bims-meract 2025-09-28 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–09–28
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
Targeting the crosstalk of metabolism reprogramming and replication stress: novel strategy to combat cancer.
TMEM164 enhances radioresistance of GBM cells by inhibiting the FASN-NADPH-ROS axis.
UDP-glucose ceramide glucosyltransferase promotes radioresistance via membrane reorganization to maintain redox balance in glioblastoma.
ACYP2 induces temozolomide resistance in glioblastoma by promoting PARP1-mediated DNA damage repair.
Proteomic Characterization Reveals CYP2S1 as a Mediator of Drug Resistance in PDAC.
Adenosine 2A receptor-dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming.
Inhibition of BCL-2 and MCL-1 disrupts mitochondrial respiration and overcomes radioresistance in choroidal melanoma.
Targeting SQLE-mediated cholesterol metabolism to enhance CD8+ T cell activation and immunotherapy efficacy in hepatocellular carcinoma.
Auranofin facilitates gemcitabine sensitivity by regulating TXNRD1-related ferroptosis in pancreatic ductal adenocarcinoma.
CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma.
Glutamine synthetase shields triple-negative breast cancer cells from ferroptosis in metastasis triggered by glutamine deprivation.
Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
Overexpression of alcohol dehydrogenase 1 A inhibits the progress of triple negative breast cancer via Wnt/β-catenin signaling.

bioRxiv. 2025 Sep 20. pii: 2025.09.19.675739. [Epub ahead of print]

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.

Alica K Beutel, Sabrina Calderon, Ethan Nghiem, Kevin Gulay, Leonor P S Santana, Eleni Zimmer, Rima Singh, Cecily Anaraki, Natalie Yousefian, Chantal Allgöwer, Gregory Tong, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy. However, resistance remains a major hurdle in clinical care. Resistance can arise from microenvironmental metabolites or through direct metabolic reprogramming of pancreatic cancer cells. Here, we generated PDAC models of acquired gemcitabine resistance to determine the relationship between these mechanisms. We observed that physiological levels of exogenous pyrimidines have a diminished ability to impact gemcitabine response in PDAC cells with acquired resistance. This occurs as the metabolic reprogramming of PDAC cells in response to gemcitabine treatment forces a suppression of the pyrimidine salvage pathway. Importantly, this metabolic rewiring renders gemcitabine-resistant PDAC cells highly susceptible to inhibition of the rate limiting enzyme of the mevalonate biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), using statins. Notably, statin treatment inhibits the growth of gemcitabine-resistant tumors in immunocompetent mouse models. Through metabolite rescue experiments, we identified geranylgeranyl pyrophosphate as the critical metabolite lost during statin treatment, resulting in reduced protein geranylation in PDAC cells. Finally, as downregulation of the HMGCR is gradually acquired during gemcitabine resistance, we observed that HMGCR expression predicts patient response to gemcitabine. Collectively, these data demonstrate that the mevalonate biosynthesis pathway represents a promising therapeutic target in gemcitabine resistance and may serve as a biomarker to stratify treatment selection in PDAC patients.

DOI: https://doi.org/10.1101/2025.09.19.675739
Med Oncol. 2025 Sep 26. 42(11): 494

Targeting the crosstalk of metabolism reprogramming and replication stress: novel strategy to combat cancer.

Wenbo Liu, Xiangyan Jiang, Yong Ma, Huiguo Qing, Yingcun Bao, Zuoyi Jiao.

  The induction of replication stress has emerged as a potent strategy for cancer therapy, with alkylating agents, nucleoside analogs, and inhibitors of cyclin and cyclin-dependent kinase remaining prominent drugs. As mechanistic insights into responses to replication stress are evolving, novel therapeutic agents targeting replication stress response pathways have been progressively developed. Despite the demonstrated pharmacological and clinical efficacy of certain agents, the therapeutic landscape remains characterized by suboptimal patient prognoses. Mounting evidence implicates cancer cell metabolic reprogramming as a critical determinant in both modulating replication stress and attenuating genotoxic drug efficacy. In addition, some metabolic enzymes demonstrate non-canonical functions that potentiate DNA damage response, while some metabolic pathways contribute vulnerability to replication stress in malignant cells. Therefore, this review seeks to elucidate the mechanisms by which metabolic reprogramming modulates replication stress in cancer cells and to provide an overview of the latest advancements in therapeutic regimens development.

