bims-meract 2025-03-02 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–03–02
twenty-one papers selected by
Andrea Morandi, Università degli Studi di Firenze

NOX4 modulates breast cancer progression through cancer cell metabolic reprogramming and CD8+ T cell antitumor activity.
Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
Glycolysis reprogramming in CAFs promotes oxaliplatin resistance in pancreatic cancer through circABCC4 mediated PKM2 nuclear translocation.
Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.
SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance.
NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer.
Chlorogenic Acid Enhances Beta-Lapachone-Induced Cell Death by Suppressing Autophagy in NQO1-Positive Cancer Cells.
Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.
CD47 blockade reverses resistance to HDAC inhibitor by liberating anti-tumor capacity of macrophages.
Adaptive Proteomic Changes in Protein Metabolism and Mitochondrial Alterations Associated with Resistance to Trastuzumab and Pertuzumab Therapy in HER2-Positive Breast Cancer.
Glutathione peroxidase 4 (GPX4) and obesity interact to impact tumor progression and treatment response in triple negative breast cancer.
STX17-DT facilitates axitinib resistance in renal cell carcinoma by inhibiting mitochondrial ROS accumulation and ferroptosis.
Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer.
NUPR1 contributes to endocrine therapy resistance by modulating BIRC5 expression and inducing luminal B-ERBB2+ subtype-like characteristics in estrogen receptor-positive breast cancer cells.
USP2 reversed cisplatin resistance through p53-mediated ferroptosis in NSCLC.
Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation.
SPICE1 promotes osteosarcoma growth by enhancing the deubiquitination of FASN mediated by USP10.
NAD+ Boosting Through NRH Supplementation Enhances Treatment Efficacy in EOC In Vitro.
DLGAP5 enhances bladder cancer chemoresistance by regulating glycolysis through MYC stabilization.
Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer.
Metal-organic layer delivers 3-bromopyruvate to mitochondria for metabolic regulation and cancer radio-immunotherapy.

Front Immunol. 2025 ;16 1534936

NOX4 modulates breast cancer progression through cancer cell metabolic reprogramming and CD8+ T cell antitumor activity.

Yingying Xiong, Yiming Weng, Shan Zhu, Jian Qin, Jia Feng, Xiaopeng Jing, Chao Luo, Wei Gong, Rui Sun, Min Peng.

   Introduction: Breast cancer is the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Although NADPH oxidase 4 (NOX4) has been implicated in various oncogenic processes, its exact function in breast cancer progression, metabolic reprogramming, and immune modulation remains unclear.
Methods: We used murine 4T1 and EO771 breast cancer models to generate NOX4 knockout (KO) cell lines via CRISPR/Cas9. In vitro assays (cell proliferation, colony formation, wound healing, and Seahorse metabolic analyses) and in vivo orthotopic tumor studies assessed the impact of NOX4 loss. Transcriptomic changes were identified through RNA sequencing and gene set enrichment analysis. We performed MYC knockdown in NOX4 KO cells to investigate its mechanistic role. Flow cytometry characterized tumor-infiltrating immune cells. Finally, NOX4-overexpressing cells were tested for survival benefit and response to dual-checkpoint immunotherapy (anti-PD-1/anti-CTLA-4).
Results: NOX4 deletion accelerated tumor growth in vivo and enhanced proliferation, colony formation, and migratory capacity in vitro. Metabolic profiling showed that NOX4 KO cells had elevated glycolysis and fatty acid oxidation, along with increased mitochondrial mass. Transcriptomic and enrichment analyses revealed MYC pathway activation in NOX4 KO cells; suppressing MYC reversed these hyperproliferative and metabolic changes. Immunologically, NOX4 KO reduced CD8+ T cell infiltration and function, partially due to lowered CCL11/CCL5 levels, while PD-L1 expression was upregulated. In contrast, NOX4 overexpression improved survival in mice and synergized with checkpoint blockade, demonstrating a positive effect on anti-tumor immunity.
Discussion: These findings show that NOX4 constrains breast cancer aggressiveness by limiting MYC-driven metabolic adaptations and supporting CD8+ T cell-mediated immunity. Loss of NOX4 promotes a more malignant phenotype and dampens T cell responses, whereas its overexpression prolongs survival and enhances checkpoint inhibitor efficacy. Therapeutically targeting the NOX4-MYC axis and leveraging NOX4's immunomodulatory capacity could offer promising strategies for breast cancer management.

Keywords:  MYC; NOX4; breast cancer; fatty acid oxidation; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2025.1534936
J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00198-X. [Epub ahead of print] 108349

Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.

Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.

  Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. Therefore, we must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY. We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and shifts the cellular metabolic profile towards oxidative stress and cell death. Mechanistically, MAT2a and AHCY regulate spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevent oxidative damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM. Significance We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM has the potential to reduce tumor growth and improve survival in patients.

Keywords:  glioblastoma; lipid peroxidation; metabolism; metabolomics; methionine; mitochondria; oxidative stress

DOI:  https://doi.org/10.1016/j.jbc.2025.108349
Cell Death Dis. 2025 Feb 23. 16(1): 126

Glycolysis reprogramming in CAFs promotes oxaliplatin resistance in pancreatic cancer through circABCC4 mediated PKM2 nuclear translocation.

