bims-meract 2025-06-29 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–06–29
23 papers selected by
Andrea Morandi, Università degli Studi di Firenze

GDF-15 upregulates the SLC7A11/GPX4 signaling axis and promotes mitoxantrone resistance in AML cells.
The Landscape of Cancer Metabolism as a Therapeutic Target.
ELOVL2 mediated stabilization of AR contributes to enzalutamide resistance in prostate cancer.
MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer.
DUSP1 protein's impact on breast cancer: Anticancer response and sensitivity to cisplatin.
Landscape of metabolic alterations and treatment strategies in breast cancer.
D-lactate and glycerol as potential biomarkers of sorafenib activity in hepatocellular carcinoma.
Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.
Chronic PFAS Exposure Induces Chemotherapy Resistance by Promoting Mitochondria-Related Alterations in Ovarian Cancer Cells.
Inhibition of CYP1B1 by miR-200b-3p increases the sensitivity of paclitaxel in hepatocellular carcinoma treatment.
Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD.
HSD3B1 Upregulation via LRH1 Sustains Estrogen Receptor Signaling and Promotes Endocrine Resistance in Breast Cancer.
Targeting carbonic anhydrase IX/XII prevents the anti-ferroptotic effect of stromal lactic acid in prostate carcinoma.
Citrullinated ENO1 Vaccine Enhances PD-1 Blockade in Mice Implanted with Murine Triple-Negative Breast Cancer Cells.
Adipocytes Promote Cisplatin Resistance through Secreting A1BG and Regulating NAMPT/PARP1 Axis-Mediated DNA Repair in Osteosarcoma.
Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets.
The Nrf2-HMOX1 pathway as a therapeutic target for reversing cisplatin resistance in non-small cell lung cancer via inhibiting ferroptosis.
EGFR inhibitor suppresses tumor growth by blocking lipid uptake and cholesterol synthesis in non-small cell lung cancer.
Benserazide‑mediated targeting hexokinase 2 enhances the cytotoxicity of cisplatin in non-small cell lung cancer cell models.
Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.
Metabolites as agents and targets for cancer immunotherapy.
Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti-PD-1 resistance in hepatocellular carcinoma.
USP7-DDX5-FASN axis drives fatty acid metabolism and supports hepatocellular carcinoma progression.

Eur J Med Res. 2025 Jun 21. 30(1): 504

GDF-15 upregulates the SLC7A11/GPX4 signaling axis and promotes mitoxantrone resistance in AML cells.

Qian-Wei Lu, Yang Liao.

  Chemotherapy resistance poses a significant challenge in the initial treatment of acute myeloid leukemia (AML). Growth differentiation factor 15 (GDF-15) has been shown to play a critical role in cancer progression; however, the potential mechanisms by which GDF-15 contributes to AML progression and chemotherapy resistance remain unclear. We found that M2 macrophages secrete high levels of GDF-15, promoting resistance of AML cells to mitoxantrone (MTX). Furthermore, we demonstrated that MTX induces downregulation of the SLC7A11/GPX4 signaling axis in AML cells, mediating ferroptosis. GDF-15 enhances the expression of the SLC7A11/GPX4 axis, thereby inhibiting ferroptosis in AML cells and contributing to drug resistance. In addition, GDF-15 mitigates the decline in mitochondrial membrane potential and mitochondrial quality induced by MTX. In vivo experiments indicate that blocking GDF-15 effectively enhances the sensitivity of AML cells to mitoxantrone by reducing the expression of the SLC7A11/GPX4 axis.

Keywords:  Acute myeloid leukemia; Chemoresistance; Ferroptosis; GDF-15

DOI:  https://doi.org/10.1186/s40001-025-02787-x
Pathol Int. 2025 Jun 24.

The Landscape of Cancer Metabolism as a Therapeutic Target.

Kenji Ohshima.

  Cancer cells reprogram their metabolism during progression to adapt to the tumor microenvironment, which is characterized by distinct differences in nutrient availability, oxygen concentrations, and acidity. This metabolic reprogramming can simultaneously create metabolic vulnerabilities unique to cancer cells, making cancer metabolism a promising therapeutic target. Since the clinical application of folate antimetabolites in the 1940s, numerous therapeutic strategies targeting cancer metabolism have been developed. In recent years, advancements in technologies such as metabolome analysis have facilitated the development of agents that more specifically target cancer cell metabolism. However, these newly developed agents often face challenges in demonstrating efficacy as monotherapies in clinical trials. Nevertheless, combination therapies, designed based on precise mechanistic insights and incorporating agents such as immune-checkpoint and signaling-pathway inhibitors, have shown promising efficacy. This review provides an overview of the current landscape of therapeutic strategies targeting cancer metabolism, with a particular focus on approaches targeting amino acid, fatty acid, and glucose metabolism in cancer cells.