Keywords:  Cancer therapy; Drug combination; Metabolic reprogramming; Replication stress

DOI:  https://doi.org/10.1007/s12032-025-03053-0
J Neurooncol. 2025 Sep 22.

TMEM164 enhances radioresistance of GBM cells by inhibiting the FASN-NADPH-ROS axis.

Zhaoyan Jiang, Xiaoya Jin, Hetian Xue, Jialing Zhang, Liang Zeng, Yuchuan Zhou, Yan Pan, Jianghong Zhang, Chunlin Shao.

   PURPOSE: Glioblastoma multiforme (GBM), one of the most aggressive primary brain malignancies, remains a major therapeutic challenge in contemporary neuro-oncology. Radiotherapy, an essential component of current standard therapeutic protocol, still has persistently poor clinical efficacy in the intrinsic radioresistance of GBM. Therefore, elucidating the underlying mechanisms of radioresistance is critical for optimizing therapeutic outcomes in GBM patients.
METHODS: Radioresistant GBM cell lines U251R were established by irradiating U251 cells with fractionated dose of 60 Gy in total. RNA-seq and TMT assays were applied, combined with GEO, KEGG and other databases to analyze the role of TMEM164 in regulating the radiosensitivity of GBM cells. Pharmacological inhibition of cell death pathways was employed to identify the predominant cell death mechanism influencing TMEM164-mediated radioresistance in GBM cells. The intracellular levels of NADPH, lipid droplet and ROS were detected after radiation to assess the effect of TMEM164 on lipid metabolism. The effect of TMEM164 on necroptosis through FASN-NADPH-ROS axis was verified by rescue experiments.
RESULTS: Through bioinformatics analysis, TMEM164 was identified as a key gene regulating GBM cells' radiosensitivity. Knockdown of TMEM164 significantly increased necroptosis in U251R and T98G cells. Integrated enrichment analysis of RNA-seq and TMT data revealed that FASN interacted with TMEM164. Excessive NADPH consumption led to intracellular ROS accumulation, thereby increasing radiosensitivity in GBM cells.
CONCLUSIONS: Our findings indicated that TMEM164 might serve as a critical biological target of GBM cells radioresistance, providing a novel theoretical basis for GBM radiotherapy.

Keywords:  FASN; Glioblastoma cells; Necroptosis; Radioresistance; TMEM164

DOI:  https://doi.org/10.1007/s11060-025-05216-5
Br J Cancer. 2025 Sep 22.

UDP-glucose ceramide glucosyltransferase promotes radioresistance via membrane reorganization to maintain redox balance in glioblastoma.

Haksoo Lee, Dahye Kim, Byeongsoo Kim, DongJoo Joung, Jaewan Jeon, Tae-Oh Kim, HyeSook Youn, BuHyun Youn.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor characterized by a poor prognosis and resistance to radiotherapy. Although multiple mechanisms of radioresistance have been proposed, the contribution of membrane-driven metabolic adaptations to radioresistance remains poorly understood.
METHODS: The role of UDP-glucose ceramide glucosyltransferase (UGCG) was investigated using radioresistant GBM cell lines and in vivo xenograft models. After inhibiting UGCG function through genetic or pharmacological (miglustat) approaches, we assessed the effects on lipid raft integrity, localization of the ASCT2 transporter, glutamine uptake, oxidative stress, and radiosensitivity.
RESULTS: UGCG was upregulated in radioresistant GBM cells and promoted lipid raft stabilization. This facilitated the membrane recruitment of the glutamine transporter ASCT2 (SLC1A5), thereby sustaining redox homeostasis under radiation stress. Genetic or pharmacological inhibition of UGCG disrupted lipid raft integrity, impaired ASCT2 localization, reduced glutamine uptake, and increased oxidative stress, leading to enhanced radiosensitivity. In GBM xenograft models, UGCG inhibition combined with radiotherapy significantly suppressed tumor growth and extended survival.
CONCLUSIONS: These findings reveal a previously underexplored, membrane-centric mechanism of radioresistance in which UGCG orchestrates lipid raft remodeling to facilitate glutamine-dependent redox balance. This highlights UGCG as a potential therapeutic target to enhance the efficacy of radiotherapy in GBM.

