bims-meract 2025-09-07 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–09–07
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.
Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.
Light-Activated CD36-Targeted Cuproptosis Triggers Metabolic-Immune Synergy for Precision Breast Cancer Therapy.
PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.
Tissue-specific iron levels modulate lipid peroxidation and the FLASH radiotherapy effect.
SOD2-mediated TMZ-resistant Glioblastoma Cells Exhibit Cross-resistance to Irradiation.
Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.
Lipid Composition Alters Ferroptosis Sensitivity.
Exploiting metabolic vulnerabilities to improve cancer therapeutics.
SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer.
A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer.
An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.
Rewiring of cortical glucose metabolism fuels human brain cancer growth.
Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.
Protein lipoylation in cancer: metabolic reprogramming and therapeutic potential.
Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting.
PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.
TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
Cryptotanshinone instigates ferroptosis to inhibit the development of tamoxifen-resistant breast cancer via the AMPK induced BECN1-SLC7A11 complex axis.
DDR2 confers ferroptosis resistance to cancer-associated fibroblasts and attenuates PARPi sensitivity of ovarian tumor cells.

Mol Biol Rep. 2025 Sep 03. 52(1): 861

The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.

Yan Zhang, Ying Wu, Aoxing Cheng, Fengjuan Cui, Zhenye Yang, Jing Guo.

   BACKGROUND: Malignant tumors are characterized by their reliance on hyperactive glycolysis (Warburg effect), marked by increased glucose uptake, lactate secretion, and preferential glucose flux into glycolysis and the pentose phosphate pathway (PPP). These metabolic shifts provide energy, biosynthetic precursors, and maintain redox balance, supporting tumor proliferation. However, the regulatory crosstalk between glycolysis and PPP remains poorly understood. This study investigates how tumors coordinate these pathways to drive progression via metabolic reprogramming.
METHODS AND RESULTS: Exogenous lactate supplementation in A549 cells increased the NADPH/NADP+ ratio, enhanced fatty acid synthesis, and upregulated the PPP. Western blotting revealed lactylation of glucose-6-phosphate dehydrogenase (G6PD), which correlated with intracellular lactate levels, modulated by rotenone treatment or lactate dehydrogenase A (LDHA) overexpression. LDHA knockdown significantly reduced G6PD lactylation. Enzyme assays confirmed that lactylation enhanced G6PD activity. Through truncation and mutagenesis analyses, we identified lysines 45-47 as the key lactylation site, which enhances NADP⁺ binding and promotes G6PD dimerization. Mutation of this site impaired cancer cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, G6PD lactylation serves as a metabolic switch, linking PPP activation to oncogenic progression.
CONCLUSIONS: Lactate drives tumor progression through G6PD lactylation, activating the PPP and facilitating glycolysis-PPP crosstalk. This study uncovers a novel metabolic rewiring mechanism that promotes oncogenic synergy.

Keywords:  Cancer; Glucose-6-phosphate dehydrogenase; Lactylation; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11033-025-10960-y
Nat Commun. 2025 Sep 02. 16(1): 8181

Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.

Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang, Boyi Gan, Cheng Zhan.

Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN's oxidoreductase function by occluding its active site. We also show that either restoring ALDH16A1 levels or inhibiting TXN significantly enhances the effectiveness of chemo/immunotherapy in a ferroptosis-dependent manner in SMARCA4-deficient NSCLC. Collectively, our findings elucidate an intricate SMARCA4-ALDH16A1-TXN stability/function dual regulatory axis that governs ferroptosis and informs a therapeutic strategy for overcoming resistance to chemotherapy or immunotherapy in SMARCA4-deficient NSCLC.

DOI: https://doi.org/10.1038/s41467-025-63687-6
ACS Appl Mater Interfaces. 2025 Aug 31.

Light-Activated CD36-Targeted Cuproptosis Triggers Metabolic-Immune Synergy for Precision Breast Cancer Therapy.

Shiwen Wang, Ying Shen, Binbin Hu, Qiping Wu, Nanzhou Wang, Zichao Wang, Zifeng Zhang, Yujie Li, Jianhui Jiang.

