bims-meract 2026-02-01 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–02–01
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Lipid Droplets in Cancer: New Insights and Therapeutic Potential.
Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers.
Targeting GNG4 inhibits tumor progression and restores enzalutamide sensitivity in prostate cancer by suppressing autophagy.
p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer.
Coupling proteostasis and de novo purine biosynthesis of PSMD14 fuels glioblastoma progression and chemoresistance.
Tumor Cell AMPK Activation Enhances NK Cell Anti-tumor Immunity and Synergizes with PD-L1 Blockade Therapy.
Overexpression of biliverdin reductase A leads to ROS-independent sensitization of ovarian adenocarcinoma cells to gemcitabine.
Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.
Metabolic reprogramming-driven resistance to multi-kinase inhibitors in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities.
FASN at the Crossroads of Tumor Metabolism, Immune Evasion, and Therapy Resistance: Mechanistic Insights and Therapeutic Opportunities.
SREBP-1 increases glucose uptake to promote tumor resistance to lysosome inhibition.
Targeting the WWP2-ASPP2 axis overcomes cisplatin resistance by inhibiting the mevalonate pathway in TP53-mutant bladder cancer.
Loss of BOK increases vulnerability of p53 deficient non-small cell lung cancer cells to ATR inhibition through its role in uridine metabolism.
Ether lipids influence cancer cell fate by modulating iron uptake.

Int J Mol Sci. 2026 Jan 16. pii: 918. [Epub ahead of print]27(2):

Lipid Droplets in Cancer: New Insights and Therapeutic Potential.

Shriya Joshi, Chakravarthy Garlapati, Amartya Pradhan, Komal Gandhi, Adepeju Balogun, Ritu Aneja.

  The progression of neoplastic diseases is driven by a complex interplay of biological processes, including uncontrolled proliferation, enhanced invasion, metastasis, and profound metabolic reprogramming. Among the hallmarks of cancer, as revised by Hanahan and Weinberg, the reprogramming of energy metabolism has emerged as a critical feature that enables cancer cells to meet their heightened bioenergetic and biosynthetic demands. One significant aspect of this metabolic adaptation is the accumulation of lipid droplets (LDs) dynamic, cytoplasmic organelles primarily involved in lipid storage and metabolic regulation. LDs serve as reservoirs of neutral lipids and play a multifaceted role in cancer cell physiology. Their accumulation is increasingly recognized as a marker of tumor aggressiveness and poor prognosis. By storing lipids, LDs provide a readily accessible source of energy and essential building blocks for membrane synthesis, supporting rapid cell division and growth. Moreover, LDs contribute to cellular homeostasis by modulating oxidative stress, maintaining redox balance, and regulating autophagy, particularly under nutrient-deprived or hypoxic conditions commonly found in the tumor microenvironment. Importantly, LDs have been implicated in the development of resistance to cancer therapies. They protect cancer cells from the cytotoxic effects of chemotherapeutic agents by buffering endoplasmic reticulum (ER) stress, inhibiting apoptosis, and facilitating survival pathways. The presence of LDs has been shown to correlate with increased resistance to a variety of chemotherapeutic drugs, although the precise molecular mechanisms underlying this phenomenon remain incompletely understood. Emerging evidence suggests that chemotherapy itself can induce changes in LD accumulation, further complicating treatment outcomes. Given their central role in cancer metabolism and therapy resistance, LDs represent a promising target for therapeutic intervention. Strategies aimed at disrupting lipid metabolism or inhibiting LD biogenesis have shown potential in sensitizing cancer cells to chemotherapy and overcoming drug resistance. In this review, we comprehensively examine the current understanding of LD biology in cancer, highlight studies that elucidate the link between LDs and drug resistance, and discuss emerging approaches to target lipid metabolic pathways to enhance therapeutic efficacy across diverse cancer types.

Keywords:  cancer metabolism; drug resistance; lipid droplets (LDs); metabolic reprogramming; therapeutic targeting

DOI:  https://doi.org/10.3390/ijms27020918
ACS Biomater Sci Eng. 2026 Jan 28.

Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers.

Meabh Doherty, Jie Feng, Tongchuan Wang, Cancan Yin, Niall M Byrne, Sarah Chambers, Rayhanul Islam, Dimitrios A Lamprou, Jonathan A Coulter.