DOI: https://doi.org/10.1038/s41416-025-03191-2
Mol Cancer Res. 2025 Sep 26.

ACYP2 induces temozolomide resistance in glioblastoma by promoting PARP1-mediated DNA damage repair.

Mengjun Sui, Qing Cai, Zhiwei Sun, Jinjin Li, Yiyang Zhang, Mengdan Li, Penggao Dai, Gang Li.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis. Temozolomide (TMZ) is the most widely used chemotherapeutic agent and can significantly improve patient survival rates. However, numerous patients develop TMZ resistance, leading to limited therapeutic benefits. Therefore, it is crucial to investigate the mechanisms of TMZ resistance in patients with GBM and identify the sensitizing targets of TMZ to improve its clinical efficacy. Here, we demonstrated that acylphosphatase 2 (ACYP2) was involved in regulating the sensitivity of GBM to TMZ. ACYP2 knockdown significantly reduced the IC50 values of TMZ in GBM cells, while overexpression of ACYP2 increased their IC50 values. The combination of ACYP2 knockdown and TMZ treatment not only inhibited the malignant behavior of GBM cells in vitro but also slowed the progression of intracranial GBM in mice. Additionally, comet tail and γ-H2AX staining assays showed that ACYP2 knockdown enhanced the TMZ-induced DNA damage. Mechanistically, ACYP2 upregulates the transcription factor c-Myc to promote the transcription of its downstream target poly ADP-ribose polymerase 1 (PARP1), an important regulatory molecule for DNA damage repair, ultimately inducing TMZ resistance in GBM cells. Thus, this study demonstrated that ACYP2 is a potential therapeutic target for TMZ-resistant GBM patients. Implications: The ACYP2-driven c-Myc/PARP1 signaling axis defines a critical pathway driving temozolomide resistance and represents a translationally actionable target for therapeutic intervention in glioblastoma.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0423
Pancreas. 2025 Aug 29.

Proteomic Characterization Reveals CYP2S1 as a Mediator of Drug Resistance in PDAC.

Vera Thiel, Wiebke M Nadler, Alexander Kerner, Laura Kuhlmann, Manuel Reitberger, Tim Vorberg, Paul Schwerd-Kleine, Elisa Noll, Nathalia A Giese, Hsi-Yu Yen, Katja Steiger, Vanessa Vogel, Corinna Klein, Thilo Hackert, Ronald Koschny, Christiane A Opitz, Andreas Trumpp, Martin R Sprick, Christoph Rösli.

   OBJECTIVES: To investigate the proteomic profile of different molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and understand their impact on patient outcomes, particularly focusing on pathways involved in xenobiotic metabolism and drug resistance.
METHODS: The study utilized the serum-free PACO cell culture model and a quantitative prefractionation-based MALDI/MS approach to establish the proteomic profiles of various PDAC subtypes. Differential protein regulation was analyzed to identify systematic alterations in metabolic and drug resistance pathways. Mechanistic studies involved the knockdown and overexpression of key proteins to assess their role in drug resistance.
RESULTS: Proteomic analysis revealed subtype-specific alterations, particularly in pathways associated with xenobiotic metabolism and drug resistance. Notably, CYP2S1, a member of the CYP450 family, was upregulated in the HNF1A+ PDAC subtype. CYP2S1 levels were further inducible by polyaromatic hydrocarbons (PAHs) and SN38, the active metabolite of irinotecan via AHR. Mechanistic studies demonstrated that knockdown of AHR or CYP2S1 sensitized PDAC cells to SN38, whereas overexpression of CYP2S1 increased resistance to SN38.
CONCLUSIONS: The findings highlight the significant role of CYP2S1 in mediating drug resistance in certain PDAC subtypes. Targeting CYP2S1 and its regulatory pathways could enhance the efficacy of chemotherapeutic agents like irinotecan in treating PDAC. These results provide new insights into the molecular mechanisms underlying PDAC subtype-specific drug resistance and suggest potential therapeutic targets.

