bims-meract 2025-11-23 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–11–23
eighteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.
Spermidine Secreted by Apoptotic Cells Enhances Chemotherapy Resistance by Modulating β-Catenin Activity in Osteosarcoma.
P2Y12 Receptor Antagonists Decrease the Radiation Resistance of B16 Melanoma by Suppressing DNA Repair.
Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models.
Regorafenib promotes ferroptosis in acute myeloid leukemia by upregulating NOX4.
ACSL6 modulates docosahexaenoic acid-induced cytotoxicity to potentiate chemotherapy response in colorectal and breast cancer.
Triggering ferroptosis to tackle cancer.
Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.
Mitophagy is responsible to ionizing radiation but plays a very limited role in the radiosensitivity of adenocarcinoma cells.
Targeting cancer stem-like cells via cholesterol modulation and ferroptosis induction using a multifunctional nanoplatform to overcome drug resistance.
MMP28 promotes tumorigenesis and gemcitabine resistance in pancreatic cancer by promoting glycolysis through interaction with SND1.
Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia.
Anti-tumor response by targeting glucose metabolism and depletion of membrane cholesterol in breast cancer and melanoma cells.
Alteration of metabolic activity regulates mitochondrial temperature in diagnosis in HepG2 hepatocellular carcinoma cells.
Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC.
FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer.
CD36 Inhibits Triple-Negative Breast Cancer Progression by Transcriptionally Upregulating Caveolin-1 and Promoting Lipid-Reactive Oxygen Species-Related Ferroptosis.
DRESIS 2.0: the comprehensive landscape of drug resistance information.

Cancer Res. 2025 Nov 21.

Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Rajendra Kumar, Sheila Jonnatan, David E Sanin, Varsha Vakkala, Anoushka Kadam, Shivani Kumar, D Marc Rosen, Susan L Dalrymple, Liang Zhao, Jackson R Foley, Cassandra E Holbert, Ashley Nwafor, Srushti Kittane, Elizabeth Penner, Petya Apostolova, Samuel Warner, Chi V Dang, Eneda Toska, Elizabeth A Thompson, John T Isaacs, Angelo M De Marzo, W Nathaniel Brennen, Erika L Pearce, Tracy Murray Stewart, Robert A Casero, Samuel R Denmeade, Laura A Sena.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. AR binding at enhancer sites upstream of the ODC1 promoter increased the abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhanced prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased efficacy of SPA. Mechanistically, AR activation combined with loss of negative feedback by polyamines increased the activity of S-adenosylmethionine decarboxylase 1 (AMD1), leading to depletion of its substrate S-adenosylmethionine and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic castration-resistant prostate cancer. Pharmacodynamic studies of this therapeutic combination in the first five patients on trial indicated that this approach effectively depleted polyamines in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1532
Clin Cancer Res. 2025 Nov 20.

Spermidine Secreted by Apoptotic Cells Enhances Chemotherapy Resistance by Modulating β-Catenin Activity in Osteosarcoma.

Qifeng Yu, Mei Geng, Yanghu Lu, Xiangyang Zhang, Shichao Tong, Yi Wang, Xiaojian Ye, Wei Xu, Zhikun Li.

