherein targeting eIF5A2 hypusination disrupts TFEB-dependent autophagy to overcome lenvatinib resistance in HCC cells.

Keywords:  Autophagy; Hepatocellular carcinoma; Hypusination; Lenvatinib; eIF5A2

DOI:  https://doi.org/10.1007/s13577-026-01426-9
Int J Radiat Oncol Biol Phys. 2026 Jul 14. pii: S0360-3016(26)03997-0. [Epub ahead of print]

Mitochondrial Responses to Conventional and Ultra-high Dose Rate (FLASH) Radiation.

Emily G Caggiano, Maryam E Elizondo, Alan Lopez Hernandez, Trey Waldrop, Kevin Liu, Henry Gatica-Gutierrez, Sofía Vargas-Hernández, Nefetiti Mims, Ariana Acevedo-Diaz, Brett Velasquez, Denae Neil, Edgardo Aguilar, Matthew D Meyer, Gloria V Echeverria, Albert C Koong, Michael T Spiotto, Anna-Karin Gustavsson, Emil Schüler.

   PURPOSE: Ultra-high dose rate (>40 Gy/s, FLASH) radiation therapy (RT) provides equivalent tumor control while reducing normal tissue toxicity relative to conventional dose rate (CONV) RT. However, the mechanisms underlying the observed FLASH effect are unknown. We hypothesized that the preservation of mitochondrial integrity in nontumorigenic cells by FLASH RT could be a key factor in reducing normal tissue toxicity and improving overall treatment outcomes.
METHODS: We examined mitochondrial health and function after CONV and FLASH in vitro, ex vivo, and in vivo through assays of metabolic flux, mitochondrial membrane potential, mitochondrial reactive oxygen species (ROS), mitochondrial DNA damage and copy number, mitochondrial morphology, and tumor growth and survival.
RESULTS: In in vitro assays, murine pancreatic cancer (PDAC) cells showed similar levels of mitochondrial damage in response to CONV and FLASH, but nontumorigenic pancreatic cells were spared by FLASH. Ex vivo measurements recapitulated the in vitro findings, and in vivo, mice bearing subcutaneous KPC tumors had comparable tumor growth delay with FLASH and CONV, whereas longer survival after FLASH reflected reduced radiation-induced toxicity rather than greater tumor control.
CONCLUSIONS: Collectively, these results suggest that FLASH spares mitochondrial function in nontumorigenic cells, but not in PDAC cells, relative to CONV. The preservation of mitochondrial integrity in nontumorigenic cells may be a key mechanism underlying the reduced normal tissue toxicity observed with FLASH RT.

Keywords:  FLASH radiation; metabolism; mitochondria; pancreatic cancer; radiation

DOI:  https://doi.org/10.1016/j.ijrobp.2026.07.006
Cancer Res Commun. 2026 Jul 16.

Targeting the NAD+ salvage pathway blocks metabolic recovery and enhances β-lapachone toxicity in NQO1-expressing glioblastoma cells.

Bruce Chang-Gu, Tuvshintugs Baljinnyam, Mark L Sowers, Rahul Dilawari, Jason Herring, Lawrence Sowers.