Keywords:  AHR; CYP2S1; GeLC-based MALDI/MS; MSQBAT; PDAC

DOI:  https://doi.org/10.1097/MPA.0000000000002553
Sci Signal. 2025 Sep 23. 18(905): eadr3177

Adenosine 2A receptor-dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming.

Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A J O'Neill, Georgina Xanthou.

Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A-treated TH17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.

DOI: https://doi.org/10.1126/scisignal.adr3177
Biochem Biophys Res Commun. 2025 Sep 14. pii: S0006-291X(25)01366-X. [Epub ahead of print]784 152650

Inhibition of BCL-2 and MCL-1 disrupts mitochondrial respiration and overcomes radioresistance in choroidal melanoma.

Yi Ding, Qing Huang.

  Choroidal melanoma is the most common primary intraocular malignancy in adults. Radioresistance is a major therapeutic obstacle in choroidal melanoma with underlying mechanisms poorly understood. In this study, we established radioresistant OCM-3-r and 92-1-r cell lines and identified upregulation of BCL-2 as a key survival mechanism. BCL-2 knockdown impaired mitochondrial respiration, reduced ATP production, and induced apoptosis. Pharmacological inhibition with venetoclax recapitulated these effects in resistant cells, suppressing mitochondrial function and triggering dose-dependent apoptosis. In vivo, venetoclax significantly inhibited tumor growth without affecting body weight and increased cleaved caspase-3 expression in xenografts. However, venetoclax alone did not improve survival. Combination therapy with venetoclax and the MCL-1 inhibitor MIK665 exhibited strong synergy, resulting in enhanced tumor regression and significantly prolonged survival. These findings demonstrate that dual inhibition of BCL-2 and MCL-1 effectively overcomes radioresistance in choroidal melanoma by disrupting mitochondrial function and promoting apoptosis.

Keywords:  Bcl-2; Choroidal melanoma; MIK665; Mcl-1; Radioresistance; Venetoclax

DOI:  https://doi.org/10.1016/j.bbrc.2025.152650
J Immunother Cancer. 2025 Sep 26. pii: e012345. [Epub ahead of print]13(9):

Targeting SQLE-mediated cholesterol metabolism to enhance CD8+ T cell activation and immunotherapy efficacy in hepatocellular carcinoma.

Shuang Qiao, Hao Zou, Yulan Weng, Yi-Fan Liu, Weihao Li, Xing-Juan Yu, Lian Li, Limin Zheng, Jing Xu.

   BACKGROUND: The sustained effectiveness of anti-programmed cell death protein-1 (PD1) treatment is limited to a subgroup of patients with hepatocellular carcinoma (HCC) due to the tumor microenvironment heterogeneity, highlighting the need to identify targetable biomarkers that synergize with PD1 blockade. Abnormal cholesterol metabolism plays a critical role in HCC progression, along with growing evidence indicating its complex immunomodulatory effects within the tumor microenvironment. However, the interplay between cholesterol homeostasis and immune evasion remains elusive.
METHODS: Transcriptomic and clinical data from HCC datasets were analyzed to identify cholesterol metabolism-related targets. Multiplex immunostaining and flow cytometry were applied to examine the immune landscape association with squalene epoxidase (SQLE) in human and murine tumors. Mechanistic studies were conducted in vitro, and co-culture experiments of tumor cells and T cells were followed by metabolomics and transcriptome analyses. Therapeutic efficacy was evaluated in mouse HCC models.
RESULTS: We demonstrated that elevated SQLE expression in human HCC was associated with poor clinical outcomes and correlated with reduced CD8+ T cell infiltration and activation. Pharmacological inhibition or genetic knockdown of SQLE in tumor cells promoted CD8+ T cell proliferation and activation in co-culture experiments. Untargeted metabolomics identified 27-hydrocholesterol, an oxysterol derived from tumor cells, as a key factor impairing CD8+ T cell function via cholesterol dysregulation. SQLE inhibition in tumor cells suppressed oxysterols secretion, therefore overcoming cholesterol restrictions and enhancing the immune responses of CD8+ T cells. Moreover, SQLE targeting with terbinafine restored antitumor immunity and synergized with anti-PD1 therapy in HCC.
CONCLUSION: Targeting tumorous SQLE restores CD8+ T cell function by overcoming cholesterol restrictions via oxysterol-SREBP2 signaling, highlighting SQLE as a potential therapeutic target to enhance immunotherapy efficacy in HCC.