Keywords:  amino acid metabolism; cancer metabolism; cancer therapy; combination therapy; fatty acid metabolism; glucose metabolism

DOI:  https://doi.org/10.1111/pin.70034
Front Cell Dev Biol. 2025 ;13 1598400

ELOVL2 mediated stabilization of AR contributes to enzalutamide resistance in prostate cancer.

Jinpeng Cen, Jiading Guo, Xianzi Zeng, Xianlu Song, Shengdong Ge, Mingkun Chen, Qianyi Li, Yuzhong Yu, Daojun Lv, Shanchao Zhao.

   Introduction: To investigate the molecular mechanisms underlying enzalutamide resistance in castration-resistant prostate cancer (CRPC) and explore potential therapeutic strategies to overcome resistance.
Methods: We conducted comprehensive bioinformatic analysis using LNCaP/enzalutamide-resistant cells to identify key pathways associated with resistance. Functional validation was performed through targeted inhibition of the elongation of very-long chain fatty acid protein 2 (ELOVL2), followed by assays to assess cancer cell proliferation and enzalutamide sensitivity. Mechanistic studies were conducted to evaluate the impact of ELOVL2 on the ubiquitin-proteasome system and AR signaling pathways.
Results: Bioinformatic analysis revealed that activation of fatty acid metabolism, particularly through upregulation of ELOVL2, plays a critical role in driving enzalutamide resistance in PCa. Functional studies demonstrated that targeted inhibition of ELOVL2 significantly suppressed cancer cell proliferation and restored enzalutamide sensitivity in resistant cells. Mechanistically, ELOVL2 facilitates enzalutamide resistance by impairing the ubiquitin-proteasome system, leading to the subsequent activation of AR signaling pathways.
Discussion: Our findings demonstrate that ELOVL2 drives enzalutamide resistance in CRPC by stabilizing AR through inhibition of ubiquitin-proteasome-mediated degradation. Targeting ELOVL2 represents a promising therapeutic strategy to overcome resistance in CRPC, with potential to improve clinical outcomes for patients.

Keywords:  CRPC; ELOVL2; androgen receptor; enzalutamide resistance; prostate cancer

DOI:  https://doi.org/10.3389/fcell.2025.1598400
Adv Sci (Weinh). 2025 Jun 23. e00421

MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer.

Yin-Ling Zhang, Min-Ying Huang, Shao-Ying Yang, Jia-Yang Cai, Qian Zhao, Fang-Lin Zhang, Xin Hu, Zhi-Min Shao, Li Liao, A-Yong Cao, Da-Qiang Li.

  Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective targeted therapeutics. Mitochondrial metabolism is intimately linked to TNBC progression and therapeutic resistance and is an attractive therapeutic target for TNBC. Here, it is first reported that human transmembrane protein 65 (TMEM65), a poorly characterized mitochondrial inner-membrane protein-encoding gene in human cancer, acts as a novel oncogene in TNBC to promote tumor growth, metastasis, and cisplatin resistance both in vivo and in vitro. Transcription factor MYC and DNA demethylase ten-eleven translocation 3 (TET3) coordinately upregulate TMEM65 in TNBC, and its upregulation is associated with poor patient survival. Moreover, pharmacological inhibition or knockdown of MYC and TET3 attenuates TMEM65-driven TNBC progression. Mechanistic investigations reveal that TMEM65 enhances mitochondrial oxidative phosphorylation and its byproduct reactive oxygen species (ROS) production. Increased ROS induces the expression of hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates serpin family B member 3 (SERPINB3) to enhance TNBC stemness, thus leading to TNBC progression and cisplatin resistance. Collectively, these findings identify TMEM65 as a vital oncogene of TNBC, unveil its regulatory mechanisms, and shed light on its potential role in TNBC therapy.

Keywords:  cancer stemness; chemoresistance; mitochondrial metabolism; transmembrane protein; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.202500421
Biochim Biophys Acta Gene Regul Mech. 2025 Jun 25. pii: S1874-9399(25)00028-8. [Epub ahead of print] 195103

DUSP1 protein's impact on breast cancer: Anticancer response and sensitivity to cisplatin.

Sefa Metin, Hilal Altan, Ergün Tercan, Bala Gur Dedeoglu, Hakan Gurdal.