PURPOSE: Chemoresistance remains a key hurdle in osteosarcoma (OS) therapy. This study aims to delineate the role and underlying mechanisms of spermidine (SPD) in OS chemoresistance.
EXPERIMENTAL DESIGN: Using OS cell lines and xenografts, we combined flow cytometry, Western blotting, proteomic mass spectrometry, and RNA sequencing to characterize SPD-driven changes in cellular pathways and resistance signatures. We tested whether pharmacological inhibition of SPD biosynthesis, alone or in combination with standard chemotherapy, improves therapeutic response in vivo.
RESULTS: Following chemotherapy, either cisplatin (CDP) or doxorubicin (DOX), apoptotic OS cells exhibit an upregulation of ornithine decarboxylase 1 (ODC1) and spermidine synthase (SRM), key enzymes involved in SPD synthesis, resulting in heightened levels of this polyamine. SPD diminishes the therapeutic efficacy of CDP and DOX in OS cells, both in vitro and in vivo. Mechanistically, SPD enhances β-catenin activity, which subsequently upregulates genes associated with cancer stemness and ATP-binding cassette (ABC) transporters, both of which are implicated in drug resistance. Furthermore, pharmacological inhibition of SPD synthesis using DFMO markedly increases the chemosensitivity of OS cells to CDP and DOX.
CONCLUSIONS: These findings illuminate the critical role of apoptotic cell metabolites in mediating treatment resistance and suggest that targeting SPD may offer a promising therapeutic strategy to augment the effectiveness of chemotherapy in OS.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4275
Biol Pharm Bull. 2025 ;48(11): 1775-1783

P2Y12 Receptor Antagonists Decrease the Radiation Resistance of B16 Melanoma by Suppressing DNA Repair.

Yuma Mizoguchi, Natsuki Mori, Kazuki Kitabatake, Shuhei Ogawa, Fumiaki Uchiumi, Mitsutoshi Tsukimoto.

  Radiation therapy exerts its therapeutic effect by killing cells via the induction of DNA double-strand breaks (DSBs) in malignant tumors, but cancer cells can repair damaged DNA, leading to radiation resistance (radioresistance). Therefore, a radiosensitizing effect can be expected by suppressing mechanism(s) involved in DNA repair after irradiation. Here, we show that the P2Y12 receptor is involved in the radioresistance of mouse B16 melanoma cells, and that P2Y12 antagonist treatment decreases the radioresistance both in vitro and in vivo by inhibiting DNA repair after γ-irradiation. P2Y12 receptor antagonists Clopidogrel and PSB0739 increased cellular sites of unrepaired DNA by suppressing the DNA damage response (DDR) after γ-irradiation and enhanced radiation-induced proliferative death in B16 melanoma cells. On the other hand, ADP (a P2Y12 receptor agonist) enhanced DDR after γ-irradiation and increased radioresistance. Knockdown of the P2Y12 receptor resulted in an increase of unrepaired DNA damage and enhanced proliferative death after γ-irradiation. Suppression of the P2Y12 receptor also contributed to the enhancement of the cancer-killing effect of γ-irradiation, even in fractionated irradiation samples in which the cancer-killing effect decreased due to sublethal damage recovery. Finally, PSB0739 significantly enhanced the antitumor effect of γ-irradiation in vivo. Our results suggest that P2Y12 receptor antagonists are promising candidates as radiosensitizers to improve radiation therapy.

Keywords:  DNA damage response; P2Y12 receptor; cancer; radiation therapy; sublethal damage recovery

DOI:  https://doi.org/10.1248/bpb.b25-00420
J Clin Invest. 2025 Nov 17. pii: e193370. [Epub ahead of print]135(22):

Targeting plasticity in the pyrimidine synthesis pathway potentiates macrophage-mediated phagocytosis in pancreatic cancer models.

Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan.

  Macrophage-mediated phagocytosis plays a critical role in the elimination of cancer cells and shaping antitumor immunity. However, the tumor-intrinsic pathways that regulate cancer cell sensitivity to macrophage-mediated phagocytosis remain poorly defined. In this study, we performed a genome-wide CRISPR screen in murine pancreatic cancer cells cocultured with primary macrophages and identified that disruption of the tumor-intrinsic pyrimidine synthesis pathway enhances phagocytosis. Mechanistically, we discovered that macrophages inhibit the pyrimidine salvage pathway in tumor cells by upregulating Upp1-mediated uridine degradation through cytokines TNF-α and IL-1. This shift increased tumor cells' reliance on de novo pyrimidine synthesis. As a result, tumor cells with impaired de novo pyrimidine synthesis showed depleted UMP and displayed enhanced exposure of phosphatidylserine (PtdSer), a major "eat-me" signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models, Cad-deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the Cad-mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-α. Pharmacological inhibition of DHODH, which blocks de novo pyrimidine synthesis, similarly decreased tumor burden with enhanced phagocytosis in pancreatic cancer models. These findings highlight the critical role of the tumor-intrinsic pyrimidine synthesis pathway in modulating macrophage-mediated antitumor immunity, with potential therapeutic implications.