  Breast cancer therapy confronts dual challenges of metabolic plasticity-driven drug resistance and immunosuppression. To address this, we developed DCP-TPP, a therapeutic nanoplatform that integrates dysregulation of copper homeostasis and lipid metabolism for precise breast cancer therapy. Leveraging the overexpression of cluster of differentiation 36 (CD36) in breast cancer cells, DCP-TPP employs fatty acid camouflage (PCM) to deliver disulfiram (DSF) and photothermal Cu3BiS3 to cancer cells and features triphenylphosphonium (TPP) modification for targeted mitochondrial drug delivery. Near-infrared (NIR) irradiation triggers the phase transition of DCP-TPP's outer layer, inducing spatiotemporal release of DSF to liberate copper ions from inert Cu3BiS3, thereby generating diethyldithiocarbamate-copper complex (CuET). This disrupts copper homeostasis and induces cuproptosis, which subsequently triggers S-acetyltransferase (DLAT) aggregation, impairing tricarboxylic acid (TCA) cycle flux, acetyl-CoA production, ATP citrate lyase (Acly)-dependent lipogenesis, and ultimately collapses mitochondrial oxidative phosphorylation. Multiomics profiling revealed oleic acid depletion, arachidonic acid oxidation, and glutathione exhaustion, collectively amplifying metabolic collapse. DCP-TPP-induced cell death enhanced dendritic cell (DC) activation and CD8+ T cell infiltration. In breast cancer models, DCP-TPP achieved 90.9% tumor suppression, with 60% of mice resisting rechallenge. By transforming lipid metabolic dependency into a therapeutic vulnerability and coupling it with copper ion toxicity, DCP-TPP offers a promising strategy for breast cancer therapy.

Keywords:  CD36; cancer immunotherapy; cuproptosis; lipid metabolism reprogram; phase-transitional material

DOI:  https://doi.org/10.1021/acsami.5c11318
Cancer Res. 2025 Sep 05.

PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.

Katrina I Paras, Julia S Brunner, Angela M Montero, Jacob A Boyer, Benjamin T Jackson, Sangita Chakraborty, Abigail Xie, Kristina Guillan, Armaan Siddiquee, Lourdes Pajuelo Torres, Joshua D Rabinowitz, Andrew L Kung, Daoqi You, Filemon S Dela Cruz, Lydia W S Finley.

PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here, we showed that PAX3-FOXO1+ RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1+ cells displayed increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence was rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimicked the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slowed the growth of multiple PAX3-FOXO1+ tumor xenograft models but not the fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominate methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0315
Cell Death Dis. 2025 Sep 02. 16(1): 668

Tissue-specific iron levels modulate lipid peroxidation and the FLASH radiotherapy effect.

Nuria Vilaplana-Lopera, Jiyoung Kim, Gilyeong Nam, Iain D C Tullis, Salome Paillas, Jia-Ling Ruan, Pei Ju Lee, Yanyan Jiang, Sohee Park, Tianxu Hou, Ayesha Nasir, Eve Charlesworth, Ellie Walker, Ammar Abu-Halawa, Mark A Hill, Changhoon Choi, Ik Jae Lee, Youngtae Jeong, Samira Lakhal-Littleton, Chee Kin Then, Shing-Chuan Shen, Amato J Giaccia, Kristoffer Petersson, Eui Jung Moon.

Iron is vital to living cells, playing a key role in cellular respiration, DNA synthesis, and various metabolic functions. Importantly, cancer cells have a higher dependency on iron compared to normal cells to support their rapid growth and survival. Due to this fact, tumors are more vulnerable to ferroptosis, an iron-dependent form of regulated cell death. Radiation therapy (RT), a standard treatment for many cancer patients, is known to induce ferroptosis. Ultra-high dose rate FLASH RT offers an improved therapeutic window by minimizing damage to normal tissues while preserving tumor control. However, the precise biological mechanisms behind the protective effects of FLASH RT on normal tissues remain unclear. In this study, we propose that variations in lipid peroxidation and ferroptosis, driven by intrinsic differences in iron levels between normal and cancerous tissues, contribute to this effect. Our findings show that FLASH RT increases lipid peroxidation and induces ferroptosis in tumor cells but does not significantly elevate lipid peroxidation and ferroptosis in normal tissues compared to conventional RT. To determine whether raising iron levels in normal tissues could abrogate the protective effects of FLASH, mice were fed a high-iron diet before RT. A high-iron diet before and after RT reversed the protective effect of FLASH, resulting in increased intestinal damage and lipid peroxidation. This suggests that baseline iron levels and iron-driven lipid peroxidation are critical factors in mediating the protective outcomes of FLASH RT. Overall, our study sheds light on the role of iron in modulating RT responses and provides new mechanistic insights into how FLASH RT influences normal and cancerous tissues.