  Dual-Specificity Phosphatase 1 (DUSP1) modulates the activity of members of the Mitogen-Activated Protein Kinase (MAPK) family, including p38, JNK, and ERK1/2, which affects various cellular functions in cancer. Moreover, DUSP1 is known to influence the outcomes of cancer chemotherapy. This study aimed to reduce DUSP1 protein expression using CRISPR/Cas9 and siRNA and assess its effects on cell proliferation, migration, and tumor growth potential in triple-negative breast cancer (TNBC) cells. We examined the expression levels of p38, JNK, and ERK1/2, along with their phosphorylated forms, and investigated DUSP1's influence to cisplatin sensitivity. Our findings revealed that the downregulation of DUSP1 expression inhibited the proliferation, migration, and tumor growth potential of TNBC cells. Additionally, BCI, an inhibitor of DUSP1/6, demonstrated anti-proliferative effects on these cells. Decreasing the expression of DUSP1 increased the phosphorylation ratio of p38 and JNK, but not ERK1/2. Moreover, the anticancer response induced by cisplatin was enhanced by reducing DUSP1 expression or by treating the cells with BCI. Notably, cisplatin treatment increased p38 phosphorylation, which was significantly augmented by reduced DUSP1 expression. We also demonstrated that the DUSP1 inhibition-induced anticancer response in these cells predominantly relied on p38 activity. These findings contribute to a better understanding of the role of DUSP1 in breast cancer and offer insights into potential therapeutic strategies targeting DUSP1 to enhance the efficacy of cisplatin treatment. Our study highlights that decreased DUSP1 protein expression and activity mediates an anticancer response and increases the sensitivity of MDA-MB231 cells to cisplatin by regulating p38.

Keywords:  Breast Cancer; Cisplatin; DUSP1; ERK; JNK; p38

DOI:  https://doi.org/10.1016/j.bbagrm.2025.195103
Genes Dis. 2025 Sep;12(5): 101521

Landscape of metabolic alterations and treatment strategies in breast cancer.

Xiujuan Wu, Xuanni Tan, Yangqiu Bao, Wenting Yan, Yi Zhang.

  Breast cancer, the most prevalent cancer in women, poses a significant threat to their health. One of the prominent characteristics of malignant transformation in breast cancer cells is metabolic reprogramming, which encompasses glucose, lipid, and amino acid metabolism. Notably, breast cancer cells exhibit augmented energy metabolism and heightened glycolysis. In addition, there is an escalated demand for glutamine, which is met through intrinsic synthesis, uptake from extracellular sources via membrane transport proteins, or up-regulation of key metabolic enzymes in the glutamine metabolism pathway. Lipids not only serve as an energy source for tumor cells but also function as signaling molecules for intercellular communication. Extensive research in recent years has focused on unraveling the intricate mechanisms underlying metabolic reprogramming. Consequently, genes implicated in these processes have emerged as clinical therapeutic targets for cancer treatment. This review provides a comprehensive summary of the common metabolic alterations observed in cancer cells, discusses the factors and regulatory mechanisms influencing these changes, and explores potential therapeutic targets and strategies within the realm of cancer metabolism.

Keywords:  Amino acid metabolism; Breast cancer; Glucose metabolism; Lipid metabolism; Metabolic alterations

DOI:  https://doi.org/10.1016/j.gendis.2025.101521
Signal Transduct Target Ther. 2025 Jun 27. 10(1): 200

D-lactate and glycerol as potential biomarkers of sorafenib activity in hepatocellular carcinoma.

Silvia Pedretti, Francesca Palermo, Miriana Braghin, Gabriele Imperato, Pasquale Tomaiuolo, Meral Celikag, Marta Boccazzi, Veronica Vallelonga, Lorenzo Da Dalt, Giuseppe Danilo Norata, Giorgia Marisi, Ilario Giovanni Rapposelli, Andrea Casadei-Gardini, Serena Ghisletti, Maurizio Crestani, Emma De Fabiani, Nico Mitro.