Keywords:  Cancer immunotherapy; Immunology; Innate immunity; Macrophages; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI193370
Biochem Biophys Res Commun. 2025 Nov 14. pii: S0006-291X(25)01697-3. [Epub ahead of print]792 152981

Regorafenib promotes ferroptosis in acute myeloid leukemia by upregulating NOX4.

Rong Mu, Xintong Pei, Nahua Xu, Baiping Liu, Lubin Liu, Hui Li, Qi Yao.

  Acute Myeloid Leukemia (AML) is a challenging hematologic malignancy with limited long-term survival rates. This study explored the role of Regorafenib in promoting ferroptosis in AML cells through modulation of NOX4 expression. We demonstrated that Regorafenib sensitizes AML cells to ferroptosis induction both in vitro and in vivo. Mechanistically, Regorafenib treatment upregulated the expression of the NOX4 protein, leading to increased lipid peroxidation. Consistently, NOX4 inhibitor significantly rescued the ferroptosis promoting effect of Regorafenib. Importantly, combining Regorafenib with ferroptosis inducers showed synergistic effect of blocking tumor growth in vivo. This study highlights the potential of Regorafenib as an agent that modulates NOX4 expression, offering new insights into the treatment of AML.

Keywords:  AML; Ferroptosis; NOX4; Regorafenib

DOI:  https://doi.org/10.1016/j.bbrc.2025.152981
Oncogenesis. 2025 Nov 21. 14(1): 45

ACSL6 modulates docosahexaenoic acid-induced cytotoxicity to potentiate chemotherapy response in colorectal and breast cancer.

I-Sung Chen, Chi-Che Hsieh, Chun-Chun Li, You-Lin Wei, Chao-Chun Cheng, Sheng-Wei Feng, Hsin-Lun Lee, Nai-Jung Chiang, Che-Hung Shen, Hui-Ping Hsu.

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, exhibits anticancer properties by modulating cell membrane composition, inducing oxidative stress, and triggering ferroptosis. Acyl-CoA synthetase long chain family member 6 (ACSL6) catalyzes DHA activation, yet its role in tumor growth and tumor sensitivity to DHA treatment remains unclear. We characterized the role of ACSL6 in regulating cell growth and DHA sensitivity in vitro cancer cells and in vivo xenograft tumors. ACSL6 expression was positively associated DHA sensitivity and enhanced chemotherapy efficacy in both colorectal and breast cancer cell lines, as well as with improved responsiveness to standard treatments in patients with these cancers. ACSL6 suppressed cell growth, inhibited AKT/ERK signaling, reduced ATP production, and activated AMPK signaling, supporting its tumor-suppressive role. Importantly, ACSL6 knockdown increased GPX4 expression and colony growth, partially rescuing DHA-induced suppression, whereas ACSL6 overexpression enhanced DHA-mediated GPX4 reduction and colony inhibition, effects reversible by RSL3 or ferrostatin-1. Moreover, ACSL6 enhances DHA-induced lipid peroxidation. These support that ACSL6 enhances DHA-induced ferroptosis, leading to growth suppression. In vivo, DHA supplementation potentiated oxaliplatin-suppressed tumor growth in tumors with upregulated ACSL6 expression, accompanied by GPX4 reduction. Together, these findings highlight ACSL6 as a critical determinant of DHA sensitivity in cancer, underscoring its potential as a predictive biomarker for chemotherapy-DHA combination strategies. By modulating key metabolic and signaling pathways, ACSL6 could influence cellular susceptibility to ferroptosis and may guide therapeutic approaches that enhance chemotherapy through DHA supplementation.