Keywords:  Hepatocellular Carcinoma; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2025-012345
Cancer Lett. 2025 Sep 20. pii: S0304-3835(25)00630-5. [Epub ahead of print] 218058

Auranofin facilitates gemcitabine sensitivity by regulating TXNRD1-related ferroptosis in pancreatic ductal adenocarcinoma.

Si-Yuan Lu, De-Liang Fang, Zi-Yi Zhao, Ying-Qin Zhu, Zhi-De Liu, Ming-Jian Ma, Jing-Yuan Ye, Qiong-Cong Xu, Xiao-Yu Yin.

  Gemcitabine-based combination chemotherapy remains the first-line treatment for pancreatic ductal adenocarcinoma (PDAC). However, numerous patients with PDAC develop resistance to gemcitabine, highlighting the need to identify sensitizers or resistance targets. In this study, we constructed a patient-derived xenograft (PDX) model using resected PDAC tissue from patients and established stable gemcitabine-resistant and -sensitive PDX models. RNA sequencing analysis of the gemcitabine-resistant PDX model and cell lines revealed that altered iron ion metabolism significantly affected gemcitabine resistance in PDAC. Gemcitabine-resistant cell lines exhibited altered iron ion levels, which contributed to decreasing lipid peroxidation and ferroptosis. To identify biomarkers of gemcitabine resistance, we established PDX-based machine learning features and found that they may differentiate the effectiveness of chemotherapy and immunotherapy in different patients. TXNRD1 was identified as a potential oncogene that promotes cell migration and proliferation, while inhibiting cell apoptosis. Mechanistically, TXNRD1 knockdown restricted P65 expression and phosphorylation, leading to SLC7A11 depletion and enhanced ferroptosis. This activated ferroptosis, induced by SLC7A11 inhibition, further suppressed gemcitabine resistance in PDAC. Auranofin, a TXNRD1 inhibitor, induced ferroptosis and exerted synergistic effects with gemcitabine in PDAC therapy. Auranofin additionally enhanced the anticancer effects of gemcitabine in a drug-resistant PDAC PDX model. Collectively, TXNRD1 is a potential target for overcoming gemcitabine resistance. Auranofin can inhibit TXNRD1 activation, thereby sensitizing PDAC cells to gemcitabine. Combination therapy with auranofin and gemcitabine may have translational potential for PDAC chemotherapy.

Keywords:  Chemoresistance; Ferroptosis; SLC7A11; Synergistic therapy; TXNRD1

DOI:  https://doi.org/10.1016/j.canlet.2025.218058
Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2519568122

CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma.

Wu Yang, Siying Wang, Shuyi Ji, Jian Wang, Shuo Lian, Zhe Li, Robin A Jansen, Wei Wu, Kongyan Niu, Zhen Sun, Qi Jia, Jiaojiao Zheng, Huijue Zhu, Xuan Deng, Liqin Wang, Zhoulong Fan, Yaoping Shi, Cor Lieftink, Ming Guan, Roderick L Beijersbergen, Wenxin Qin, Qiang Gao, René Bernards, Haojie Jin.

  Cholangiocarcinoma (CCA) remains a lethal malignancy with limited therapeutic options. Through genome-wide CRISPR-Cas9 screening, we identified the adenosine triphosphatase (ATPase) valosin-containing protein (VCP) as a critical dependency in CCA. Compound screens revealed that the VCP inhibitor CB-5339 potently suppresses CCA proliferation in a panel of patient-derived organoids by inducing cellular senescence. It is known that senescent cells persist, and this can contribute to therapy resistance. To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a "one-two punch" strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA.

Keywords:  CRISPR-Cas9 screening; VCP; cholangiocarcinoma; senescence

DOI:  https://doi.org/10.1073/pnas.2519568122
Breast Cancer Res. 2025 Sep 26. 27(1): 165

Glutamine synthetase shields triple-negative breast cancer cells from ferroptosis in metastasis triggered by glutamine deprivation.

Zhaoting Yang, Xinyu Lian, Yuan Luo, Qiao Ye, Guangjin Guo, Guoquan Liu.