Rihua He, Chonghui Hu, Yuan Yuan, Tingting Li, Qing Tian, Tianhao Huang, Qing Lin, Shangyou Zheng, Chujie Chen, Zhiqiang Fu, Rufu Chen.

Cancer-associated fibroblasts (CAFs) play a key role in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). However, the potential mechanisms by which CAFs promote chemotherapy resistance have not yet been explored. In this study, we found that circABCC4 (hsa_circ_0030582) was positively correlated with poor platinum-chemotherapeutic response and a shorter progression-free survival (PFS) time in late-stage PDAC patients. CircABCC4 enhanced the ability of CAFs to induce oxaliplatin resistance in pancreatic cancer cells through glycolysis reprogramming. Mechanistically, circABCC4 enhanced the interaction between PKM2 and KPNA2 to promote PKM2 nuclear translocation in CAFs, leading to the transcription of glycolysis-related genes. The glycolytic reprogramming of CAFs promoted the secretion of IL-8, which in turn enhanced DNA damage repair in pancreatic cancer. Blocking PKM2 nuclear translocation abolished circABCC4-driven oxaliplatin resistance of pancreatic cancer in vivo. Collectively, our study reveals a circRNA-mediated glycolysis reprogramming of CAFs to induce oxaliplatin resistance and highlights circABCC4 as a potential therapeutic target.

DOI: https://doi.org/10.1038/s41419-025-07431-4
Stem Cell Res Ther. 2025 Feb 23. 16(1): 87

Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.

Hsin-Yi Tsai, Kuen-Jang Tsai, Deng-Chyang Wu, Yaw-Bin Huang, Ming-Wei Lin.

   BACKGROUND: Gastric cancer is the malignant disease. The problems associated with cancer stemness and chemotherapy resistance in gastric cancer therapy remain unresolved. Glucose-regulated protein 78 (GRP78) is a biomarker of gastric cancer and modulates cancer stemness and chemoresistance. Previous studies have shown that mitochondrial transplantation from healthy cells is a promising method for treating various diseases and that the regulation of mitochondrial metabolism is crucial for modulating the stemness and chemoresistance of cancer cells. The aim of this study was to investigate the therapeutic effect of mitochondrial transplantation from normal gastric epithelial cells into gastric cancer and the associated mechanisms.
METHODS: The expression of cancer stemness markers, intracellular oxidative stress, or apoptotic-related proteins were evaluated via flow cytometry. Western blotting was used to investigate the molecular mechanism involved in MKN45 or AGS human gastric cancer cells after transplantation with human gastric epithelial mitochondria. The mitochondrial metabolic function of gastric cancer cells was determined via a Seahorse bioanalyzer, and extracellular lactate was evaluated via bioluminescent assay. The viability of 5-fluorouracil (5-FU)-treated gastric cancer cells was detected via a CCK-8 assay. Furthermore, a xenograft tumor animal study was performed to validate the therapeutic effects of human gastric epithelial mitochondrial transplantation in gastric cancer. Immunohistochemistry and Western blotting were then used to assess the expressions related to cancer stemness and mitochondrial metabolism-related proteins in tumor tissues.
RESULTS: Transplanting human gastric epithelial mitochondria downregulates gastric cancer mitochondrial biogenesis, glycolysis, GRP78-mediated cancer stemness, and increases oxidative stress, cell apoptosis under hypoxic conditions and chemosensitivity in response to 5-FU treatment. Moreover, the transplantation of epithelial mitochondria into gastric tumors inhibited the tumor growth in vivo tumor graft animal models. Therefore, mitochondrial transplantation can be considered for the treatment of gastric cancer.

Keywords:  Apoptosis; Cancer stemness; Chemoresistance; GRP78; Gastric cancer; Metabolism; Mitochondrial transplantation

DOI:  https://doi.org/10.1186/s13287-025-04223-7
Cell Death Discov. 2025 Feb 23. 11(1): 75

SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance.

Guojiang Wei, Ying Huang, Wenya Li, Yuxin Xie, Deyi Zhang, Yuanjie Niu, Yang Zhao.

Metabolic reprogramming in prostate cancer has been widely recognized as a promoter of tumor progression and treatment resistance. This study investigated its association with ferroptosis resistance in prostate cancer and explored its therapeutic potential. In this study, we identified differences in the epithelial characteristics between normal prostate tissue and tissues of various types of prostate cancer using single-cell sequencing. Through transcription factor regulatory network analysis, we focused on the candidate transcription factor, SREBF1. We identified the differences in SREBF1 transcriptional activity and its association with ferroptosis, and further verified this association using hdWGCNA. We constructed a risk score based on SREBF1 target genes associated with the biochemical recurrence of prostate cancer by combining bulk RNA analysis. Finally, we verified the effects of the SREBPs inhibitor Betulin on the treatment of prostate cancer and its chemosensitization effect. We observed characteristic differences in fatty acid and cholesterol metabolism between normal prostate tissue and prostate cancer tissue, identifying high transcriptional activity of SREBF1 in prostate cancer tissue. This indicates that SREBF1 is crucial for the metabolic reprogramming of prostate cancer, and that its mediated metabolic changes promoted ferroptosis resistance in prostate cancer in multiple ways. SREBF1 target genes are associated with biochemical recurrence of prostate cancer. Finally, our experiments verified that SREBF1 inhibitors can significantly promote an increase in ROS, the decrease in GSH, and the decrease in mitochondrial membrane potential in prostate cancer cells and confirmed their chemosensitization effect in vivo. Our findings highlighted a close association between SREBF1 and ferroptosis resistance in prostate cancer. SREBF1 significantly influences metabolic reprogramming in prostate cancer cells, leading to ferroptosis resistance. Importantly, our results demonstrated that SREBF1 inhibitors can significantly enhance the therapeutic effect and chemosensitization of prostate cancer, suggesting a promising therapeutic potential for the treatment of prostate cancer.