DOI: https://doi.org/10.1038/s41389-025-00588-9
Nat Rev Drug Discov. 2025 Nov 19.

Triggering ferroptosis to tackle cancer.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-025-00189-6
Cancer Res. 2025 Nov 17.

Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.

Maria Dubisova, Klara Bohacova, Zuzana Nahacka, Daniel Kraus, Jaromir Novak, Sarka Dvorakova, Petra Brisudova, Natalie Danesova, Saba Selvi, Mariia Hrysiuk, Berwini B Endaya, Panagiotis Botsios, Dan-Diem Thi Le, Monika Novotna, Sona Vodenkova, Jaroslav Truksa, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Stepana Boukalova, Michael V Berridge, Renata Zobalova, Jiri Neuzil.

Cancer cells with severe defects in mitochondrial DNA (mtDNA) can import mitochondria via horizontal mitochondrial transfer (HMT) to restore respiration. Mitochondrial respiration is necessary for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme of the inner mitochondrial membrane that catalyzes the fourth step of de novo pyrimidine synthesis. Here, we investigated the role of de novo synthesis of pyrimidines in driving tumor growth in mtDNA-deficient (ρ0) cells. While ρ0 cells grafted in mice readily acquired mtDNA, this process was delayed in cells transfected with alternative oxidase (AOX), which combines the functions of mitochondrial respiratory complexes III and IV. The ρ0 AOX cells were glycolytic but maintained normal DHODH activity and pyrimidine production. Deletion of DHODH in a panel of tumor cells completely blocked or delayed tumor growth. The grafted ρ0 cells rapidly recruited tumor-promoting/stabilizing cells of the innate immune system, including pro-tumor M2 macrophages, neutrophils, eosinophils, and mesenchymal stromal cells (MSCs). The ρ0 cells recruited MSCs early after grafting, which were potential mitochondrial donors. Grafting MSCs together with ρ0 cancer cells into mice resulted in mitochondrial transfer from MSCs to cancer cells. Overall, these findings indicate that cancer cells with compromised mitochondrial function readily acquire mtDNA from other cells in the tumor microenvironment to restore DHODH-dependent respiration and de novo pyrimidine synthesis. The inhibition of tumor growth induced by blocking DHODH supports targeting pyrimidine synthesis as a potential widely applicable therapeutic approach.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0737
Hum Cell. 2025 Nov 21. 39(1): 12

Mitophagy is responsible to ionizing radiation but plays a very limited role in the radiosensitivity of adenocarcinoma cells.

Chen Yan, Kai Huang, Yong Xu, Wei-Hang Lu, Jing Cai, Tao-Sheng Li.

  Radioresistance of adenocarcinoma cells limits the efficiency of radiotherapy. In addition to the cell nucleus, ionizing radiation (IR) also induces damage to the mitochondria. Mitophagy, a selective degradation of impaired mitochondria via autophagy, has been found to respond to IR, but its role in the radiosensitivity of adenocarcinoma cells remains unclear. Using several different adenocarcinoma cell lines, we confirmed that exposing the adenocarcinoma cells to 5 Gy X-ray enhanced the expression of some mitophagy receptors and increased mitophagy activity. However, pharmacological inhibition of mitophagy by mdivi-1 did not significantly change the radiosensitivity of HCT116 and A549 cells. Similarly, molecular targeting inhibition of mitophagy by BNIP3L knockdown in HCT116 and A549 cells that showed significant IR-induced BNIP3L up-regulation did also not significantly affect the radiosensitivity of adenocarcinoma cells, although the IR-induced enhancement of mitophagy activity was effectively suppressed. According to our data, mitophagy is responsible to IR but plays a very limited role in the radiosensitivity of adenocarcinoma cells. Further in vivo studies are warranted to elucidate the radiosensitizing effect of targeting mitophagy on malignant tumors.