Sorafenib, a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), often encounters resistance within months of treatment, limiting its long-term efficacy. Despite extensive efforts, reliable plasma biomarkers to monitor drug activity remain elusive. Here, we demonstrate that metabolic reprogramming is a strategic response implemented by cancer cells to survive the therapeutic pressure. Sorafenib suppresses oxidative phosphorylation by disrupting electron transport chain supercomplex assembly and enhancing glycolysis. To mitigate the accumulation of harmful glycolytic byproducts such as advanced glycation end-products (AGEs), sorafenib-treated cells reroute excess dihydroxyacetone phosphate (DHAP) toward glycerol-3-phosphate (G3P) synthesis, supporting glycerolipid metabolism, NAD+ regeneration, and redox balance, rather than producing D-lactate via the glyoxalase pathway. Alongside, resistant cells enhance serine metabolism to boost glutathione synthesis, reinforcing antioxidant defenses. Additionally, sorafenib increases reliance on exogenous non-esterified free fatty acids and triglycerides for phospholipid remodeling. The combined effects of glycerolipid remodeling and enhanced antioxidant capacity facilitate ferroptosis escape, diminishing sorafenib's activity. Leveraging these metabolic insights, we validate our findings by investigating plasma metabolites alteration in HCC patients. We identify D-lactate accumulation as a predictor of treatment response and glycerol accumulation as a marker of resistance, highlighting their potential as novel biomarkers for sorafenib activity. As sorafenib is used in advanced HCC, early detection of treatment response is critical to guiding the therapeutic decision, optimizing treatment strategies, and improving patient outcomes.

DOI: https://doi.org/10.1038/s41392-025-02282-z
Cell Death Differ. 2025 Jun 23.

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.

Jan Dreute, Julia Stengel, Jonas Becher, David van den Borre, Maximilian Pfisterer, Marek Bartkuhn, Vanessa M Beutgen, Benardina Ndreshkjana, Ulrich Gärtner, Johannes Graumann, Michael Huck, Stephan Klatt, Chloe Leff, Henner F Farin, Andrea Nist, Roland Schmitz, Thorsten Stiewe, Julia Teply-Szymanski, Jochen Wilhelm, Alfredo Cabrera-Orefice, M Lienhard Schmitz.

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

DOI: https://doi.org/10.1038/s41418-025-01532-5
Environ Res. 2025 Jun 21. pii: S0013-9351(25)01462-8. [Epub ahead of print] 122211

Chronic PFAS Exposure Induces Chemotherapy Resistance by Promoting Mitochondria-Related Alterations in Ovarian Cancer Cells.

Brittany P Rickard, Lauren A Sapienza Lundie, Marta Overchuk, Justin Tulino, Mateus Prates Mori, James P McCord, Vesna A Chappell, Carl D Bortner, Victoria L Bae-Jump, Janine H Santos, Suzanne E Fenton, Imran Rizvi.

  Resistance to chemotherapy is a major barrier to the effective treatment of ovarian cancer; however, the role of environmental exposures in the onset of chemoresistance remains elusive. Our previous work in ovarian cancer cells suggests that short-term perfluoroalkyl substances (PFAS) exposure induce chemoresistance, potentially by influencing mitochondrial parameters, but little is known about the effects of longer-term exposures, which are more human-relevant. Since mitochondria play a critical role in determining ovarian cancer chemotherapy response, it is also important to understand the role of environmental exposures in modulating mitochondrial function. This study explored how varying durations of PFAS exposure (2-35 days) affect mitochondrial parameters known to drive chemoresistance in human ovarian cancer cell lines. An ovarian cancer cell line (OVCAR-3) that was chronically exposed to PFAS (26-35 days) was generated. Compared to short-term PFAS exposure, chronic PFAS exposures significantly increased resistance to both carboplatin and doxorubicin. Chemotherapy resistance was accompanied by increased mitochondrial superoxide production, alterations in bioenergetics, and elevated mitochondrial content. These findings suggest that PFAS exposure induces chemotherapy resistance in ovarian cancer cells in a duration-dependent manner, worsened by human-relevant chronic exposures, and that mechanisms driving these effects are influenced by the modulation of mitochondrial parameters. Future studies should focus on targeting mechanisms underlying PFAS-induced chemotherapy resistance to improve survival outcomes.

Keywords:  PFAS; chemoresistance; mitochondria; ovarian cancer; perfluoroalkyl substances; platinum resistance

DOI:  https://doi.org/10.1016/j.envres.2025.122211
J Pharmacol Sci. 2025 Aug;pii: S1347-8613(25)00059-3. [Epub ahead of print]158(4): 322-330

Inhibition of CYP1B1 by miR-200b-3p increases the sensitivity of paclitaxel in hepatocellular carcinoma treatment.

Jiaqi Wang, Jiayi Wu, Haihong Hu, Lushan Yu, Xiaoli Zheng, Su Zeng.

  Liver cancer ranks as the third leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90 % of primary liver cancer cases. Elevated expression of drug-metabolizing enzyme CYP1B1 in HCC has been identified as a potential contributor to primary paclitaxel (PTX) resistance. This study demonstrated that miR-200b-3p suppresses CYP1B1 expression in HCC cells. Meanwhile, miR-200b-3p was significantly downregulated in HCC tissues compared to adjacent normal tissues and negatively correlated with CYP1B1 expression. In addition, miR-200b-3p sensitized HCC to PTX in vitro and in vivo patient-derived xenograft (PDX) models by inhibiting CYP1B1, promoting PTX-induced microtubule polymerization, and enhancing its cell cycle-blocking effects. These findings indicate that miR-200b-3p could serve as a promising therapeutic strategy by directly targeting CYP1B1 in HCC.