DOI: https://doi.org/10.1038/s41420-025-02354-7
Cell Death Dis. 2025 Feb 22. 16(1): 124

NF-κB-mediated EAAT3 upregulation in antioxidant defense and ferroptosis sensitivity in lung cancer.

Donghua Wen, Wenjing Li, Xiang Song, Min Hu, Yueling Liao, Dongliang Xu, Jiong Deng, Wenzheng Guo.

Cellular glutathione (GSH) in lung cancer cells represents the most abundant antioxidant. GSH production is regulated not only by upregulated cystine/glutamate exchanger (xCT) but also by the involvement of glutamate transporters, specifically excitatory amino acid transporter 3 (EAAT3). Our prior research established that the uptake of glutamate via EAAT3 plays a pivotal role in driving cystine uptake through xCT, contributing to GSH biosynthesis during lung tumorigenesis. Nevertheless, the underlying mechanism governing the upregulation of EAAT3 remains enigmatic. In this study, we conducted a comprehensive reanalysis of publicly available data and employed the Gprc5a-/-/SR-IκB mouse model alongside in vitro cell experiments to elucidate the correlations between NF-κB and EAAT3 in lung cancer. We observed that EAAT3 knockdown, similar to NF-κB inhibition, led to the accumulation of reactive oxygen species (ROS) and increased sensitivity to ferroptosis induction by RAS-selective lethal 3 (RSL3). Mechanistic insights were obtained through chromatin immunoprecipitation and luciferase reporter assays, revealing that NF-κB induces EAAT3 expression via two putative cis-elements within its promoter. Furthermore, our investigation unveiled the upregulation of EAAT3 in a subset of clinical non-small cell lung cancer (NSCLC) tissues, exhibiting a positive correlation with the P65 protein. In addition, the inflammatory factor of smoking was found to augment EAAT3 expression in both human and murine experimental models. These findings collectively emphasize the pivotal role of the NF-κB/EAAT3 axis in managing antioxidant stress and influencing lung cancer development. Moreover, this research offers insights into the potential for a combined ferroptosis therapy strategy in lung cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07453-y
Cell Biol Int. 2025 Feb 27.

Chlorogenic Acid Enhances Beta-Lapachone-Induced Cell Death by Suppressing Autophagy in NQO1-Positive Cancer Cells.

Sahib Zada, Md Entaz Bahar, Wanil Kim, Deok Ryong Kim.

  Resistance to apoptosis-inducing drugs frequently occurs in cancer cells, limiting their usefulness in ongoing cancer treatment. Despite ongoing efforts to overcome drug resistance, a definitive solution remains elusive. However, autophagy inhibition has been shown to enhance the effectiveness of some anticancer drugs and is a possible strategy for overcoming drug resistance. In this study, we demonstrate that chlorogenic acid (CGA), a natural antioxidant, significantly enhances beta-lapachone (β-Lap)-induced cell death in cancer cells. The augmented apoptosis induced by CGA is associated with activation of protein kinase A (PKA) in β-Lap-treated cells, independent of the antioxidant properties of CGA. As a result, PKA activation in cancer cells co-treated with β-Lap and CGA effectively inhibits autophagy. Notably, PKA activation leads to phosphorylation of microtubule-associated protein 1 A/1B-light chain 3 (LC3) at the serine 12 residue, causing autophagy suppression irrespective of mTORC activity. Importantly, the cell death induced by β-Lap and CGA in NQO1-overexpressing breast or lung cancers is closely linked to autophagy inhibition. These findings suggest that combining β-Lap and CGA might be a novel strategy for cancer therapy, particularly for overcoming drug resistance caused by autophagy induction in cancer cells.

Keywords:  PKA; apoptosis; autophagy; beta‐Lapachone; chlorogenic acid; combination therapy

DOI:  https://doi.org/10.1002/cbin.70006
Cancer Res. 2025 Feb 24.

Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.

Yanyun Lin, Yanhong Zhang, Tianze Huang, Junguo Chen, Guanman Li, Bin Zhang, Liang Xu, Kai Wang, Hui He, Hao Chen, Danling Liu, Shuang Guo, Xiaosheng He, Ping Lan.

Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer (CRC) due to the deficiency of ornithine transcarbamylase (OTC). Accordingly, CRC cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of CRC to arginine deprivation, which dramatically decreased proliferation in CRC cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that CRC cells may be vulnerable to ferroptosis during arginine deprivation, and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1940
J Exp Clin Cancer Res. 2025 Feb 24. 44(1): 67

CD47 blockade reverses resistance to HDAC inhibitor by liberating anti-tumor capacity of macrophages.

Xutao Xu, Qianqian Wang, Ke Guo, Junjie Xu, Yunkun Lu, Huijuan Chen, Weilin Hu, Yilin Fu, Lu Sun, Ying He, Zhehang Chen, Wenhao Xia, Mengtian Pan, Beibei Lin, Wenjuan Yang, Qingqing Wang, Zhenzhen Wen, Qian Cao, Peng Xiao.

   BACKGROUND: Targeting oncogenic histone modification by histone deacetylase inhibitors (HDACis) demonstrates promising prospects in clinical cancer treatment, whereas a notable proportion of patients cannot benefit from HDACi therapy. This study aims to explore how HDACi influences the tumor microenvironment, in order to identify potential targets for reversing the resistance to HDACi therapies.
METHODS: Macrophage infiltration was compared between HDACi-responding and HDACi-nonresponding cancer patients. The impact of HDACis on the phagocytic capacity of macrophages was investigated through macrophage-tumor cell co-culture system. CD47 expression in tumor cell lines and patient-derived organoids was evaluated by quantitative polymerase chain reaction (QPCR) and flow cytometry. Mechanistic studies were conducted through co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP). The synergistic effect of HDACis and CD47 neutralizing antibody was assessed in subcutaneous murine tumor models. Bioinformatics approaches were adopted to analyze how macrophage infiltration determines the prognostic significance of CD47 expression in cancer patients.
RESULTS: High macrophage infiltration is a determinant of therapeutic non-response to HDACi, cancer patients who did not respond to HDACi exhibit massive infiltration of tumor-associated macrophages (TAMs). TAM depletion reversed the resistance to HDACi therapy. Mechanistically, HDACi impaired the phagocytic capacity of macrophages against tumor cells through epigenetically upregulating CD47 expression. Reciprocally, HDACi-upregulated CD47 polarized macrophages towards a pro-tumor M2 phenotype through SIRPα ligation. In tumor-bearing mice, HDACi monotherapy only marginally delayed tumor progression, while the concurrent neutralization of CD47 exhibited potent anti-tumor effect through re-educating TAMs towards a tumoricidal phenotype. In cancer patients, CD47 was found to determine the prognostic significance of TAMs.
CONCLUSIONS: Our study offers a rationale for targeting macrophage infiltration or blocking CD47 to sensitize HDACi therapies in cancer patients.

Keywords:  CD47; Cancer; HDAC inhibitor; Macrophage; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-025-03335-5
Int J Mol Sci. 2025 Feb 12. pii: 1559. [Epub ahead of print]26(4):

Adaptive Proteomic Changes in Protein Metabolism and Mitochondrial Alterations Associated with Resistance to Trastuzumab and Pertuzumab Therapy in HER2-Positive Breast Cancer.

Juan Madoz-Gúrpide, Juana Serrano-López, Marta Sanz-Álvarez, Miriam Morales-Gallego, Socorro María Rodríguez-Pinilla, Ana Rovira, Joan Albanell, Federico Rojo.

  HER2 (human epidermal growth factor receptor 2) is overexpressed in approximately 15-20% of breast cancers, leading to aggressive tumour growth and poor prognosis. Anti-HER2 therapies, such as trastuzumab and pertuzumab, have significantly improved the outcomes for patients with HER2-positive breast cancer by blocking HER2 signalling. However, intrinsic and acquired resistance remains a major clinical challenge, limiting the long-term effectiveness of these therapies. Understanding the mechanisms of resistance is essential for developing strategies to overcome it and improve the therapeutic outcomes. We generated multiple HER2-positive breast cancer cell line models resistant to trastuzumab and pertuzumab combination therapy. Using mass spectrometry-based proteomics, we conducted a comprehensive analysis to identify the mechanisms underlying resistance. Proteomic analysis identified 618 differentially expressed proteins, with a core of 83 overexpressed and 118 downregulated proteins. Through a series of advanced bioinformatics analyses, we identified significant protein alterations and signalling pathways potentially responsible for the development of resistance, revealing key alterations in the protein metabolism, mitochondrial function, and signalling pathways, such as MAPK, TNF, and TGFβ. These findings identify mitochondrial activity and detoxification processes as pivotal mechanisms underlying the resistance to anti-HER2 therapy. Additionally, we identified key proteins, including ANXA1, SLC2A1, and PPIG, which contribute to the tumour progression and resistance phenotype. Our study suggests that targeting these pathways and proteins could form the basis of novel therapeutic strategies to overcome resistance in HER2-positive breast cancer.

Keywords:  HER2-positive; bioinformatics; breast cancer; label-free proteomics; pertuzumab; resistance; targeted therapy; trastuzumab

DOI:  https://doi.org/10.3390/ijms26041559
Cancer Metab. 2025 Feb 25. 13(1): 11

Glutathione peroxidase 4 (GPX4) and obesity interact to impact tumor progression and treatment response in triple negative breast cancer.