Keywords:  Adenocarcinoma; Autophagy; BNIP3L; Mitophagy; Radiotherapy

DOI:  https://doi.org/10.1007/s13577-025-01328-2
J Nanobiotechnology. 2025 Nov 19. 23(1): 722

Targeting cancer stem-like cells via cholesterol modulation and ferroptosis induction using a multifunctional nanoplatform to overcome drug resistance.

Leiguang Ye, Jinying Zhu, Xiaoman Wang, Nianhan Chen, Ying Sun, Xuemei Zeng, Shijian Liu, Shuangqian Yan.

  Overcoming therapy resistance in triple-negative breast cancer (TNBC) requires the effective targeting of cancer stem-like cells (CSCs). TNBC is characterized by hyperactivation of the mevalonate pathway, leading to cholesterol accumulation in CSC membranes, which alters membrane properties, enhances stemness, and restricts both drug penetration and lipid peroxidation-a key driver of ferroptosis. Here, we develop Fe/CDP, a nanoparticle with a Fe3O4 core coated with chondroitin sulfate and loaded with pravastatin, a mevalonate pathway inhibitor, and doxorubicin (DOX). In TNBC mouse models, Fe/CDP selectively targets tumors and CSCs via CD44-chondroitin sulfate interactions, enabling localized drug release. Pravastatin suppresses cholesterol biosynthesis, restoring membrane rigidity and fluidity, thereby reducing CSC stemness, disrupting P-glycoprotein function, and downregulating ALDH1, which enhances DOX sensitivity via the EGFR/Src/HMGCR axis. Moreover, cholesterol depletion facilitates lipid peroxidation, synergizing with Fe3O4 to trigger ferroptosis through CoQ10/GPX4/FSP1 downregulation. By eliminating both bulk tumor cells and CSCs, Fe/CDP provides a cholesterol-modulating strategy to overcome TNBC drug resistance.

Keywords:  Cancer stem cell; Cholesterol depletion; Drug resistance; MVA pathway; Membrane modulation

DOI:  https://doi.org/10.1186/s12951-025-03796-y
Biochem Pharmacol. 2025 Nov 19. pii: S0006-2952(25)00821-4. [Epub ahead of print] 117556

MMP28 promotes tumorigenesis and gemcitabine resistance in pancreatic cancer by promoting glycolysis through interaction with SND1.

Yang Liu, Shan Liao, Bowen Yuan, Xinrong Liu, Wentao Yu, Han Zhan, Yan Jiang, Xiaojing Li, Ruihan Li, Juan Tan.

  Pancreatic cancer is highly challenging, with most patients developing intrinsic or acquired resistance to first-line chemotherapy drug gemcitabine (GEM). Although Matrix Metalloproteinase 28 (MMP28) is upregulated in pancreatic cancer and predicts a poor prognosis, its role in GEM resistance and molecular mechanism remain unclear. Here, we aimed to investigate the role of MMP28 in GEM resistance and molecular mechanism. First, differentially expressed genes in pancreatic cancer were identified through bioinformatics and validated in clinical samples and cells. MMP28 was significantly overexpressed in pancreatic cancer tissues and Capan-1 and PANC-1 cells, correlating with poor prognosis. Then, MMP28 knockdown was performed in Capan-1 and PANC-1 cells, followed by GEM treatment. Furthermore, in vivo experiments evaluated GEM sensitivity after MMP28 knockdown. The results showed that MMP28 knockdown enhanced GEM sensitivity both in vitro, reducing cell proliferation and survival, and in vivo, where tumor growth was significantly suppressed. Additionally, glycolysis-related changes were assessed. We revealed that glycolysis was implicated as a key pathway in this process, with reduced glucose uptake and lactate production observed after MMP28 knockdown. Protein-protein interaction analysis identified Staphylococcal nuclease domain-containing protein 1 (SND1) as a key interactor, and SND1 expression was upregulated in pancreatic cancer tissues. Moreover, MMP28 interacted with SND1 to regulate SND1's recruitment of HK2 mRNA to promote glycolysis. However, overexpression of SND1 reversed the effects of MMP28 knockdown, restoring glycolysis and GEM resistance. In conclusion, MMP28 promoted tumor growth and GEM resistance in pancreatic cancer by regulating glycolysis via interaction with SND1.