Keywords:  CYP1B1; Hepatocellular carcinoma; Paclitaxel; miR-200b-3p; microRNA

DOI:  https://doi.org/10.1016/j.jphs.2025.05.014
Nat Metab. 2025 Jun 26.

Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD.

Wesley Huang, Yuezhong Zhang, Nupur K Das, Sumeet Solanki, Chesta Jain, Marwa O El-Derany, Imhoi Koo, Hannah N Bell, Noora Aabed, Rashi Singhal, Cristina Castillo, Kathryn Buscher, Yinzhi Ying, James Dimitroff, Ankit Sharma, Jiaqi Shi, Simon P Hogan, Michael K Dame, Peter D R Higgins, Justin A Colacino, Tae Gyu Oh, Jason R Spence, Andrew D Patterson, Andrew S Greenberg, Joel K Greenson, Asma Nusrat, Yatrik M Shah.

Increased reactive oxygen species (ROS) levels are a hallmark of inflammatory bowel disease (IBD) and constitute a major mechanism of epithelial cell death. Approaches to broadly inhibit ROS have had limited efficacy in treating IBD. Here we show that lipid peroxidation contributes to the pathophysiology of IBD by promoting ferroptosis, an iron-dependent form of programmed cell death. Mechanistically, we provide evidence of heterocellular crosstalk between intestinal fibroblasts and epithelial cells. In IBD tissues and mouse models of chronic colitis, acyl-CoA synthetase long-chain family 4 (ACSL4) is overexpressed in fibroblasts. ACSL4 in fibroblasts reprograms lipid metabolism and mediates intestinal epithelial cell sensitivity to ferroptosis. In mouse models, overexpressing ACSL4 in fibroblasts results in increased intestinal epithelial ferroptosis and worsened colitis, while pharmacological inhibition or deletion of fibroblast ACSL4 ameliorates colitis. Our work provides a targeted approach to therapeutic antioxidant treatments for IBD.

DOI: https://doi.org/10.1038/s42255-025-01313-x
J Biol Chem. 2025 Jun 20. pii: S0021-9258(25)02255-0. [Epub ahead of print] 110405

HSD3B1 Upregulation via LRH1 Sustains Estrogen Receptor Signaling and Promotes Endocrine Resistance in Breast Cancer.

Xiuxiu Li, Yoon-Mi Chung, Monaben Patel, Nima Sharifi.

  Endocrine resistance is a major challenge in the treatment of estrogen receptor-positive (ER+) breast cancer, often leading to disease recurrence and metastasis. 3β-Hydroxysteroid dehydrogenase 1 (3βHSD1, encoded by HSD3B1) catalyzes the rate-limiting conversion of dehydroepiandrosterone (DHEA) to androstenedione (AD), the major substrate for aromatase and a key precursor for estrogen biosynthesis. However, the regulation of HSD3B1 in endocrine-resistant breast cancer remains unclear. We show that long-term estrogen deprivation (LTED) or tamoxifen treatment induces HSD3B1 expression and enzymatic activity, sustaining DHEA metabolism and ER signaling in resistant ER+ breast cancer cells. T47D-LTED and T47D-4OHT cells exhibited increased HSD3B1 expression and enhanced DHEA metabolism. HSD3B1 deficiency impaired DHEA-driven survival, confirming its role in endocrine resistance. Mechanistically, we identify liver receptor homolog-1 (LRH1/NR5A2) as a key transcriptional regulator of HSD3B1. LRH1 inhibition suppressed HSD3B1 expression, DHEA metabolism, and ER target gene activation, demonstrating its role in sustaining estrogen synthesis and tumor adaptation. Our findings establish HSD3B1 as a critical mediator of endocrine resistance and identify LRH1 as an upstream regulator. Targeting HSD3B1 or LRH1 may offer a new therapeutic strategy to restore endocrine sensitivity in ER+ breast cancer.

Keywords:  Breast Cancer; Endocrine Resistance; HSD3B1, estrogen synthesis

DOI:  https://doi.org/10.1016/j.jbc.2025.110405
Mol Oncol. 2025 Jun 26.

Targeting carbonic anhydrase IX/XII prevents the anti-ferroptotic effect of stromal lactic acid in prostate carcinoma.