Glioblastoma (GBM) is a highly heterogeneous tumor, with some cell populations overexpressing genes that give them a survival advantage. One such gene is NAD(P)H quinone oxidoreductase 1 (NQO1), which protects cells from oxidative stress. Although NQO1 overexpression shields cells from endogenous oxidants, the enzyme can also bioactivate certain compounds, including the naphthoquinone β lapachone (β lap). This activation triggers repeated cycles of oxidative stress that ultimately drive cell death. Here, we investigated whether NQO1 overexpression could be exploited as a selective vulnerability to induce toxicity in GBM cells. NQO1-expression status in the U87 GBM cell line, multiple patient-derived GBM cell lines, and normal human astrocytes (NHA) were evaluated. Dose-response studies, NAD+ quantification, and immunoblot were utilized to evaluate the link between NAD+ synthesis and β-lap toxicity. We demonstrate NQO1 is highly expressed in multiple GBM cell lines, and β-lap induces selective cytotoxicity in these cells while sparing low NQO1-expressing cells including NHA. β-lap induces acute NAD+ depletion and DNA damage. However high NQO1-expressing GBM cells may regenerate NAD+ and evade β-lap toxicity. We identified the NAD+ salvage pathway to be the primary pathway responsible for maintaining NAD+ levels in GBM. We demonstrate that targeting this pathway with the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 prevents NAD+ regeneration after β-lap exposure and enhances β-lap cytotoxicity in NQO1-expressing GBM. Altered NAD+ metabolism in GBM represents a potential metabolic vulnerability. Our results suggest targeting NQO1-expressing GBM with NQO1 bioactivatable compounds in combination with NAMPT-inhibitors, is a promising therapeutic strategy for the treatment of GBM.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0275
Cancer Res. 2026 Jul 14.

PDE5a Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking Through a Non-canonical cGMP-Dependent Pathway.

Yarden Ariav, Samah Hayek, Thomas Cantore, Neel Sanghvi, Lital N Adler, Naama Darzi, Lipika R Pal, David Robert Crawford, Tomer Malleron, Josh Silverbeck, Eliane Yardeni, Emma Hajaj, Efrat Ben-Zeev, Sanju Sinha, Shahar Ziman, Amir Shlomai, Sergey Malitsky, Maxim Itkin, Smadar Levin-Zaidman, Inna Goliand, Omer Goldman, Hila Tishler, Alexander Brandis, Tevie Mehlman, Yuri Kuznetsov, Noga Kozer, Karen Shamash, Ella Itzhaki, Neta Ben-Chaim Moskovits, Dean Ranmar, Salomon M Stemmer, Shay Ben-Shachar, Eytan Ruppin, Ayelet Erez.

Non-canonical metabolic functions of signaling molecules contribute to cancer plasticity and metastatic progression. Here, we demonstrated that PDE5a inhibitors, including sildenafil (Viagra), induced lysosomal cholesterol accumulation across multiple mouse and human cancer models, reducing cholesterol bioavailability and impairing cancer cell migration and metastasis. Cancer cells exhibited heightened sensitivity due to reduced lysosomal gene expression, rendering them particularly vulnerable to disrupted cholesterol trafficking. Mechanistically, elevated cGMP bound the lysosomal cholesterol transporter NPC1, impairing cholesterol export and phenocopying Niemann-Pick type C pathology. The resulting cholesterol depletion disrupted membrane lipid rafts and mitochondrial bioenergetics, thereby limiting metastatic capacity and triggering compensatory SREBP2 activation with increased cholesterol synthesis. Combining sildenafil with statins yields additive antimetastatic effects by concurrently blocking lysosomal cholesterol export and cholesterol biosynthesis. Consistently, analysis of digital health records demonstrated significantly improved survival among sildenafil users, with a dose-dependent additive benefit observed when combined with statins. Together, these findings identify increasing cGMP levels through PDE5a inhibition as a potential strategy to restrict metastasis and offer a potential mechanistic basis for the beneficial effects of sildenafil.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-1818
Cell Mol Life Sci. 2026 Jul 16.

ENO3-mediated glycolytic reprogramming participates in β-glucan-induced dendritic cells activation and anti-tumor responses.

Jun Ding, Yongzhe Hao, Meng Yuan, Jie Pan, Yewen Xie, Xiao Sun, Yongling Ning, Chunjian Qi.