Keywords:  Gemcitabine resistance; Glycolysis; MMP28; Pancreatic cancer; SND1

DOI:  https://doi.org/10.1016/j.bcp.2025.117556
Cell. 2025 Nov 19. pii: S0092-8674(25)01233-4. [Epub ahead of print]

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia.

Alexander C Lewis, Emily Gruber, Rheana Franich, Jessica Armstrong, Madison J Kelly, Carlos M Opazo, Yau C Low, Léa Flippe, Kevin Wijanarko, Caitlin L Rowe, Celeste H Mawal, Alexandra Birrell, Joan So, Srimayee Vaidyanathan, Keziah Ting, Liana N Semcesen, Karena Last, Ching-Seng Ang, Giovanna Pomilio, Fiona C Brown, Andrew H Wei, Jason A Powell, Elizabeth S Ng, Ann E Frazier, Kate McArthur, Najoua Lalaoui, David A Stroud, Kristin K Brown, Ricky W Johnstone, Lev M Kats.

  The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal. Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis.

Keywords:  acute myeloid leukemia; cuproptosis; heme biosynthesis; metabolic vulnerability; metabolism; mitochondrial Complex IV

DOI:  https://doi.org/10.1016/j.cell.2025.10.028
Biochim Biophys Acta Mol Cell Res. 2025 Nov 16. pii: S0167-4889(25)00193-4. [Epub ahead of print]1873(1): 120088

Anti-tumor response by targeting glucose metabolism and depletion of membrane cholesterol in breast cancer and melanoma cells.

Himanshi Yaduvanshi, Bhavana Deshmukh, Abhijeet Singh, Shyamananda Singh Mayengbam, Manoj Kumar Bhat.

  Enhanced lactate production and cholesterol accumulation in cancer cells are often correlated with poor prognosis and the development of resistance to therapies. This study investigates a unique dual-pronged approach for abrogating tumor development by combining methyl-β-cyclodextrin (MCD)-mediated cholesterol depletion with sodium oxamate (OXA)-induced inhibition of lactate dehydrogenase A. The cytotoxic effects of MCD and OXA were validated by MTT and long-term colony formation assay. Cell cycle arrest and apoptosis were assessed via flow cytometry. The involvement of key signaling intermediates in proliferative pathways was evaluated by immunoblotting. The Seahorse analyzer was used to measure the real-time metabolic flux in mouse cancer cells. In vivo, studies and immunophenotyping were performed to investigate the impact of MCD+OXA treatment on tumor growth and immune cell infiltration in tumor and periphery organs. The results indicate that concurrent administration of a low-dose MCD and OXA elicited a synergistic cytotoxic effect and retarded tumor progression while being non-toxic to vital organs. Mechanistically, this combination downregulated ERK/AKT signaling, induced apoptosis, and suppressed cellular metabolism at the glycolysis/OXPHOS level, including ATP production. Interestingly, it promoted the infiltration of effector Th1 cells and B cells, while reducing the presence of PMN-MDSCs in the tumor microenvironment and peripheral organs. These findings suggest that the combination of MCD and OXA provides a dual-targeted approach by disrupting cholesterol as well as lactate metabolism and eliciting an anti-tumor immune response, leading to a reduction in the growth of tumor cells. This pre-clinical strategy demonstrates potential advantages over single-agent treatment, which warrants further investigations for its therapeutic implications. SUMMARY BLURB: In pre-clinical investigations, co-targeting membrane cholesterol, and lactate dehydrogenase A with methyl-β-cyclodextrin and sodium oxamate inhibits cell growth and restricts breast cancer and melanoma tumor progression.