DOI: https://doi.org/10.1038/s41419-025-07988-0
Anticancer Res. 2025 Sep;45(9): 3711-3718

SOD2-mediated TMZ-resistant Glioblastoma Cells Exhibit Cross-resistance to Irradiation.

Wei-Ting Hsueh, Kwang-Yu Chang, Jian-Ying Chuang, Ming-Sheng Liu, Pei-Hsuan Chung, Jui-Mei Chu, Chia-Hung Chien.

   BACKGROUND/AIM: Glioblastoma (GBM) is a highly aggressive brain tumor associated with poor prognosis and frequent resistance to standard treatments, including temozolomide (TMZ) and radiotherapy. Our previous study identified superoxide dismutase 2 (SOD2) as a key contributor to TMZ resistance through enhanced antioxidant defenses. This study aimed to determine whether SOD2 also plays a role in reduced radiation sensitivity in TMZ-resistant GBM cells.
MATERIALS AND METHODS: Clonogenic assays were used to assess the radiation response of TMZ-resistant U87MG and A172 cells. A pharmacological SOD inhibitor (SODi), sodium diethyldithiocarbamate trihydrate, was applied to evaluate its effect on radiosensitivity. An in vivo subcutaneous xenograft model derived from resistant U87MG cells was used to examine the efficacy of combination therapy with TMZ, irradiation, and SODi. Tumor progression was monitored using a bioluminescence imaging system.
RESULTS: TMZ-resistant GBM cells demonstrated enhanced survival after 4 Gy radiation exposure, indicating a cross-resistance phenotype. SODi treatment significantly reduced colony formation in vitro and restored sensitivity to irradiation. In vivo, the triple combination of TMZ, irradiation, and SODi markedly suppressed tumor growth compared to other treatment groups.
CONCLUSION: SOD2 contributes to both TMZ and radiation resistance in GBM. Targeting resistance-associated pathways may offer a promising strategy to improve the efficacy of radiochemotherapy in treatment-refractory glioblastoma.

Keywords:  Glioblastoma; SOD2; cross-resistance; irradiation; temozolomide resistance

DOI:  https://doi.org/10.21873/anticanres.17722
Adv Sci (Weinh). 2025 Sep 04. e05356

Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.

Xinyue Zhang, Leng Han, Zimu Wang, Hanghui Yu, Jiao Liu, Rui Kang, Daolin Tang, Zhengjia Liu, Xianlong Du, Enyong Dai.

  Ferroptosis, characterized by iron-dependent lipid peroxidation, is a form of oxidative cell death increasingly recognized for its role in cancer therapy. The susceptibility of cancer cells to ferroptosis varies, highlighting the need to elucidate its underlying metabolic mechanisms. This study identifies a novel pathway in which the E3 ubiquitin ligase, praja ring finger ubiquitin ligase 1 (PJA1), mediates the proteasomal degradation of glyoxalase I (GLO1) exclusively in ferroptosis-sensitive cancer cells. This degradation pathway is absent in ferroptosis-resistant cells, resulting in differing management of methylglyoxal (MGO). The accumulation of MGO, as opposed to its clearance, facilitates ferroptosis by promoting the autophagic degradation of key anti-ferroptotic proteins, specifically ferritin and glutathione peroxidase 4 (GPX4). Targeting the PJA1-GLO1 axis through genetic and pharmacological means enhances the sensitivity of tumors to ferroptosis inducers across various preclinical models, including xenografts, orthotopic, and patient-derived models. Additionally, clinical data demonstrate that elevated GLO1 expression is associated with poorer survival outcomes in pancreatic cancer patients. These findings suggest that modulating the MGO metabolism pathway, particularly through targeting the PJA1-GLO1 axis, can amplify the effectiveness of ferroptosis-inducing agents in cancer therapy.

Keywords:  autophagy; degradation; ferroptosis; methylglyoxal; pancreatic cancer

DOI:  https://doi.org/10.1002/advs.202505356
Cancer Res. 2025 Sep 05.

Lipid Composition Alters Ferroptosis Sensitivity.

Vivian S Park, Lauren E Pope, Justin P Ingram, Grace A Alchemy, Julie J Purkal, Magdalena B Murray, Sha Jin, Eli Y Andino-Frydman, Sanjana Singh, Anlu Chen, Priya Narayanan, Sarah Kongpachith, Darren C Phillips, Scott J Dixon, Relja Popovic.