  Dendritic cells (DCs) are key initiators of antitumor immunity, yet the metabolic drivers governing their activation remain incompletely defined. Here, we show that the fungal immunomodulator β-glucan induces robust immune-metabolic reprogramming in bone marrow-derived DCs (BMDCs), characterized by coordinated increases in glycolysis and tricarboxylic acid cycle activity. This metabolic shift is essential for BMDCs activation, as inhibition of glycolysis or oxidative metabolism diminishes β-glucan-induced costimulatory molecule expression, proinflammatory cytokine production and T-cell priming. Multi-omics profiling identifies enolase 3 (ENO3) as a key glycolytic regulator selectively upregulated by β-glucan. ENO3 knockdown reduces glycolytic flux, decreases mitochondrial ATP and ROS production, and consequently impairs BMDCs maturation and CD8⁺ T-cell responses. In DC-specific ENO3-knockout mice, ENO3 deficiency significantly compromises the antitumor efficacy of β-glucan, which characterized by accelerated tumor growth, impaired DCs activation, reduced CD8⁺ T-cell infiltration, and an immunosuppressive tumor milieu. These findings reveal ENO3 as a critical metabolic regulator linking β-glucan sensing to DC-mediated antitumor immunity.

Keywords:  Dectin-1 agonist; Glycolytic metabolism; Immune cells; Tumor microenvironment; β-enolase

DOI:  https://doi.org/10.1007/s00018-026-06350-7
Br J Cancer. 2026 Jul 14.

Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.

Salma Sharmin, Jennifer A Kashatus, Sara J Adair, Emma Bakall Loewgren, Mohammad Fallahi-Sichani, Todd W Bauer, David F Kashatus.

BACKGROUND: In RAS-mutant tumours, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumour-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown.
METHODS: We developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance.
RESULTS: We find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signalling axis drives reactivation of mitochondrial fission in the absence of MAPK signalling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitisation to trametinib in resistant lines.
CONCLUSION: These findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.

DOI: https://doi.org/10.1038/s41416-026-03542-7
Cell Death Dis. 2026 Jul 17.

The spliceosome component SNRPC promotes glioma progression by sustaining mitochondrial function and TNFAIP2 signaling.

Peng Ma, Jiang Wu, Zhen Ma, Kai Xu, Xingqi Wang, Kun Yuan, Ya Peng.

Human glioma is a devastating primary brain tumor with a dismal prognosis, necessitating the identification of novel therapeutic targets. The small nuclear ribonucleoprotein C (SNRPC), a core spliceosome component, is implicated in cancer, but its role in glioma remains unexplored. This study aimed to delineate the expression, function, and underlying mechanisms of SNRPC in human glioma. The bioinformatic analysis revealed that SNRPC is significantly upregulated in glioma tissues, with expression levels correlating strongly with higher tumor grade, aggressive molecular subtypes (IDH wild-type, 1p/19q non-codeleted), and poor patient prognosis, establishing it as a robust independent biomarker. Single-cell analysis pinpointed SNRPC enrichment in malignant glioma cells, and co-expression studies linked it to mitochondrial metabolism and oxidative phosphorylation. SNRPC expression is also upregulated in locally-resected glioma tissues and various glioma cell types. Functionally, silencing (by targeted shRNA) or knocking out (via CRISPR/Cas9 method) of SNRPC profoundly attenuated glioma cell proliferation, migration, and invasion, while inducing G1-S arrest and apoptosis. These effects were specifically observed in malignant glioma cells, sparing normal astrocytes. Mechanistically, loss of SNRPC led to severe mitochondrial dysfunction, characterized by impaired mitochondrial respiration, ATP depletion, membrane depolarization, and excessive ROS (reactive oxygen species) production. Conversely, SNRPC overexpression enhanced mitochondrial bioenergetics and promoted malignant phenotypes. SNRPC promoted glioma malignancy by regulating the expression of a key oncogene tumor necrosis factor alpha-induced protein 2 (TNFAIP2), which acts as a key downstream effector to drive increased cell proliferation and migration. Critically, SNRPC knockdown suppressed subcutaneous glioma xenograft growth and disrupted mitochondrial bioenergetics. Its knockout also impeded the intracranial glioma growth in an orthotopic mouse model. Our findings establish SNRPC as a pivotal driver of glioma malignancy by sustaining mitochondrial hyperfunction and TNFAIP2 expression essential for tumor cell proliferation.