   BACKGROUND: Epithelial-mesenchymal transition (EMT) in cancer cell metastasis involves complicated metabolic plasticity to survive the highly challenging environment, such as oxidative stress, after subsequent circulation in the bloodstream. Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia to glutamine (Gln) during Gln deprivation stress. This study revealed for the first time that GS plays an important role in protecting triple-negative breast cancer (TNBC) cells from ferroptosis during Gln deprivation-induced EMT, namely ferroptosis-resistant EMT (FR-EMT).
METHODS: To better understand this finding, we focused on the mechanism of GS-mediated FR-EMT in TNBC through transcriptomic analysis and murine metastasis modeling.
RESULTS: This study specifically investigated the effects of GS on lipid peroxidation and iron metabolism, the two major metabolic disorders in ferroptosis. An abnormal increase in monounsaturated fatty acids (MUFAs) mediated by mechanistic target of rapamycin complex 1 (mTORC1) decreased the ferroptosis sensitivity under Gln deprivation. Additionally, aberrant iron metabolism via lipocalin 2 (LCN2) and transferrin receptor (TFRC) affected the sensitivity to ferroptosis. Moreover, this study confirmed that GS protects TNBC cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood in the lung metastasis mouse model.
CONCLUSION: This investigation provides insights into the role of ferroptosis in metastasis and demonstrates that GS may be a viable target for preventing metastases in TNBC.

Keywords:  Epithelial-mesenchymal transition; Ferroptosis; Glutamine; Glutamine synthetase; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s13058-025-02115-5
Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2506417122

Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.

Sara Violante, Aye Kyaw, Lana Kouatli, Kaushik Paladugu, Lauren Apostolakis, Macy Jenks, Amy Johnson, Ryan D Sheldon, Douglas Whitten, Anthony L Schilmiller, Pablo E Visconti, Justin R Cross, Lonny R Levin, Jochen Buck, Melanie Balbach.

  Prior to ejaculation, mammalian sperm are stored in the epididymis in a "resting" metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD+) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.

Keywords:  aldolase; glycolysis; metabolic reprogramming; sperm; stable isotope labeling

DOI:  https://doi.org/10.1073/pnas.2506417122
Sci Rep. 2025 Sep 26. 15(1): 32986

Overexpression of alcohol dehydrogenase 1 A inhibits the progress of triple negative breast cancer via Wnt/β-catenin signaling.

Lihong Su, Chunlin Qiao, Jin Luo, Bianling Zhu, Yunxiao Liu.

  The identification of novel therapeutic targets in triple negative breast cancer (TNBC) continues to be of paramount importance. In this context, ADH1A (Alcohol Dehydrogenase 1 A), a protein involved in tyrosine metabolism, was comprehensively examined to assess its expression and functional roles in TNBC. A combination of bioinformatics approaches and local tissue analyses was utilized to determine the expression levels of ADH1A in TNBC samples. Genetic manipulation techniques were employed to alter ADH1A expression, and the subsequent effects on TNBC cell behavior were systematically analyzed. This study is the first to report on the alterations of 14 genes related to tyrosine metabolism within the TCGA-TNBC cohorts. Notably, reduced expression of these enzymes is associated with poorer survival outcomes in patients with TNBC. An analysis of the TCGA database revealed reduced levels of ADH1A in human TNBC tissues. Furthermore, ADH1A protein expression was diminished in TNBC tissues of patients who received local treatment, in contrast to the elevated expression observed in adjacent normal tissues. In the MDA-MB-231 and SUM159PT cell lines, ADH1A knockdown significantly promoted cell proliferation, migration, and invasion. On the contrary, ADH1A overexpression inhibited cell proliferation, migration, and invasion, while inducing cell apoptosis. Mechanistically, the overexpression of ADH1A may attenuate the malignant characteristics of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway. In conclusion, ADH1A may be a useful biomarker for TNBC prognosis. This study is the first to reveal that ADH1A inhibits the malignant progression of TNBC via the Wnt/β-catenin signaling pathway.

Keywords:  Breast cancer; Migration; Prognosis; Proliferation; Tyrosine metabolism

DOI:  https://doi.org/10.1038/s41598-025-17643-5