Ferroptosis is a regulated non-apoptotic cell death process characterized by iron-dependent lipid peroxidation. Peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) is necessary for the execution of ferroptosis. Glutathione peroxidase 4 (GPX4) suppresses ferroptosis by reducing lipid hydroperoxides to lipid alcohols. GPX4 may be a useful target for drug development, highlighting the need to identify factors that govern GPX4 inhibitor sensitivity. Here, we found that reduced GPX4 expression was sufficient to induce ferroptosis in multiple adherent (2D) cancer cell cultures. However, lower GPX4 protein levels did not consistently affect tumor xenograft growth in mice. Culturing cells as spheroids (3D) was sufficient to reduce sensitivity to pharmacological GPX4 inhibition. Mechanistically, growth in 3D versus 2D conditions upregulated expression of the monounsaturated fatty acid (MUFA) biosynthetic gene stearoyl-CoA desaturase (SCD), altering the ratio of MUFA-PLs to PUFA-PLs in a direction favoring ferroptosis resistance. Similar shifts in MUFA-PL to PUFA-PL ratios were observed in xenograft tumors. Thus, lipidome remodeling in 3D growth conditions and in vivo may limit GPX4 inhibitor efficacy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4207
Trends Endocrinol Metab. 2025 Aug 28. pii: S1043-2760(25)00171-7. [Epub ahead of print]

Exploiting metabolic vulnerabilities to improve cancer therapeutics.

Ibrahim H Ibrahim, Cheng-Han Lin, Ming Zhou, Jer-Yen Yang, Robert W Sobol, Ming Tan.

  Over the past decade, our understanding of cancer metabolism has advanced significantly, revealing a complex and dynamic landscape of metabolic reprogramming that facilitates tumor progression and promotes therapeutic resistance. To survive under stressful conditions, cancer cells undergo crucial metabolic adaptations while also creating vulnerabilities that can be exploited for therapeutic purposes. Here, we discuss the evolving understanding of cancer cell metabolic adaptation in the tumor environment and the recent advances in identifying potential therapeutic mechanisms, including synthetic lethality, post-translational modifications (PTMs), as well as the interplay between metabolism and epigenetics. Furthermore, we discuss the integration of metabolic targeting with immune-based therapies and provide insights underscoring the potential of metabolic interventions to resensitize drug-resistant cancers and enhance efficacy for cancer treatment.

Keywords:  cancer metabolism; immuno-metabolism; metabolic vulnerabilities; synthetic lethality; therapeutic resistance

DOI:  https://doi.org/10.1016/j.tem.2025.08.002
Cell Rep. 2025 Sep 01. pii: S2211-1247(25)00910-6. [Epub ahead of print]44(9): 116139

SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer.

Xiaojun Zhou, Genxin Wang, Yuhang Wu, Mingzhi Wu, Xiang Zhai, Chenhui Tian, Edward V Prochownik, Congqing Jiang, Youjun Li.

  Tumor metabolic reprogramming is critical for providing energy to support proliferation and resistance to stress-induced cell death. However, the regulatory mechanisms linking these processes remain incompletely understood. Here, using untargeted metabolomics, we demonstrate that creatine potently induces ferroptosis in colorectal cancer (CRC). Mechanistically, creatine binds extracellular signal-regulated kinase 2 (ERK2), impairing its activation by mitogen-activated protein kinase kinase 1 (MEK1). Inhibiting the creatine transporter SLC6A8 reduces creatine uptake and activates ERK2. Activated ERK2 then binds, phosphorylates ferroptosis suppressor protein 1 (FSP1) at Thr109, and stabilizes it to inhibit ferroptosis. Creatine supplementation suppresses tumor growth, enhances CD8+ T cell infiltration, and sensitizes tumors to anti-programmed cell death protein 1 (PD-1) immunotherapy. Our study identifies ERK2 as a creatine sensor regulating FSP1 stability and ferroptosis resistance, highlighting the therapeutic potential of creatine supplementation in combination cancer immunotherapy.

Keywords:  CP: Cancer; CP: Metabolism; creatine; ferroptosis; mmune checkpoint blockade; tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.celrep.2025.116139
Cell Stem Cell. 2025 Aug 28. pii: S1934-5909(25)00298-X. [Epub ahead of print]

A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer.