  Lactate, the main product of the Warburg effect, exerts both intrinsic effects on cancer cell metabolism and noncell autonomous effects that promote tumor development, metastasis, and treatment resistance. As such, glycolytic dependence in tumors is frequently associated with poor clinical outcomes. Targeting lactate metabolism has emerged as a promising strategy to enhance the efficacy of conventional therapies. Here, we investigate the therapeutic potential of targeting lactate metabolism via inhibiting MCT1, MCT4, and MPC in PC3 and FaDu tumor cell models. We confirmed lactate as a substrate that fuels mitochondrial respiration and supports cell survival under hypoxic conditions. Inhibition of lactate influx mediated by 7ACC2 reduced oxygen consumption, sensitizing tumor cells to radiation in both 2D-cell cultures and 3D-spheroid models. Encapsulation of 7ACC2 in DPPC liposomes using microfluidics preserved radiosensitizing activity in both systems, promoting reoxygenation, while overcoming the pharmacological limitations of the free drug. This liposomal formulation therefore represents a promising therapeutic approach to help mitigate hypoxia-induced radioresistance.

Keywords:  MCT1/4; MPC; hypoxia; lactate metabolism

DOI:  https://doi.org/10.1021/acsbiomaterials.5c02175
Cell Death Dis. 2026 Jan 28.

Targeting GNG4 inhibits tumor progression and restores enzalutamide sensitivity in prostate cancer by suppressing autophagy.

Lei Chen, Jingyan Zhang, Yanshuo Hu, Xufeng Peng, Hong Wang, Binghua Chen, Jun Xia, Wei Xue, Chun-Wu Pan.

Prostate cancer (PCa) is the most prevalent malignancy among men worldwide. Advanced prostate cancer is characterized by aggressive progression, limited therapeutic response, and poor prognosis. Elucidating its oncogenic mechanisms may provide new opportunities for targeted intervention. Increasing evidence suggests that modulating cytoprotective autophagy represents a promising strategy for improving cancer treatment efficacy and overcoming drug resistance. Here, we identified the G protein subunit GNG4 as a crucial regulator of prostate cancer development. GNG4 expression was markedly elevated in advanced prostate cancer phenotypes and positively correlated with tumor survival, apoptosis, and migration. Further analysis demonstrated that GNG4 depletion suppressed autophagy and enhanced cellular sensitivity to enzalutamide. Mechanistically, GNG4 interacts with GNB1 to stabilize the downstream effector protein GNAI3 through the ubiquitination-proteasome pathway. These three distinct G protein subunits form a functional complex that regulates intracellular autophagy and subsequently influences the malignant behavior of prostate cancer. Furthermore, inhibition of autophagy or GNG4 knockdown significantly increased the antitumor efficacy of enzalutamide both in vitro and in vivo. Our findings identified GNG4 as a pivotal modulator of prostate cancer progression and proposed it as a promising therapeutic target to enhance the clinical response to enzalutamide.GNG4 interacts with GNB1 to stabilize GNAI3 via the ubiquitination-proteasome pathway, thereby activating autophagy. This process promotes prostate cancer progression and resistance to androgen receptor signaling inhibitors (ARSis). In contrast, GNG4 knockdown or pharmacological inhibition of autophagy restores ARSI sensitivity and suppresses tumor growth.

DOI: https://doi.org/10.1038/s41419-026-08421-w
Redox Biol. 2026 Jan 19. pii: S2213-2317(26)00041-8. [Epub ahead of print]90 104043

p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer.

Jing Tong, Tao Han, Jun Deng, Yu Gan, Ruiwen Ruan, Wei Zhao, Chen Xiong, Quan Liao, Shiqi Chen, Huitong Bu, Jianping Xiong, Xiang Zhou, Qian Hao.

  In colorectal cancer (CRC), p53 can either suppress or potentiate tumor sensitivity to ferroptosis under oxidative stress conditions. However, it remains to be elucidated how p53 differentially regulates ferroptosis, and whether it can initiate ferroptosis. Our findings reveal that p53 induces ferroptosis in the presence of abundant polyunsaturated fatty acids (PUFAs). FBXO2, which is encoded by a p53-inducible target gene, interacts with FABP5 and promotes the lysosomal degradation of FABP5 through chaperone-mediated autophagy. This results in a decrease in the levels of PUFAs, thereby increasing resistance to ferroptosis in CRC. Notably, the supplementation of arachidonic acid not only reverses p53-mediated ferroptosis resistance, but also coordinates with p53 to initiate ferroptosis independently of additional oxidative stress, effectively suppressing the growth of CRC cells both in vitro and in vivo. Altogether, our study uncovers that the availability of PUFAs is crucial for p53 to exert a pro-ferroptotic function in CRC.