DOI: https://doi.org/10.1038/s41419-026-09065-6
Nature. 2026 Jul 15.

Metabolite glues as a means of purine sensing and chemotherapeutic response.

Samuel R Witus, Megan M Kober, Heegwang Roh, Zhi Yang, Fouad Choueiry, Avani S Ghate, Denis V Titov, Michael Rapé.

Molecular glues stabilize weak interactions to impart new functionalities to complexes1-3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.

DOI: https://doi.org/10.1038/s41586-026-10790-3
Mol Cancer Ther. 2026 Jul 15.

LIG1 Loss in TP53-mutant Triple Negative Breast Cancer Rewires DNA Repair and Confers Sensitivity to PARP-ATR Inhibitor Combinations.

Anh Minh Tran Huynh, Jonathan T Lei, Rachel Brough, Christina Sallas, Jun Xu, Jacob B Pilcher, Xuxu Gou, Junkai Wang, Lacey E Dobrolecki, Diana M Fandino, Mariah J Berner, Allison Greer, Fei Fei Song, Sarah Latka, Hugo Villanueva, Sumimasa Arimura, Sufeng Mao, Zhongqiu Guo, Sofía I Aramburu, Anran Chen, Thanh Nguyen, Carolina Gutierrez, Dolores H Lopez-Terrada, Bora Lim, Susan G Hilsenbeck, Michael T Lewis, George Miles, Jason C Mills, Gloria V Echeverria, Stephen J Pettitt, Simon N Powell, Susan M Rosenberg, Andrew N J Tutt, Christopher J Lord, Matthew J Ellis, Meenakshi Anurag.

Proteogenomic analyses have identified an association between LIG1 (DNA Ligase I) loss and chemotherapy resistance in a subset of triple negative breast cancer (TNBC) enriched for TP53 mutations. Here, we demonstrate that co-occurrence of TP53 mutations and LIG1 loss is associated with upregulated DDR activity, including homologous recombination, likely contributing to reduced platinum sensitivity. Unbiased genetic and monotherapy drug screens identified PARP inhibitors (PARPi) as a potential treatment for LIG1-depleted tumors; however, the increase in sensitivity was modest and lower than that observed in TNBC models with homologous recombination deficiency. Subsequently, a screen of PARP inhibition in combination with each of 120 clinically relevant DDR inhibitors revealed that PARPi sensitivity in LIG1-loss cells was significantly enhanced by the addition of an ATR inhibitor (ATRi). Olaparib and ceralasertib demonstrated synergistic cytotoxicity in LIG1-loss cell line models; the combination significantly reduced tumor volume in a LIG1-low PDX model compared to either monotherapy, and showed greater ex vivo cytotoxicity in a LIG1-low PDXO model versus a LIG1-high control. Hence, this study highlights LIG1 status as a stratification factor for ongoing and future clinical trials of DDR-targeted combinations in TNBCs.

DOI: https://doi.org/10.1158/1535-7163.MCT-26-0182
Cancer Res. 2026 Jul 17.

Targeting p300 Reverses Acidic Microenvironment-Induced PARP Inhibitor Resistance.