Emily N Devericks, Bennett H Brosnan, Alyssa N Ho, Elaine M Glenny, Hannah M Malian, Dorothy Teegarden, Michael K Wendt, Michael F Coleman, Stephen D Hursting.

INTRODUCTION: Triple-negative breast cancer (TNBC), which tends to be more advanced when diagnosed and more aggressive than other breast cancer subtypes, is accelerated by obesity. Hypertrophic adipocytes and cancer cells exhibit increased oxidative stress and altered redox homeostasis, influencing therapeutic outcomes. Enzymes implicated in both redox regulation and TNBC include glutathione peroxidase 4 (GPX4; reduces lipid peroxides) and pyruvate carboxylase (PC; essential in oxidative stress protection). Using preclinical models, we characterized interactions between GPX4, PC, and oxidative stress in TNBC cells, and established effects of GPX4 suppression on TNBC progression. In TNBC cells, PC knockdown increased GPX4 expression, while GPX4 knockdown increased PC expression. GPX4 inhibition by erastin or RSL3 enhanced TNBC cell death in vitro, and antioxidants mitigated the cytotoxicity. In obese mice, GPX4 knockdown, versus scramble control: (i) reduced tumor burden following orthotopic transplantation of TNBC cells; and (ii) reduced lung metastasis following tail vein injection of TNBC cells in combination with chemotherapy (carboplatin) but not immunotherapy (anti-CTLA4 plus anti-PD1). We conclude that GPX4 and PC expression are inversely related in TNBC cells, and GPX4 and obesity interact to impact TNBC progression and treatment responses. Moreover, GPX4-mediated redox defense, alone or in combination with chemotherapy, is a targetable vulnerability for treating TNBC, including obesity-related TNBC.
IMPLICATION: GPX4 suppression, alone or with current TNBC therapies, impacts outcomes in preclinical TNBC models with or without obesity and offers a new, plausible mechanistic target for TNBC treatment.

DOI: https://doi.org/10.1186/s40170-025-00380-8
Cell Death Dis. 2025 Feb 23. 16(1): 125

STX17-DT facilitates axitinib resistance in renal cell carcinoma by inhibiting mitochondrial ROS accumulation and ferroptosis.

Yihui Pan, Shuang Liu, Guannan Shu, Minyu Chen, Liangmin Fu, Cheng Chen, Yimeng Chen, Qianfeng Zhuang, Dong Xue, Xiaozhou He.

Axitinib resistance remains a serious challenge in the treatment of advanced renal cell carcinoma (RCC), and the underlying mechanisms are not fully understood. Here, we constructed an in vivo axitinib-resistant RCC model and identified the long non-coding RNA STX17-DT as a driver of therapy resistance in RCC. The expression of STX17-DT was significantly elevated in axitinib-resistant RCC cells and correlated with poorer prognosis in RCC patients. Elevated levels of STX17-DT contributed to the development of resistance to axitinib both in vitro and in vivo. Mechanistically, STX17-DT modulated the stability of IFI6 mRNA by recruiting and binding to hnRNPA1, leading to decreased accumulation of mitochondrial reactive oxygen species (ROS) and attenuated ferroptosis. Meanwhile, STX17-DT was packaged into extracellular vesicles through hnRNPA1, thus transmitting axitinib resistance to other cells. Compared with axitinib monotherapy, combined treatment of axitinib and STX17-DT-targeted in vivo siRNA demonstrated enhanced therapeutic efficacy. These findings indicate a novel molecular mechanism of axitinib resistance in RCC and suggest that STX17-DT may serve as a prognostic indicator and potential therapeutic target to overcome resistance to targeted therapy.

DOI: https://doi.org/10.1038/s41419-025-07456-9
Neoplasia. 2025 Feb 24. pii: S1476-5586(25)00022-3. [Epub ahead of print]62 101143

Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer.

Travis Vander Steen, Ingrid Espinoza, Cristina Duran, Guillem Casadevall, Eila Serrano-Hervás, Elisabet Cuyàs, Sara Verdura, George Kemble, Scott H Kaufmann, Robert McWilliams, Sílvia Osuna, Daniel D Billadeau, Javier A Menendez, Ruth Lupu.

  Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of "FASN-high" expressing PDAC cells to the BCL2/BCL-XL/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.

Keywords:  BH3 mimetics; Fatty acid synthase; Gemcitabine; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.neo.2025.101143
J Cancer. 2025 ;16(5): 1694-1708

NUPR1 contributes to endocrine therapy resistance by modulating BIRC5 expression and inducing luminal B-ERBB2+ subtype-like characteristics in estrogen receptor-positive breast cancer cells.

Chun-Hui Lee, Yi-Chen Lin, Yung-Chieh Chang, Pin-Chen Chen, Kai-Hsuan Lin, Tzu-Miao Yeh, Euphemia Yee Leung, I-Li Lin, Shang-Hung Chen, Chun Hei Antonio Cheung.