Keywords:  Cancer therapy; Chaperone-mediated autophagy (CMA); Ferroptosis; Polyunsaturated fatty acid (PUFA); p53

DOI:  https://doi.org/10.1016/j.redox.2026.104043
Theranostics. 2026 ;16(7): 3599-3615

Coupling proteostasis and de novo purine biosynthesis of PSMD14 fuels glioblastoma progression and chemoresistance.

Jiazheng Wang, Qun Cao, Zhikai Li, Xuxiu Lu, Zhuo Li, Chenghui Guo, Yuan Pan, Qing Zhang, Wenjie Li, Guo Xiang, Anjing Chen.

  Background: Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor characterized by rapid proliferation, profound invasiveness, and resistance to conventional therapies. Deubiquitinating enzymes (DUBs), crucial regulators of protein homeostasis, have recently been implicated in GBM pathogenesis. However, the specific DUBs that play central roles in GBM pathogenesis and their exact molecular mechanisms remain to be further elucidated. Methods: We systematically analyzed GBM datasets and clinical samples to identify differentially expressed DUBs. Functional experiments, including genetic manipulation, immunoprecipitation coupled mass spectrometry (IP-MS), comprehensive metabolic assays, mitochondrial function assessments, and orthotopic mouse models, were conducted. Results: Here, we identified PSMD14 as a protein significantly upregulated in GBM, with a close correlation to poor prognosis of patients. Mechanistic exploration revealed that PSMD14 stabilized IMPDH2, the rate-limiting enzyme of purine nucleotide biosynthesis, by selectively removing K48-linked polyubiquitin chains. When PSMD14 is inhibited genetically or pharmacologically, IMPDH2 stability diminishes, causing impaired nucleotide metabolism, mitochondrial dysfunction, increased DNA damage signaling, and reduced tumor malignancy. Importantly, these metabolic issues can be reversed by exogenous guanosine, highlighting the key role PSMD14 in metabolic regulation. In translational medicine, the PSMD14 inhibitor, Thiolutin, curbed GBM progression in vitro and in vivo by disrupting the de novo purine biosynthesis and resulting in mitochondrial fragmentation. Moreover, Thiolutin synergized with TMZ to overcome resistance and boost efficacy. This study reveals a new GBM metabolic axis and presents a promising PSMD14-targeting therapy. Conclusions: PSMD14-IMPDH2 axis serves as a crucial hub integrating post-translational modifications and metabolic homeostasis in GBM. Targeting PSMD14 enhances therapeutic sensitivity, presenting a promising strategy to overcome TMZ resistance and improve GBM treatment efficacy.

Keywords:  IMPDH2; PSMD14; de novo purine biosynthesis; deubiquitination; glioblastoma; thiolutin

DOI:  https://doi.org/10.7150/thno.124409
Mol Ther. 2026 Jan 28. pii: S1525-0016(26)00033-X. [Epub ahead of print]

Tumor Cell AMPK Activation Enhances NK Cell Anti-tumor Immunity and Synergizes with PD-L1 Blockade Therapy.

Zhen Lu, Jiacheng Bi, Chaoyue Zheng, Lulu Cui, Houjun Xia, Xiaochun Wan, Youhai H Chen.

Immune checkpoint blockade targeting the PD-1 or PD-L1 pathway has shown great clinical results, but only in a small subpopulation of cancer patients. The underlying mechanism of resistance to immune checkpoint therapy remains largely elusive. AMP-activated protein kinase (AMPK) senses metabolic stress, restores energy balance, and plays important roles in tumorigenesis. Here we report that tumor cell-intrinsic AMPK activation dictates the sensitivity of tumor cells to PD-L1 immunotherapy and NK cell-mediated antitumor immunity. PD-L1 checkpoint blockade resulted in increased phosphorylation of AMPK in anti-PD-L1 responsive, but not nonresponsive tumors. Pharmacological inhibition of AMPK activation diminished the therapeutic effect of PD-L1 checkpoint blockade. Conversely, pharmacological or genetic activation of AMPK in cancer cells sensitized them to NK cell-mediated killing through perforin, and synergized with PD-L1 blockade therapy to suppress tumor growth in mice in an NK cell-dependent manner. Transcriptomic analyses revealed that AMPK activation in tumor cells triggered the expression of pattern recognition receptor genes and a chemokine gene expression signature that is associated with longer overall survival of cancer patients. These findings indicate that AMPK controls tumor responsiveness to checkpoint blockade therapy through NK cell-dependent mechanisms.