Elisa Pardella, Giuseppina Comito, Luigi Ippolito, Erica Pranzini, Marta Iozzo, Giulia Gangarossa, Francesca Virgilio, Silvia Bua, Alessio Nocentini, Giada Sandrini, Nicla Lorito, Marina Bacci, Gabriella Nesi, Pietro Spatafora, Sergio Serni, Claudiu T Supuran, Andrea Morandi, Paola Chiarugi, Elisa Giannoni.

  Ferroptosis is a form of regulated cell death dependent on iron-driven phospholipid peroxidation and is controlled by both cell autonomous and non-cell autonomous mechanisms. In prostate cancer (PCa), tumor cells engage in a metabolic crosstalk with cancer-associated fibroblasts (CAFs), resulting in increased utilization of CAF-secreted lactic acid, that ultimately supports cancer aggressiveness. In this context, the effect of the prostate tumor microenvironment in modulating ferroptosis sensitivity has not yet been extensively investigated. Here, we demonstrate that CAF-secreted lactic acid protects PCa cells from ferroptosis induction and supports the upregulation of the antioxidant enzyme glutathione peroxidase 4 (GPX4). Interestingly, targeting carbonic anhydrase IX/XII (CA IX/XII), the main regulators of microenvironmental acidosis, in tumor and stromal compartments hinders lactic acid shuttle within the tumor-stroma interplay and thus, prevents ferroptosis resistance induced by lactic acid. Analyses of tissue samples from PCa patients also revealed that GPX4, CA IX, and CA XII expression levels increase during PCa progression. Overall, these findings support a role for stromal lactic acid in mediating ferroptosis resistance in PCa, identifying CA IX/XII as potential therapeutic targets regulating ferroptosis sensitivity.

Keywords:  cancer‐associated fibroblasts; carbonic anhydrase; ferroptosis; lactic acid; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.70083
Vaccines (Basel). 2025 Jun 11. pii: 629. [Epub ahead of print]13(6):

Citrullinated ENO1 Vaccine Enhances PD-1 Blockade in Mice Implanted with Murine Triple-Negative Breast Cancer Cells.

Ricardo A León-Letelier, Alejandro M Sevillano-Mantas, Yihui Chen, Soyoung Park, Jody Vykoukal, Johannes F Fahrmann, Edwin J Ostrin, Candace Garrett, Rongzhang Dou, Yining Cai, Fu-Chung Hsiao, Jennifer B Dennison, Eduardo Vilar, Banu K Arun, Samir Hanash, Hiroyuki Katayama.

  Background/Objectives:Cancer vaccine targets mostly include mutations and overexpressed proteins. However, cancer-associated post-translational modifications (PTMs) may also induce immune responses. Previously, our group established the enzyme protein arginine deiminase type-2 (PADI2), which catalyzes citrullination modification, is highly expressed in triple-negative breast cancer (TNBC), promoting antigenicity. Methods: Here, we show the workflow of designing citrullinated enolase 1 (citENO1) vaccine peptides identified from breast cancer cells by mass spectrometry and demonstrate TNBC vaccine efficacy in the mouse model. Immunized mice with citENO1 peptides or the corresponding unmodified peptides, plus Poly I:C as an adjuvant, were orthotopically implanted with a TNBC murine cell line. Results: Vaccination with citENO1, but not unmodified ENO1 (umENO1), induced a greater percentage of activated CD8+ PD-1+ T cells and effector memory T cells in skin-draining lymph nodes (SDLNs). Remarkably, the citENO1 vaccine delayed tumor growth and prolonged overall survival, which was further enhanced by PD-1 blockade. Conclusions: Our data suggest that cancer-restricted post-translational modifications provide a source of vaccines that induce an anti-cancer immune response.

Keywords:  PD-1 blockade; cancer vaccine; immunopeptidome; post-translational modification; triple-negative breast cancer

DOI:  https://doi.org/10.3390/vaccines13060629
Adv Sci (Weinh). 2025 Jun 25. e02926

Adipocytes Promote Cisplatin Resistance through Secreting A1BG and Regulating NAMPT/PARP1 Axis-Mediated DNA Repair in Osteosarcoma.

Yonghui Liang, Zhaohui Li, Lina Tang, Zhen Pan, Xiang Fei, Chen Tan, Aina He, Qingcheng Yang, Dongdong Cheng.