Kaixin Cheng, Hao Nie, Wei Zhou, Dajiang Guo, Liping Liao, Xu Zhang, Chen Wang, Rafal J Zielinski, Janardan N Gavade, Shruthi Sriramkumar, Yiming Fang, Siyu Xia, Shuai Wu, Hsin-Yao Tang, Andrew V Kossenkov, Yuan Qi, Jinsong Liu, Kang Le, Dorothea Gruber, Michael J Soth, Miriam D Post, Anil K Sood, Stefanie Flückiger-Mangual, Timothy A Yap, Benjamin G Bitler, Rugang Zhang.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are a first-line treatment for epithelial ovarian cancer (EOC) patients, but the development of resistance limits long-term therapeutic efficacy. Tumor acidosis is a hallmark of the tumor microenvironment that has been shown to promote resistance to cancer therapies, suggesting that it may impact PARPi response. Here, we demonstrated that the acidic tumor microenvironment drives a p300-dependent mechanism of PARPi resistance in EOC. Pathologically acidic pH enhanced DNA damage repair, reduced PARPi-induced PARP1 trapping, and attenuated the anti-tumor efficacy of PARPi. A CRISPR-Cas9 screen identified p300 as a druggable mediator of acidosis-induced PARPi resistance. Mechanistically, acidic pH activated an ERK-p300-PARP1 signaling axis that acetylated PARP1 at lysine 505 (PARP1 K505Ac), thereby alleviating PARPi-mediated PARP1 trapping and DNA damage. Elevated PARP1 K505Ac was associated with clinical resistance to PARPi and poor overall survival. In patient-derived and syngeneic EOC models, pharmacologic inhibition of p300 synergized with PARPi to suppress tumor growth. Together, these findings identify p300 as a key mediator of acidosis-induced PARPi resistance and a promising therapeutic target to enhance PARPi efficacy.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0834
Cancer Sci. 2026 Jul 13.

Proteomic Analysis Reveals AMPKα-Mediated Antiandrogen Resistance via Ferroptosis Suppression in Prostate Cancer.

Masaki Shiota, Tokiyoshi Tanegashima, Takahiko Hajime, Miho Ushijima, Shigehiro Tsukahara, Shohei Nagakawa, Satoshi Kobayashi, Takashi Matsumoto, Masatoshi Eto.

  Metastatic prostate cancer often develops resistance to second-generation androgen receptor pathway inhibitors (ARPIs) such as enzalutamide and darolutamide, limiting their long-term efficacy. In this study, we applied the high-precision absolute quantitative proteomics platform iMPAQT to comprehensively profile protein expression changes in multiple prostate cancer cell lines and their ARPI-resistant derivatives. Our analysis revealed consistent dysregulation of ferroptosis suppressor pathway alongside elevated phosphorylation of AMPKα signaling in resistant cells. While antiandrogen treatment increased lipid peroxidation in parental cells, resistant cells adapted by upregulating key ferroptosis-regulating proteins including FTH1 and GPX4, thereby evading ferroptosis. Functional assays demonstrated that the GPX4 inhibitor RSL3 selectively suppressed proliferation of resistant cells more potently than parental cells. Moreover, combination treatment with AMPKα inhibitors enhanced the anti-proliferative effect of RSL3. These findings suggest that ferroptosis suppression is a critical mechanism underpinning resistance to ARPIs in prostate cancer. Targeting pathways involved in ferroptosis regulation in combination with AMPKα inhibitors holds promise for overcoming therapeutic resistance and improving patient outcomes.

Keywords:  AMPKα; antiandrogen; ferroptosis; prostate cancer; proteome analysis

DOI:  https://doi.org/10.1111/cas.70477
Cell Death Differ. 2026 Jul 14.

Targeting of Gpx8-CSF1 axis resets the immune milieu of lung tumor and overcomes resistance to anti-PD-1 therapy.

Heng Zhang, Jialin Ma, Meng Shi, Liang Chen, Yu-Fei Zhang, Zhi Gao, Zhuo-Ran Wang, Biao Liu, Wenwu Luo, Huadong Pei, Bin Wang, Ling Chen, Zhi-Gang Li, Xing Feng, Wen-Yong Zhou.