  Acquired resistance to endocrine therapy is a major clinical challenge in the treatment of luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (ERBB2/HER2)-, and low Ki-67] breast cancer. Recently, molecular subtype conversion has been suggested as one of the possible causes of the development of drug-resistant breast cancer. However, the molecular mechanism underlying the molecular subtype conversion and the induction of endocrine therapy resistance in luminal A breast cancer is still incompletely understood. Here, we found that the ER+ MCF7-derived endocrine therapy-resistant MCF7-TamC3 breast cancer cells exhibit increased expression of an intrinsically disordered chromatin protein, NUPR1, compared to the parental luminal-A subtype like MCF7 breast cancer cells. Intriguingly, MCF7-TamC3 cells also exhibit characteristics that resemble the luminal B-ERBB2+ breast tumor subtype, like the increased expression of ERBB2 and the increased sensitivity to monoclonal ERBB2-targeting antibody Trastuzumab in vitro. Kaplan-Meier analysis of expression cohorts of breast tumors showed that high NUPR1 mRNA expression levels correlate with poor overall and relapse-free survival in both endocrine therapy-treated ER+ and ERBB2-enriched breast cancer patients. Results of the bioinformatics analysis showed that the NUPR1 mRNA expression level is also correlated with the clinical grading of the Tamoxifen-treated ER+ primary breast cancer. The qPCR and the western blot analysis results revealed that NUPR1 positively regulates the expression of the epigenetic regulator HDAC5, the anti-apoptotic molecule BIRC5, and the mitogenic receptor ERBB2 in MCF7-TamC3 and the ERBB2-enriched subtype like SK-BR-3 breast cancer cells. Downregulation of NUPR1 increased the sensitivity to estrogen deprivation in MCF7-TamC3 cells and decreased the viability of SK-BR-3 cells in vitro. These findings indicate that dysregulation of NUPR1 promotes the development of estrogen independence in ER+ breast cancer cells in part through expression regulation of HDAC5, ERBB2, and BIRC5. Targeting NUPR1 or its downstream regulating molecules may offer a potential strategy for overcoming resistance to endocrine therapy in patients with ER+ breast cancer.

Keywords:  BIRC5; Breast cancer; ERBB2; HDAC5; NUPR1; drug resistance

DOI:  https://doi.org/10.7150/jca.105425
BMC Med Genomics. 2025 Feb 26. 18(1): 39

USP2 reversed cisplatin resistance through p53-mediated ferroptosis in NSCLC.

Yanmei Gong, Ruichao Li, Rui Zhang, Li Jia.

   BACKGROUND: It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance.
METHODS: Ubiquitin-specific protease mRNA expression, was detected through RT-qPCR. In vitro functional assays assessed the effects of USP2 overexpression on DDP resistance, cell proliferation capability, and ferroptosis markers in A549/DDP and H1299/DDP cells. Ubiquitination assays evaluated the ubiquitination levels of p53 following USP2 overexpression. Co-immunoprecipitation (Co-IP) assays confirmed the binding relationship between USP2 and p53. In vivo experiments in mice explored the specific role of the USP2-p53 axis in a xenograft tumor model.
RESULTS: USP2 expression was suppressed in cisplatin-resistant NSCLC cells. USP2 overexpression inhibited cell viability in cisplatin-resistant cells. Among the ferroptosis markers, the results showed that USP2 overexpression promoted LDH release, Fe2+ level, MDA and Lipid ROS, while inhibited GPX4 activity and GSH levels. The WB results revealed that USP2 overexpression inhibited GPX4, SLC7A11 and cytoplasm p53 protein expression, while promoted the nucleus p53 protein expression. Moreover, USP2 directly bound to p53 and USP2 overexpression stabilized p53 protein by suppressing its ubiquitination. In vivo experiments further suggest that the USP2-p53 pathway plays a crucial role in regulating cisplatin sensitivity in A549/DDP cells.
CONCLUSION: USP2 acted on the K305R site of p53, which resulted in its deubiquitination. This cellular process could modulate cisplatin resistance through ferroptosis in NSCLC. This study could provide a potential therapeutic target to NSCLC.

Keywords:  Cisplatin resistance; Ferroptosis; USP2; p53

DOI:  https://doi.org/10.1186/s12920-025-02108-5
Cancer Discov. 2025 Feb 28.

Functional reprogramming of neutrophils within the brain tumor microenvironment by hypoxia-driven histone lactylation.

Alessio Ugolini, Alessandra De Leo, Xiaoqing Yu, Fabio Scirocchi, Xiaoxian Liu, Barbara Peixoto, Delia Scocozza, Angelica Pace, Michela Perego, Alessandro Gardini, Luca D'Angelo, James K C Liu, Arnold B Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A Vogelbaum, Jose R Conejo-Garcia, Paulo C Rodriguez, Filippo Veglia.

Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcomes. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and resistance to immunotherapies. However, the mechanisms underlying neutrophil reprogramming remain elusive. Here, we report that the immunosuppressive ability of brain tumor-infiltrating neutrophils was restricted to a highly glycolytic and long-lived subset expressing CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+neutrophils, leading to high lactate production. Lactate caused histone lactylation, which subsequently regulated arginase-1 expression, required for T cell suppression. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked CD71+neutrophil immunosuppressive ability, delayed tumor progression and sensitized brain tumors to immunotherapy. A distinctive gene signature characterizing immunosuppressive CD71+neutrophils correlated with adverse clinical outcomes across diverse human malignancies. This study identifies histone lactylation as a potential therapeutic target to counteract neutrophil-induced immunosuppression within tumors.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1056
J Transl Med. 2025 Feb 21. 23(1): 220

SPICE1 promotes osteosarcoma growth by enhancing the deubiquitination of FASN mediated by USP10.