DOI: https://doi.org/10.1016/j.ymthe.2026.01.032
Exp Cell Res. 2026 Jan 23. pii: S0014-4827(26)00021-2. [Epub ahead of print]456(2): 114905

Overexpression of biliverdin reductase A leads to ROS-independent sensitization of ovarian adenocarcinoma cells to gemcitabine.

Zuzana Solárová, Kristína Danková, Pavol Harvanik, Peter Bober, Petra Majerová, Radka Michalková, Mangesh Bhide, Peter Solár.

   AIMS: Biliverdin reductase A (BLVRA) is a key enzyme in bilirubin metabolism, where it reduces biliverdin to bilirubin. Bilirubin is a potent antioxidant that protects cells from oxidative stress. Therefore, reduced or deregulated BLVRA activity may contribute to increased oxidative DNA damage, which is one of the factors leading to the neoplastic transformation of cells.
METHODS: Human ovarian adenocarcinoma A2780 cells were transfected with a PiggyBac vector to achieve BLVRA overexpression. A2780 clones showing the most significant BLVRA gene overexpression were analyzed by proteomics and flow cytometry to assess rective oxygen species (ROS) production.
RESULTS: Our results indicate that BLVRA overexpression increases the sensitivity of A2780 cells to doxorubicin and gemcitabine, with the most pronounced effect observed in the J clone. In this clone, the highest level of BLVRA overexpression correlated with significant alterations in the p53 signaling pathway. Upregulation of key effectors such as Bax and CDKN2A indicates a potential role for BLVRA in promoting pro-apoptotic responses. Moreover, BLVRA overexpression increased the sensitivity of A2780 cells to gemcitabine independently of ROS.
CONCLUSIONS: This study broadens our understanding of BLVRA in ovarian cancer. In cells with intact p53 signaling, BLVRA overexpression can paradoxically enhance cytotoxic response to certain drugs, particularly gemcitabine.

Keywords:  A2780; BLVRA; Chemotherapy; Overexpression; Resistance

DOI:  https://doi.org/10.1016/j.yexcr.2026.114905
FEBS Lett. 2026 Jan 28.

Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.

Alexis Wilson, Mackenzie K Herroon, Shane Mecca, Laimar C Garmo, Jacob Lindquist, Shrila Rajendran, Steve M Patrick, Izabela Podgorski.

  The mechanisms supporting progression of metastatic prostate cancer (PCa) in adipocyte-rich bone marrow remain unclear. We hypothesized that stearoyl-coenzyme A desaturase (SCD) promotes PCa survival in bone by modulating stress responses and regulating lipid peroxidation. We show that SCD-high PCa cells are sensitive to SCD loss, showing smaller spheroids, reduced mTOR signaling, and elevated endoplasmic reticulum (ER) stress. SCD expression is further augmented by adipocytes, and SCD loss induces DNA damage and repair activation only with adipocyte exposure. In vivo, pharmacological SCD inhibition reduces tumor size and increases ER stress and DNA damage in SCD-high-expressing bone tumors. These findings suggest SCD plays a role in redox regulation and DNA repair sensitivity, with therapeutic potential for targeting DNA repair pathways in combination with SCD inhibition. Impact statement This study reveals that stearoyl-CoA desaturase (SCD) supports prostate cancer growth in adipocyte-rich bone by regulating redox balance and DNA repair responses, uncovering a metabolic mechanism linking lipid metabolism to genomic stability and suggesting therapeutic potential for combining SCD and DNA repair pathway inhibition.

Keywords:  DNA damage; ER stress; bone marrow adipocytes; bone metastasis; lipid desaturation; prostate cancer; stearoyl CoA desaturase

DOI:  https://doi.org/10.1002/1873-3468.70290
Mol Cancer. 2026 Jan 27.

Metabolic reprogramming-driven resistance to multi-kinase inhibitors in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities.

Junxin Li, Yu Huang, Jiawei Li, Min Shi, Yi Xiao, Fei Du, Gongli Hu.

  Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is frequently diagnosed at advanced stages, limiting curative options. Multi-kinase inhibitors (MKIs), such as sorafenib and lenvatinib, serve as first-line therapies for unresectable HCC. However, the widespread development of drug resistance significantly diminishes the clinical efficacy of MKIs, and current treatments lack effective strategies to enhance MKI sensitivity. Metabolic reprogramming, a hallmark of cancer cells that facilitates unchecked growth and metastasis, has emerged as a critical mechanism driving MKI resistance in HCC. This review comprehensively examines the roles of glycolysis, lipid metabolism, and amino acid metabolism in promoting MKI resistance, with a focus on key molecular regulators that could serve as potential targets to reverse resistance. Additionally, this review synthesizes preclinical and clinical evidence of therapeutic agents that synergize with MKIs by modulating metabolic pathways, and discusses the regulatory role of metabolic reprogramming in the tumor immune microenvironment (TIME) of HCC, offering innovative strategies to improve treatment outcomes for patients with HCC. These findings highlight metabolic reprogramming as a crucial target for developing novel interventions aimed at overcoming MKI resistance in clinical practice.

Keywords:  Amino acid metabolism; Drug resistance; Glycolysis; HCC; Lenvatinib; Lipid metabolism; MKIs; Metabolic reprogramming; Sorafenib; TME

DOI:  https://doi.org/10.1186/s12943-026-02578-w
Crit Rev Oncol Hematol. 2026 Jan 26. pii: S1040-8428(26)00042-9. [Epub ahead of print] 105155

FASN at the Crossroads of Tumor Metabolism, Immune Evasion, and Therapy Resistance: Mechanistic Insights and Therapeutic Opportunities.

Xuefeng Jiang, Guotao Fang, Wen Li, Yusheng Liu, Gang Chen, Silvio E Perea, Yasser Perera, Rong Ma, Xiaofei Hu, Xinan Long.

  Fatty acid synthase (FASN), the key enzyme driving de novo lipogenesis, has emerged as a central metabolic hub in cancer, linking aberrant lipid synthesis to tumor progression, immune escape, and therapy resistance. This review provides a comprehensive overview of the regulatory landscape and oncogenic functions of FASN, highlighting its modulation at transcriptional, post-transcriptional, and post-translational levels. We discuss how FASN-driven lipid remodeling supports tumor proliferation, disrupts antigen presentation, alters immune cell metabolism, and suppresses ferroptosis, thereby enabling resistance to chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibitors. Emerging therapeutic strategies-including direct FASN inhibition, targeting upstream regulators, and rational metabolic-immune-ferroptosis combinatorial regimens-are explored in the context of precision oncology. Given the metabolic plasticity of cancer cells and the heterogeneous response of the tumor immune microenvironment, future advances will rely on dynamic biomarker-guided therapy and spatiotemporal profiling of FASN activity. Together, these insights position FASN not merely as a metabolic enzyme but as a versatile therapeutic axis at the intersection of cancer metabolism, immunity, and resistance.

Keywords:  FASN; combination therapy; ferroptosis; immune evasion; metabolic checkpoint; therapy resistance; tumor metabolism

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105155
Sci Transl Med. 2026 Jan 28. 18(834): eadx6873

SREBP-1 increases glucose uptake to promote tumor resistance to lysosome inhibition.

Yaogang Zhong, Feng Geng, Huali Su, Logan Mazik, Xinmin Yin, Meixia Pan, Na Li, Cheng-Yao Chiang, Jeffrey R Tonniges, Xiaokui Mo, Amy Webb, Yongchen Guo, Masha V Poyurovsky, David P Carbone, Junran Zhang, Liqing He, Xianlin Han, Xiang Zhang, Arnab Chakravarti, Qi-En Wang, Deliang Guo.

Lysosomes are critical for maintaining cellular homeostasis and nutrient availability, yet how tumor cells survive under lysosomal inhibition remains unclear. Here, we revealed that inhibiting lysosome function with chloroquine unexpectedly stimulated glucose uptake across various cancer cells. This effect was driven by sterol regulatory element-binding protein 1 (SREBP-1), a key lipogenic transcription factor, which specifically increased the expression of glucose transporters GLUT3 and GLUT6, enhancing glucose uptake and macromolecule synthesis. Elevated glucose, induced by chloroquine, stabilized SREBP cleavage-activating protein (SCAP), the activator of SREBP-1, further amplifying its activity and contributing to tumor resistance to lysosome inhibition. Disrupting this SREBP-1-glucose uptake feedforward loop by combining chloroquine with inhibitors of glucose transporters, SREBP-1, or lipogenic enzymes induced a synergistic antitumor effect in squamous cell and adenocarcinoma lung cancer patient-derived organoids and xenografts. This combination impaired mitochondrial structure and function, inducing apoptotic tumor cell death. Our study uncovers a role for SREBP-1 in regulating glucose metabolism and provides a promising therapeutic strategy that combines lysosome inhibition with glucose transporter or lipogenic enzyme inhibition for effective cancer treatment.