  Obesity is increasingly recognized as a negative prognostic factor for cancers, including osteosarcoma. However, the mechanisms linking obesity to chemoresistance in osteosarcoma remain unclear. This study found obesity is significantly associated with poor responses to cisplatin-based chemotherapy in osteosarcoma patients. In vitro, adipocyte-conditioned medium (Adi-CM) induced cisplatin resistance, while peritumoral adipocytes and diet-induced obesity (DIO) reduce the cisplatin efficacy in vivo. Mechanistically, Adi-CM enhanced DNA repair by the PARP1/ATM pathway activation. Proteomic analysis identified A1BG, a secreted protein upregulated in adipocytes from chemoresistant patients, as a key mediator of this effect. A1BG depletion in adipocytes restored cisplatin sensitivity, whereas recombinant A1BG enhanced resistance and promoted DNA repair. Further investigation revealed a direct interaction between A1BG and NAMPT, leading to the stabilization of NAMPT and an increased NAD+ production. This enhanced PARP1 activity and subsequent DNA repair. Importantly, pharmacological inhibition of NAMPT and PARP1 using FK886 and Olaparib, respectively, reversed Adi-CM-induced cisplatin resistance and restored cisplatin sensitivity in osteosarcoma cells, DIO mouse models, and patient-derived organoids. A novel link between obesity and cisplatin resistance in osteosarcoma is established, highlighting the A1BG/NAMPT/PARP1 axis as a critical driver. Targeting this axis may represent a promising therapeutic strategy for overcoming obesity-associated chemoresistance in osteosarcoma.

Keywords:  adipocytes; cisplatin resistance; dna repair; osteosarcoma

DOI:  https://doi.org/10.1002/advs.202502926
Proc Natl Acad Sci U S A. 2025 Jul;122(26): e2425384122

Genome-scale knockout simulation and clustering analysis of drug-resistant breast cancer cells reveal drug sensitization targets.

JinA Lim, Hae Deok Jung, Soo Young Park, Moonhyeon Jeon, Da Sol Kim, Ryeongeun Cho, Dohyun Han, Han Suk Ryu, Yoosik Kim, Hyun Uk Kim.

  Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance remains a major hurdle. Metabolic reprogramming is a notable phenotype associated with the acquisition of drug resistance. Here, we develop a computational framework that predicts metabolic gene targets capable of reverting the metabolic state of drug-resistant cells to that of drug-sensitive parental cells, thereby sensitizing the resistant cells. The computational framework performs single-gene knockout simulation of genome-scale metabolic models that predicts genome-wide metabolic flux distribution in drug-resistant cells, and clusters the resulting knockout flux data using uniform manifold approximation and projection, followed by k-means clustering. From the clustering analysis, knockout genes that lead to the flux data near that of drug-sensitive cells are considered drug sensitization targets. This computational approach is demonstrated using doxorubicin- and paclitaxel-resistant MCF7 breast cancer cells. Drug sensitization targets are further refined based on proteome and metabolome data, which generate GOT1 for doxorubicin-resistant MCF7, GPI for paclitaxel-resistant MCF7, and SLC1A5 as a common target. These targets are experimentally validated where treating drug-resistant cancer cells with small-molecule inhibitors results in increased sensitivity of drug-resistant cells to doxorubicin or paclitaxel. The applicability of the developed framework is further demonstrated using drug-resistant triple-negative breast cancer cells. Taken together, the computational framework predicts drug sensitization targets in an intuitive and cost-efficient manner and can be applied to overcome drug-resistant cells associated with various cancers and other metabolic diseases.

Keywords:  anticancer drug resistance; drug sensitization; genome-scale metabolic model; metabolic reprogramming; single-gene knockout simulation

DOI:  https://doi.org/10.1073/pnas.2425384122
Cell Death Discov. 2025 Jun 21. 11(1): 287

The Nrf2-HMOX1 pathway as a therapeutic target for reversing cisplatin resistance in non-small cell lung cancer via inhibiting ferroptosis.

Ling Zuo, Xinru Zou, Jia Ge, Shuning Hu, Yixuan Fang, Yi Xu, Rui Chen, Sheng Xu, Guangyang Yu, Xiaorong Zhou, Lili Ji.