Becky K C Chan, Chu Zhang, Chi Him Poon, Marie H Y Lee, Hoi Yee Chu, Bei Wang, Sin-Guang Chen, Helen H N Yan, Suet Yi Leung, Alan S L Wong.

  The discrepancy between organoid and immortalized cell line cultures for cancer target discovery remains unclear. Here, our multi-tiered clustered regularly interspaced short palindromic repeats (CRISPR) screens reveal in vivo-relevant metabolic dependencies and synthetic lethal pairs that can be uncovered with tumor organoids but not cell lines or even three-dimensional (3D) spheroids. These screens identify lanosterol synthase and acetyl-coenzyme A (CoA) carboxylase inhibitors as effective treatments that impede xenografted tumor growth in mice. These lipid metabolic inhibitors exhibit nanomolar half-maximal inhibitory concentration (IC50) values across diverse human gastric cancer organoids resistant to first-line treatments. Mechanistically, gastric cancer organoids and in vivo tumors exhibit lipid metabolic adaptations not seen in two-dimensional (2D) in vitro cultures. Additionally, enteric neurons modulate lipid metabolism in tumor organoids, altering drug sensitivity by up to two orders of magnitude. A neuron-cocultured CRISPR screen further reveals that acetyl-CoA carboxylase expression determines lanosterol synthase inhibitor efficacy. These findings highlight the critical roles of organoid environment and neuronal interaction in cancer lipid reliance.

Keywords:  CRISPR screen; cancer neuroscience; cholesterol; coculture; enteric neuron; fatty acid; gastric cancer; lipid metabolism; organoid; tumor vulnerability

DOI:  https://doi.org/10.1016/j.stem.2025.08.006
Sci Transl Med. 2025 Sep 03. 17(814): eadt5511

An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.

Kathleen M McAndrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra.

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small-molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8+ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME), enabling responses to immune checkpoint blockade. In the long term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells and enhanced expression of immune checkpoints in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.

DOI: https://doi.org/10.1126/scitranslmed.adt5511
Nature. 2025 Sep 03.

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O'Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U Kothari, Navyateja Korimerla, Donna M Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C Andren, Junyoung O Park, Johanna Ten Hoeve, Vijay Tarnal, Kimberly A Redic, Nathan R Qi, Joshua L Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Krithika Suresh, Jann N Sarkaria, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Erina Vlashi, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.

The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

DOI: https://doi.org/10.1038/s41586-025-09460-7
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01005-8. [Epub ahead of print]44(9): 116234

Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.

Shuang Ma, Jianhua Qin, Yao Zhang, Jing Luan, Na Sun, Guoyuan Hou, Jiyuan He, Yang Xiao, Wei Zhang, Minghui Gao.

  Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.

Keywords:  AMPK; CP: Immunology; CP: Metabolism; FSP1; NRF2; chemotoxicity; ferroptosis; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.celrep.2025.116234
Cell Death Discov. 2025 Sep 02. 11(1): 420

Protein lipoylation in cancer: metabolic reprogramming and therapeutic potential.

Sainan Li, Yingchao Liu, Wanye Hu, Aoli Deng, Xueying Ren, Lulu Chen, Yajuan Lu, Yunyi Wu, Hangqi Huang, Jinghao Cao, Jing Du, Jun Xia, Yanchun Li.

Protein lipoylation, a mitochondria-specific post-translational modification (PTM) evolutionarily conserved from bacteria to mammals, plays critical role in metabolic processes. In humans, four identified lipoylated proteins serve as essential components of key enzymes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. The dynamic addition or removal of lipoylation modifications critically regulates the functional activity of these enzymes, with dysregulation strongly associated with cancers. Notably, cancer-associated metabolic reprogramming frequently coincides with functional impairment of lipoylated proteins, which subsequently modulates tumor growth through metabolic adaptation. In this review, we systematically summarized the biosynthesis of lipoic acid (LA), introduced the basic structure of lipoylated protein and presented the regulation of lipoylation. Since metabolic reprogramming is an important feature of tumorigenesis, we discussed the relationship between protein lipoylation and tumor metabolic reprogramming. Cuproptosis is a novel form of cell death characterized by copper-mediated lipoylation, which disrupts mitochondrial metabolism and induces cell death through the aggregation of lipoylated proteins in the TCA cycle. We highlighted the therapeutic potential of targeting lipoylation to disrupt cancer cell energy metabolism, particularly through cuproptosis. These insights reveal the intricate interplay between lipoylation and cancer progression and open new avenues for developing targeted therapies. Furthermore, we proposed innovative combinatorial strategies leveraging the crosstalk between cuproptosis and ferroptosis to overcome tumor drug resistance. These insights establish lipoylation as a promising therapeutic axis for developing precision cancer therapies targeting metabolic vulnerabilities.