Despite the promise of immune checkpoint blockade (ICB), only a minority of non-small-cell lung cancer (NSCLC) patients achieve long-term benefits. In this study, we present a single-cell spatial transcriptomic landscape of NSCLC, revealing a previously uncharacterized link between elevated glutathione peroxidase 8 (Gpx8) and resistance to PD-1 blockade. Through CyTOF, CODEX, and ATAC-sequencing analyses, we demonstrate that Gpx8 knockout in both immunocompetent and humanized mouse models suppress tumor growth. This suppression is accompanied by increased infiltration of antitumor T lymphocytes, reduced enrichment of pro-tumorigenic myeloid cells, and the formation of tertiary lymphoid structures (TLS). Mechanistically, Gpx8 inhibits the activity of the RNA-binding protein Celf1(CUGBP Elav-like family member 1) through disulfide bonding between cysteine 79 of Gpx8 and cysteine 177 of Celf1. This interaction stabilizes CCAAT-enhancer-binding protein β (C/EBPβ) mRNA, promotes CSF1 secretion, and drives the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Notably, resistance to anti-PD-1 treatment in Gpx8-expressing NSCLCs can be overcome through enforced expression of Celf1, CSF1R blockade, or a mimic peptide designed to disrupt the Gpx8-Celf1 interaction. Furthermore, anti-PD-1 or rCSF1 treatment activates C/EBPβ and upregulates Gpx8 transcription, establishing a Gpx8-C/EBPβ-CSF1 feedback loop that contributes to immune evasion. These findings provide new insights into the role of Gpx8 in modulating the tumor microenvironment and offer a potential framework for enhancing the sensitivity of NSCLC to PD-1 blockade therapy.

DOI: https://doi.org/10.1038/s41418-026-01818-2
J Biol Chem. 2026 Jul 16. pii: S0021-9258(26)02210-6. [Epub ahead of print] 113338

TIP60 promotes chemoresistance by limiting intracellular platinum accumulation and enhancing removal of cisplatin-DNA adducts.

Akshay Hira, Michael P Craig, Caroline McLaughlin, Jin Zhang, John J Turchi, Michael G Kemp, Ramzi W Nahhas, Madhavi P Kadakia.

  Cisplatin resistance is a major barrier to effective treatment of squamous cell carcinoma (SCC) including cutaneous SCC and Head and neck SCC, where resistance develops in more than half of advanced cases. Our previous work demonstrated that genetic knockdown or pharmacological inhibition of TIP60 (KAT5), a histone acetyl transferase, sensitizes cisplatin-resistant SCC cells, induces cell cycle arrest and promotes cell death, suggesting a key role for TIP60 in mediating resistance. Here, we use cisplatin-sensitive and resistant SCC cell lines, together with siRNA-mediated gene silencing, stable overexpression, pharmacological inhibition, immunodot-blot assays, and ICP-MS to demonstrate that TIP60 promotes resistance through two complementary pathways: (1) upregulation of the efflux transporter ABCC1, which reduces intracellular cisplatin accumulation, and (2) increased expression of XPC, a key component of the nucleotide excision repair pathway, involved in recognition and removal of cisplatin-DNA adducts. Elevated TIP60 levels correlate with reduced cisplatin-DNA adduct levels, enhanced removal of cisplatin-DNA adducts and increased cell survival in resistant lines. TIP60 depletion reduces ABCC1 expression and increases cisplatin-DNA adduct levels, effects similarly observed with the ABCC1 inhibitor, MK-571. In parallel, TIP60 knockdown impairs removal of cisplatin-DNA adducts and reduces expression of multiple DNA damage response (DDR) genes, including XPC. Combined inhibition of TIP60 with spironolactone (targeting XPB/NER) or with MK-571further reduces cell survival and increases cell death in resistant cells. These findings establish TIP60 as a regulator of cisplatin resistance that integrates drug efflux and DNA repair pathways, highlighting TIP60 inhibition as a promising therapeutic strategy to overcome platinum resistance in SCC.

Keywords:  ABCC1; DNA damage response; SCC; TIP60; XPC; chemoresistance; cisplatin-DNA adducts

DOI:  https://doi.org/10.1016/j.jbc.2026.113338