Weilai Tong, Xinsheng Xie, Zhiguo Shu, Jiangbo Nie, Xianhe Yang, Feng Yang, Zhili Liu, Jiaming Liu.

   BACKGROUND: Osteosarcoma (OS) is recognized as a prevalent primary bone malignancy, particularly affecting adolescents during their growth spurts. Despite its clinical significance, the underlying biological characteristics and associated prognostic factors remain incompletely understood. The identification of novel molecular players involved in osteosarcoma progression could enhance our understanding of its pathogenesis and potentially inform patient management strategies.
METHODS: In this study, we investigated the expression levels of Spindle and Centriole-Associated Protein 1 (SPICE1) in OS cells and tissues through quantitative analyses. We performed in vitro and in vivo experiments to evaluate the proliferation effects of SPICE1 on OS cells. Additionally, we explored the mechanistic interactions between SPICE1, Fatty Acid Synthase (FASN), and ubiquitin-specific peptidase 10 (USP10) through co-immunoprecipitation and mutation analyses, including the design of a peptide to inhibit the SPICE1-FASN interaction.
RESULTS: Our findings revealed that SPICE1 is significantly overexpressed in OS samples. Furthermore, this high expression correlates with poor patient prognosis. The elevated levels of SPICE1 were found to promote OS cell proliferation by inhibiting the ubiquitination of FASN, consequently enhancing FASN protein stability. Additionally, SPICE1 was shown to facilitate the interaction between USP10 and FASN, promoting FASN deubiquitination, with specific amino acid interactions identified between USP10 and FASN that are necessary for this process.
CONCLUSION: This study elucidates the role of SPICE1 as a potential oncogene in OS, highlighting its contribution to tumor growth through the modulation of FASN stability. Importantly, our results suggest that targeting the SPICE1/USP10/FASN signaling axis could offer a novel therapeutic approach for treating OS. Future investigations should focus on the development of specific inhibitors that disrupt this pathway, ultimately leading to improved clinical outcomes for patients with OS.

Keywords:  Deubiquitination; FASN; Osteosarcoma; SPICE1; USP10

DOI:  https://doi.org/10.1186/s12967-025-06248-1
Int J Mol Sci. 2025 Feb 18. pii: 1719. [Epub ahead of print]26(4):

NAD+ Boosting Through NRH Supplementation Enhances Treatment Efficacy in EOC In Vitro.

Kevin J Lee, Sagar Chokshi, Tanvi Joshi, Mackenzie Cummings, Catherine E Lyons, Mary Howard Singleton, Elizabeth Catranis, Luciana Madiera da Silva, Faisal Hayat, Marie Migaud, Jennifer Scalici.

  Dihydronicotinamide rioside (NRH), the reduced form of nicotinamide riboside (NR), is a recently identified, naturally occurring precursor of arguably the most crucial cofactor for cellular function, nicotinamide adenine dinucleotide (NAD+). Recent investigation suggests that NRH is more adept at increasing NAD+ stores than traditional NAD+ precursors, and such extreme NAD+ boosting via NRH supplementation induces cytotoxicity in certain cellular contexts. It has also been shown that the lack of functional BRCA protein in epithelial ovarian cancer (EOC) directly impacts intracellular NAD+ levels. Given that altered cellular metabolism and DNA repair mechanisms are central alterations in EOC, and these processes are functionally dependent on NAD+, we sought to assess whether NRH supplementation in EOC cell lines enhanced cellular cytotoxicity alone and in combination with standard therapeutic agents. Significant cytotoxicity was noted in NRH treated cells (~40%) with minimal cell death in the nicotinic acid (NA)-treated lines. Levels of NAD(P)H were confirmed to have increased with NRH supplementation, albeit at different levels among the different cell lines. Overall, the cytotoxicity associated with NRH supplementation appears to be independent of ROS generation. Strikingly, NRH supplementation enhanced cytotoxicity of carboplatin in OVCAR8, but not ES2 or SKOV3. Paclitaxel cytotoxicity was also enhanced by the addition of NRH in OVCAR8, but not ES2 or SKOV3 cell lines. NA supplementation had no effect on baseline treatment-induced cytotoxicity. PARP inhibition by olaparib requires NAD+. Interestingly, NRH supplementation enhanced olaparib cytotoxicity in SKOV3 and OVCAR8, but not ES2 cells. NRH in combination with olaparib completely altered mitochondrial respiration, thereby shutting down energy consumption, which would lead to cell death. Coupled together with expression data of key enzymes required for NRH/NAD metabolism, this could be key in understanding mechanisms of cell death with NRH supplementation. Here, we showed that in the context of EOC, exploitation of the NAD+ bioenergetic phenotype through NRH supplementation is a biologically feasible strategy to enhance the response of traditional therapy with potentially minimal toxicity. These data suggest several potential mechanisms by which cellular NAD+ availability impacts treatment efficacy and resistance and highlights the potential utility of NAD+ metabolomics as a biomarker to guide treatment decisions.