Keywords:  Breast cancer; Cholesterol; Glucose metabolism; Lactate dehydrogenase; Melanoma

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120088
Sci Rep. 2025 Nov 21. 15(1): 41155

Alteration of metabolic activity regulates mitochondrial temperature in diagnosis in HepG2 hepatocellular carcinoma cells.

Ola A Gaser, Mohamed A Nasr, Alaa E Hussein, Radwa Ayman Salah, Shams M Saad, Seif Ehab, Nourhan M Aboomar, Ahmed O Elmehrath, Ayman Salah, Young-Tae Chang, Mal Hedrick, Lázaro A M Castanedo, Peyman Fahimi, Chérif F Matta, Nagwa El-Badri.

  Oxidative phosphorylation (OXPHOS) is a key player in mitochondrial bioenergetic functions. In hepatocellular carcinoma (HCC), OXPHOS slows down or switches to glycolysis via what is known as the Warburg effect. The altered respiration in cancer was reported to affect mitochondrial temperature. We investigated the impact of the metabolic switch on the mitochondrial temperature in HepG2 HCC cell line. Metformin (N, N-dimethylbiguanide) treatment was used to suppress glycolysis to emulate lower metabolically active cells (Met-HepG2). The mitochondrial temperature was assessed using mito-thermo yellow (MTY) absorbing mitochondrial radiant heat. Mito-tracker green (MTG) fluorescent dye was used to confirm mitochondrial localization. Our data showed lower MTY dye intensity in the Met-HepG2 treated group, indicating a significant increase in mitochondrial temperature compared to untreated HepG2 cells (NT-HepG2). Genotypic analysis of the metabolic respiration gene expression showed significant down-regulation in glycolytic genes (ERR-gamma, HK2, PGK, ALDOC, TPI1, IDH1, and PKM2) in the Met-HepG2 cells compared to the NT-HepG2 cells. OXPHOS as evidenced by ATP, ROS, and NADPH production was significantly up-regulated in the Met-HepG2 group compared to the NT-HepG2 group. Transmission electron microscopy showed fewer mitochondria with swollen elongated appearance, as a marker for activated OXPHOS in the Met-HepG2 group. These data show a correlation between HepG2 altered metabolism and mitochondrial temperature and suggest that less metabolically active HepG2 cells are correlated with higher mitochondrial temperature, providing evidence for a possible role of mitochondrial temperature in diagnosis of HCC.

Keywords:  Cancer; Hepatocellular carcinoma (HCC); Mito thermo yellow (MTY); Mitochondrial bioenergetics; Mitochondrial temperature

DOI:  https://doi.org/10.1038/s41598-025-02807-0
Protein Cell. 2025 Nov 19. pii: pwaf101. [Epub ahead of print]

Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC.

Peng Wang, Shengdan Zhang, Xin Chen, Xu-Dong Yang, Shi Huang, Huiyong Yin, Hao-Yu Duan, Fuling Zhou, Jia Yu, Bo Zhong, Dandan Lin.

  Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous Kras LSL-G12D/+ Lkb1 fl/fl (KL) and Kras LSL-G12D/+ Tp53 fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.

Keywords:  GPX4; lipid droplets; lipid release; non-small cell lung cancer; triacylglycerol; tumor microenvironment

DOI:  https://doi.org/10.1093/procel/pwaf101
EMBO Rep. 2025 Nov 20.

FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer.

Suzan Ber, Ming Yang, Marco Sciacovelli, Shamith Samarajiwa, Khushali Patel, Efterpi Nikitopoulou, Annie Howitt, Simon J Cook, Ashok R Venkitaraman, Christian Frezza, Alessandro Esposito.

  Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming are unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we characterise distinctive features of each allele. We demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.

Keywords:  Colorectal Cancer; FOXO Signalling; Glutamine Metabolism; Glutamine Synthase; KRAS Mutation

DOI:  https://doi.org/10.1038/s44319-025-00641-z
MedComm (2020). 2025 Dec;6(12): e70493

CD36 Inhibits Triple-Negative Breast Cancer Progression by Transcriptionally Upregulating Caveolin-1 and Promoting Lipid-Reactive Oxygen Species-Related Ferroptosis.

Xiujuan Wu, Yan Wang, Zaihui Peng, Tingting Zhao, Xuanni Tan, Wenting Yan, Yuqin Zhou, Jie Xia, Xiaowei Qi, Yi Zhang.

  Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor prognosis. Cluster of differentiation 36 (CD36), a fatty acid transporter, plays controversial roles in tumor progression. Here, we report a tumor-suppressive function of CD36 in TNBC. Analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases, along with validation in clinical samples, revealed that CD36 expression was significantly downregulated in TNBC tissues, and its low expression correlated with advanced disease stage and poorer patient prognosis. Functional assays demonstrated that CD36 knockout promoted, whereas its overexpression inhibited, the proliferation, migration, and invasion of TNBC cells. Integrated transcriptomic and proteomic analyses linked CD36 to ferroptosis, an iron-dependent form of regulated cell death. Mechanistically, CD36 enhanced the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ), which in turn upregulated the expression of caveolin-1 (CAV1). This CD36/PPARγ/CAV1 axis increased intracellular lipid peroxidation, thereby promoting ferroptosis. In vivo, a CD36 agonist suppressed, while a ferroptosis activator inhibited the metastasis of CD36-knockdown TNBC cells. Our findings identify CD36 as a novel tumor suppressor in TNBC that acts by promoting ferroptosis, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Keywords:  CD36; caveolin‐1; ferroptosis; lipid‐reactive oxygen; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/mco2.70493
Nucleic Acids Res. 2025 Nov 20. pii: gkaf1219. [Epub ahead of print]

DRESIS 2.0: the comprehensive landscape of drug resistance information.

Xiuna Sun, Zhangle Wei, Xinyuan Yu, Kaixuan Liu, Shun Yao, Zheng Ni, Hanbing Wang, Ziming Zhao, Yinpeng Zhang, Yuxuan Liu, Hanlu Ding, Yintao Zhang, Zhiguo Liu, Mang Xiao, Feng Zhu.

Elucidating mechanisms of drug resistance is key for overcoming resistance, guiding drug design, and enabling accurate resistance prediction. Recently, disease metabolic reprogramming has emerged as a novel mechanism of resistance, which enables disease cells to adapt to therapeutic resistance by altering energy production pathways, cellular signaling, and biosynthesis processes. Moreover, protein structure alterations also play a pivotal role in resistance study, facilitating mechanistic understanding, and structure-based target discovery. In other words, integrating these recently accumulated critical data is essential for enriching the landscape of drug resistance data. Therefore, in this study, DRESIS was a significant update by providing (i) 236 molecules that drive metabolic reprogramming and confer resistance to 168 drugs, together with a detailed mechanism, (ii) 2228 protein structural variants implicated in resistance to 671 drugs across 238 diseases, and (iii) greatly expanded landscapes of drug resistance information, now featuring 398 newly added key drug-resistant molecules, 356 drugs with the latest published resistance mechanisms, and 81 new drug-resistant disease categories. All in all, DRESIS 2.0 is expected to serve as a valuable resource for the scientific community and provide important support in tackling the global challenge of drug resistance, which is now publicly accessible at https://idrblab.org/dresis/.

DOI: https://doi.org/10.1093/nar/gkaf1219