DOI: https://doi.org/10.1126/scitranslmed.adx6873
Int J Biol Macromol. 2026 Jan 23. pii: S0141-8130(26)00416-2. [Epub ahead of print]343(Pt 2): 150490

Targeting the WWP2-ASPP2 axis overcomes cisplatin resistance by inhibiting the mevalonate pathway in TP53-mutant bladder cancer.

Qixiang Fang, Chengyu You, Xi Xiao, Weiguang Yang, Longtu Ma, Qingchao Li, Yan Tao, Zhilong Dong.

  Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease.

Keywords:  ASPP2; Bladder cancer; Cisplatin; Mevalonate pathway; Ubiquitination; WWP2

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150490
Cell Death Differ. 2026 Jan 29.

Loss of BOK increases vulnerability of p53 deficient non-small cell lung cancer cells to ATR inhibition through its role in uridine metabolism.

Philippe JeanRichard, Aparna Ananthanarayan, Liyang Wu, Ali Jazaeri Jouneghani, Daniel Bachmann, Thomas Kaufmann.

BOK is a pro-apoptotic member of the BCL-2 family frequently repressed in cancer and with emerging roles beyond apoptosis. BOK interacts with and increases uridine monophosphate synthetase (UMPS) activity, thereby promoting uridine monophosphate (UMP) synthesis. We previously showed that BOK protein is downregulated in primary human lung cancer samples, correlating with poorer patient survival. Here, we demonstrate that BOK deficiency increases DNA damage, triggering p53 activation and cell cycle arrest in two independent non-small cell lung cancer (NSCLC) cell models that express either WT or defective p53. In a p53-deficient setting, BOK loss caused elevated baseline DNA damage rendering cells more dependent on alternative DNA repair pathways. We exploited this vulnerability by inhibiting the ATR-mediated DNA damage response pathway with the selective ATR inhibitor ceralasertib (AZD6738). ATR inhibition in BOK/p53 compound-deficient NSCLC cells exacerbated DNA damage and induced cell death, indicating a synthetic lethal interaction. The DNA damage in BOK-deficient cells was rescued by a cell permeable BOK-BH3-derived peptide, confirming the mechanistic link between BOK and UMPS. Taken together, our findings reveal a vulnerability in NSCLC, where combined loss of p53 and BOK sensitises cells to ATR inhibition. This synthetic interaction suggests that p53-deficient tumours with reduced BOK expression may be more reliant on ATR-mediated DNA repair, providing a mechanistic basis for their susceptibility to ATR inhibitors. Given the frequent inactivation of p53 in lung cancer, our study offers a rationale for clinical exploration of ATR inhibitors, in combination with standard chemotherapy, in the context of reduced BOK function. Future investigations into the broader role of BOK in genomic stability and nucleotide metabolism may uncover additional therapeutic strategies for cancers with repressed BOK.

DOI: https://doi.org/10.1038/s41418-026-01666-0
Nat Commun. 2026 Jan 27.

Ether lipids influence cancer cell fate by modulating iron uptake.

Ryan P Mansell, Sebastian Müller, Jia-Shu Yang, Sarah Innes-Gold, Sunny Das, Ferenc Reinhardt, Kim Janina Sigmund, Vaishnavi V Phadnis, Zhengpeng Wan, Jillian Stark, Daehee Hwang, Fabien Sindikubwabo, Laurène Syx, Nicolas Servant, Elinor Ng Eaton, Julio L Sampaio, George W Bell, Prathapan Thiru, Amartya Viravalli, Amy Deik, Clary B Clish, Paula T Hammond, Roger D Kamm, Adam E Cohen, Ilya Levental, Natalie Boehnke, Victor W Hsu, Kandice R Levental, Raphaël Rodriguez, Robert A Weinberg, Whitney S Henry.

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, resulting in significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids from plasma membranes also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-026-68547-5