DOI: https://doi.org/10.1038/s41420-025-02718-z
Cell Commun Signal. 2025 Aug 28. 23(1): 384

Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting.

Chujiao Hu, Zhirui Zeng, Xin Bao, Dahuan Li, Huading Tai, Haohao Zeng, Cheng Luo, Lei Tang, Tengxiang Chen, Shi Zuo.

  Celecoxib, a selective COX-2 inhibitor, has demonstrated anti-liver cancer effects in various preclinical models and clinical traits. However, prolonged use of celecoxib can lead to drug resistance, necessitating higher doses to maintain efficacy, which often results in severe side effects, limiting its clinical application. This study aimed to identify strategies to overcome celecoxib resistance in liver cancer. CRISPR/Cas9 screening revealed that liver cancer cells compensated for celecoxib treatment by upregulating ALOX and CYP enzymes, facilitating AA metabolism to produce alternative downstream products. STAT6 was identified as a key regulator of ALOX15, ALOX12, and CYP2E1, acting as a resister to celecoxib. Celecoxib stimulation leaded to increased phosphorylation of STAT6, enhanced binding to the promoters of target genes such as ALOX15, and upregulation of downstream gene expression. Knockdown of STAT6 significantly enhanced celecoxib sensitivity in vitro and in vivo by blocking AA shunting mediated by these enzymes. Furthermore, AS1517499, a STAT6 inhibitor, showed strong synergy with celecoxib in liver cancer cells by inhibiting AA shunting. In conclusion, targeting STAT6 enhances the efficacy of celecoxib in liver cancer by suppressing AA shunting. The combination of AS1517499 and celecoxib holds promise as a novel therapeutic strategy for liver cancer.

Keywords:  AA shunting; Celecoxib; Liver cancer; STAT6

DOI:  https://doi.org/10.1186/s12964-025-02374-x
Cell Rep. 2025 Aug 29. pii: S2211-1247(25)00970-2. [Epub ahead of print]44(9): 116199

PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.

Gurpreet K Arora, Ryan M Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Cynthia Y Zhang, Shea F Grenier, Li Ling, Sophia Crabtree, Guillem Lambies, Chantal Pauli, David A Scott, Yoav Altman, Benji Portillo, Rabi Murad, Cosimo Commisso, Brooke M Emerling.

  Phosphoinositide kinases generate distinct phosphoinositides that regulate pathways to support tumorigenesis. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. We identify PI5P4Kα as a critical dependency to support the unique metabolic demands of PDAC cells through its key role in the acquisition of essential metabolic substrates, including glucose and iron. Our data show that inhibition of PI5P4Kα creates a metabolic bottleneck that PDAC cells cannot overcome through adaptive shifts, leading to cancer-specific apoptotic cell death that is reversible by iron supplementation. Notably, we find that PI5P4Kα knockdown suppresses tumor growth in a xenograft mouse model of PDAC. These results not only illuminate the mechanistic underpinnings of PI5P4Kα function in PDAC but also position it as a promising therapeutic target for this disease.

Keywords:  CP: Cancer; CP: Metabolism; PI5P4K; PIP4K; apoptosis; autophagy; glucose; iron; metabolism; nutrient stress; pancreatic cancer; phosphoinositide kinase

DOI:  https://doi.org/10.1016/j.celrep.2025.116199
bioRxiv. 2025 Aug 31. pii: 2025.08.28.672283. [Epub ahead of print]

TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.

Ahmed M Mamdouh, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Nishtha Chitkara, Leah Hogdal, R Coleman Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of acute myeloid leukemia (AML), driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy, decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this (post-MOMP brake) is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.

DOI: https://doi.org/10.1101/2025.08.28.672283
Exp Cell Res. 2025 Aug 26. pii: S0014-4827(25)00326-X. [Epub ahead of print]451(2): 114726

Cryptotanshinone instigates ferroptosis to inhibit the development of tamoxifen-resistant breast cancer via the AMPK induced BECN1-SLC7A11 complex axis.