Keywords:  NAD+; NRH; PARP inhibitors; olaparib; ovarian cancer

DOI:  https://doi.org/10.3390/ijms26041719
Theranostics. 2025 ;15(6): 2375-2392

DLGAP5 enhances bladder cancer chemoresistance by regulating glycolysis through MYC stabilization.

Zhao Deng, Fenfang Zhou, Mingxing Li, Wan Jin, Jingtian Yu, Gang Wang, Kaiyu Qian, Lingao Ju, Yi Zhang, Yu Xiao, Xinghuan Wang.

  Rationale: Bladder cancer (BLCA), one of the most lethal urological tumors, exhibits high rates of recurrence and chemoresistance, particularly to gemcitabine (GEM). Understanding the mechanisms of GEM resistance is crucial for improving therapeutic outcomes. Our study investigates the role of DLGAP5 in promoting GEM resistance through modulation of glycolysis and MYC protein stability in BLCA cells. Methods: We utilized various BLCA cell lines and clinical tissue samples to analyze the impact of DLGAP5 on GEM resistance. Through biochemical assays, protein interaction studies, and gene expression analyses, we examined how DLGAP5 interacts with USP11 and MYC, assessed the effects on MYC deubiquitination and stability. The influence of these interactions on glycolytic activity and GEM resistance was also evaluated via mouse subcutaneous xenograft model and spontaneous BLCA model. Results: Our findings indicate that DLGAP5 enhances GEM resistance by stabilizing MYC protein via deubiquitination, a process mediated by USP11. DLGAP5 was found to facilitate the interaction between USP11 and MYC, promoting MYC-driven transcription of DLGAP5 itself, thereby creating a positive feedback loop. This loop leads to sustained MYC accumulation and increased glycolytic activity, contributing to GEM resistance in BLCA cells. Conclusion: The study highlights the critical role of DLGAP5 in regulating MYC protein stability and suggests that disrupting the DLGAP5-USP11-MYC axis may provide a novel therapeutic approach to overcome GEM resistance in BLCA. DLGAP5 represents a potential target for therapeutic intervention aimed at mitigating chemoresistance in bladder cancer BLCA.

Keywords:  DLGAP5; MYC; bladder cancer; chemoresistance; glycolysis

DOI:  https://doi.org/10.7150/thno.102730
iScience. 2025 Feb 21. 28(2): 111864

Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer.

Yanbo Pan, Olena Berkovska, Soumitra Marathe, Georgios Mermelekas, Greta Gudoityte, Amare D Wolide, Taner Arslan, Brinton Seashore-Ludlow, Janne Lehtiö, Lukas M Orre.

  Farnesylation is a lipid post-translational modification of proteins crucial for protein membrane anchoring and cellular signaling. Farnesyltransferase inhibitors (FTIs), such as tipifarnib, are being tested in cancer therapy. However, the full impact of FTIs on farnesylation substrates remains poorly understood, thus limiting their use in precision medicine. In this study, we performed a global proteomics analysis to investigate farnesylation and the effects of tipifarnib in lung cancer cell lines. Using metabolic labeling and mass spectrometry, we identified farnesylated proteins and mapped their subcellular localization. We also analyzed tipifarnib-dependent protein relocalization and proteome-wide changes. Key findings include the potential therapeutic value of FTIs for NRAS-mutated melanoma and GNAQ/GNA11-mutated uveal melanoma by inhibiting INPP5A farnesylation. Additionally, we identified a synergistic drug combination involving tipifarnib and a ferroptosis inducer and discovered PTP4A1 as a regulator of interferon signaling. Our data, covering 15,080 proteins, offer valuable insights for future studies of farnesylation and FTIs.

Keywords:  Cancer; Cell biology; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2025.111864
Chem Sci. 2025 Feb 17.

Metal-organic layer delivers 3-bromopyruvate to mitochondria for metabolic regulation and cancer radio-immunotherapy.

Wangqing Bian, Xiaomin Jiang, Jinhong Li, Langston Tillman, Chaoyu Wang, Wenyao Zhen, Ralph R Weichselbaum, Tobias Fromme, Wenbin Lin.

Abnormal cancer metabolism causes hypoxia and immunosuppression, limiting the anti-tumor efficacy of radiotherapy. Herein, we report a positively charged, mitochondria-targeted nanoscale metal-organic layer conjugated with 3-bromopyruvate (BP), BP/Hf12-Ir, for metabolic reprogramming and radiosensitization. BP/Hf12-Ir disrupts oxidative phosphorylation and glycolysis, reducing energy production and alleviating hypoxia to enhance radiotherapy and anti-tumor immunity. BP/Hf12-Ir in combination with X-ray irradiation inhibits tumor growth by 95% and prevents lung metastasis in mouse models. When further combined with immune checkpoint blockade, this treatment induces robust anti-tumor immunity, achieving 98% tumor growth inhibition.

DOI: https://doi.org/10.1039/d4sc08563a