Mengning Zhang, Hang Chen, Lujia Zhang, Aini Yuan, Jing Liu, Qi Wang, Tiantian Lei, Hong Zhao.

  The resistance of oestrogen receptor-positive (ER+) breast cancer to tamoxifen (TAM) therapy represents a significant challenge in the clinical management of ER + breast cancer. It has been demonstrated that tamoxifen-resistant breast cancer is sensitive to ferroptosis. Consequently, the targeted intervention of Solute Carrier Family 7 Member 11 (SLC7A11) to promote ferroptosis represents a promising means of treating this form of cancer. Cryptotanshinone (CTS), a fat-soluble diterpene derivative extracted from Salvia miltiorrhiza, has been demonstrated to possess favorable anti-breast cancer activity. However, it remains unclear whether CTS is effective against tamoxifen-resistant breast cancer. The objective of this study was to ascertain whether CTS-induced ferroptosis could be employed to inhibit tamoxifen-resistant breast cancer, and to elucidate the potential mechanism of action. CTS was observed to inhibit the proliferation of TAM-resistant MCF-7 cells, and this effect could be synergistically amplified by co-treatment with TAM. Furthermore, CTS was also demonstrated to increase the sensitivity of TAM-resistant MCF-7 cells to TAM. Additionally, CTS has been observed to promote ferroptosis in TAM-resistant MCF-7 cells, resulting in elevated levels of the associated indices 4 Hydroxynonenal (4HNE), Lipid Reactive oxygen species (ROS), ROS and Fe2+, while concurrently reducing the levels of SLC7A11 and Glutathione peroxidase 4 (GPX4). Further studies demonstrated that CTS promoted TAM-resistant MCF-7 cell ferroptosis based on the formation of the BECN1-SLC7A11 complex, which resulted in a decrease in SLC7A11. Validation experiments demonstrated that CTS-induced BECN1-SLC7A11 complex formation is dependent on AMPK activation. Xenotumour transplantation experiments revealed that CTS combined with TAM inhibits TAM-resistant breast cancer and promotes ferroptosis through the AMPK/BECN1/SLC7A11 axis. In conclusion, CTS retarded the growth of TAM-resistant breast cancer tumours by activating AMPK to promote the formation of the BECN1-SLC7A11 complex and inhibiting the expression of SLC7A11, thereby inducing ferroptosis.

Keywords:  AMPK; BECN1; Cryptotanshinone; Ferroptosis; Tamoxifen-resistant breast cancer

DOI:  https://doi.org/10.1016/j.yexcr.2025.114726
Mol Cancer Res. 2025 Sep 04.

DDR2 confers ferroptosis resistance to cancer-associated fibroblasts and attenuates PARPi sensitivity of ovarian tumor cells.

Julien Lesage, Alessandra DiMauro, Angela M Schab, Seth Stidham, Mary M Mullen, Katherine C Fuh, Gregory D Longmore.

In ovarian cancer, resistance to conventional treatments has prompted the search for alternative targets and/or cells within the tumor microenvironment (TME) that could enhance tumor cell death. Ferroptosis, an iron-dependent, lipid peroxide-triggered form of cell death, is one such pathway. Cancer‑associated fibroblasts (CAFs) are key stromal cells in the ovarian TME that can impact therapeutic responses. Using various genetic approaches, we generated multiple DDR2‑expressing and DDR2‑deficient human ovarian tumor and mouse breast tumor CAFs. We find that DDR2 expression in CAFs protects these cells from ferroptosis by regulating the xCT-GSH-GPX4 antioxidant pathway and cellular iron metabolism. Specifically, DDR2 regulates xCT expression through non-canonical p62‑dependent NRF2 activation and the labile iron pool (LIP) by controlling ferritinophagy. CAFs secrete factors, in a DDR2-dependent manner, that provide protection to ovarian tumor cells against Olaparib‑induced cell death, a clinically relevant PARP inhibitor (PARPi). Finally, we find that high expression of DDR2 in the stromal cells of human ovarian tumors is associated with poor response to PARPi in clinical trials. These findings suggest that ferroptotic regulation by DDR2 in ovarian tumor CAFs could impact therapeutic sensitivity and resistance to PARPi. Implications: The action of the collagen receptor tyrosine kinase DDR2 in CAFs confers PARPi protection to Ovarian tumor cells, by protecting CAFs from ferroptosis.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0268