Cisplatin resistance is a major cause of poor prognosis in non-small cell lung cancer (NSCLC). Cisplatin-induced lung cancer cell death is associated with ferroptosis, a type of recently identified programmed cell death. Nrf2 is a critical component of the antioxidant system, and its protumorigenic activity in lung cancer has been extensively studied. However, the role of Nrf2 in cisplatin-induced ferroptosis and drug resistance remains elusive. Here, we demonstrated that cisplatin treatment induced ferroptosis in parental A549 lung adenocarcinoma cells and that this effect was significantly reduced in cisplatin-resistant A549/DDP cells. Knocking down Nrf2-sensitized A549/DDP cells to cisplatin-induced cytotoxicity by enhancing ferroptosis. Moreover, we demonstrated that Nrf2 promotes the expression of HMOX1 and that the Nrf2-HMOX1 pathway is critical for mediating its anti-ferroptotic function. Additionally, immunohistochemical analysis of NSCLC specimens revealed that Nrf2 expression was correlated with HMOX1 and high levels of Nrf2 and HMOX1 were associated with poor patient survival. These findings suggest that the HMOX1-Nrf2 pathway significantly influences treatment outcomes in NSCLC. Ultimately, we demonstrated that treatment with the Nrf2 inhibitor ML385 promoted ferroptosis by inhibiting the Nrf2-HMOX1 pathway, restoring cisplatin sensitivity in drug-resistant cells. Our findings provide insights into the mechanism underlying cisplatin resistance and suggest that targeting the Nrf2-HMOX1 pathway enhances cisplatin-induced ferroptosis and improves NSCLC treatment outcomes.

DOI: https://doi.org/10.1038/s41420-025-02564-z
Biochim Biophys Acta Mol Basis Dis. 2025 Jun 20. pii: S0925-4439(25)00305-9. [Epub ahead of print]1871(7): 167957

EGFR inhibitor suppresses tumor growth by blocking lipid uptake and cholesterol synthesis in non-small cell lung cancer.

Byung-Ho Rhie, Sang Hyeon Woo, Hyun-Yi Kim, Janardhan Keshav Karapurkar, Won-Jun Jo, Jusong Kim, Dong Ha Kim, Jaesang Kim, Myeong Jun Choi, Young Jun Park, Yoonki Hong, Seok-Ho Hong, Suresh Ramakrishna, Kye-Seong Kim.

  Accelerated cholesterol and lipid metabolism are hallmarks of non-small cell lung cancer (NSCLC). Recently, epidermal growth factor receptor (EGFR) signaling has been shown to regulate de novo cholesterol synthesis and low-density lipoprotein receptor (LDLR) expression through SREBP-1-dependent pathways. This suggests that targeting EGFR signaling in cholesterol metabolism might provide a new therapeutic strategy for NSCLC. In this study, we demonstrated that AX-0085, a small-molecule drug, significantly inhibits EGFR kinase activity and subsequently suppresses cholesterol and lipid metabolism in NSCLC. Transcriptomic analysis showed that cholesterol and lipid metabolism-related transcripts were significantly downregulated in AX-0085-treated NSCLC cells compared to the mock control. In addition, AX-0085 downregulates EGF signaling-dependent SREBP1-mediated cholesterol biosynthesis-related enzymes and LDLR in NSCLC. Moreover, AX-0085 dramatically reduced proliferation, colony-forming ability, and migration in NSCLC cells by blocking EGFR signaling. Furthermore, treatment with AX-0085 decreased both tumor size and volume in the LLC-xenograft model. These results demonstrate that AX-0085 effectively suppresses cholesterol metabolism in NSCLC cells by inhibiting EGF-mediated SREBP1 signaling, suggesting a potential therapeutic strategy targeting cholesterol metabolism in NSCLC.

Keywords:  Cholesterol biosynthesis; Epidermal growth factor receptor; Kinase activity; Lipid uptake; Low-density lipoprotein receptor; Non-small cell lung cancer; Tumor growth

DOI:  https://doi.org/10.1016/j.bbadis.2025.167957
Biochem Pharmacol. 2025 Jun 24. pii: S0006-2952(25)00336-3. [Epub ahead of print] 117071

Benserazide‑mediated targeting hexokinase 2 enhances the cytotoxicity of cisplatin in non-small cell lung cancer cell models.

Kaifang Wang, Suya Wang, Wenying Shan, Shuting Huang, Tong Fang, Yan Zhou, Lizhong Liu, Ou Sha, Kin Yip Tam.

  Hexokinase 2 (HK2) is a critical rate-limiting enzyme in glycolysis, significantly linked to cancer metabolism and drug resistance. We hypothesized that targeting HK2 with Benserazide (BenZ), a known HK2 inhibitor, could potentiate the cytotoxicity of cisplatin (DDP) in non-small-cell lung cancer (NSCLC) cells. Our findings demonstrated that combination of DDP and BenZ significantly enhanced anticancer effects in NSCLC cells, either with or without acquired DDP resistance. In particular, BenZ effectively inhibited ATP and lactate productions. ATP supplementation mitigated the cytotoxicity of the combination treatment, which was restored when both the cisplatin efflux transporters, ATP7A and ATP7B, were simultaneously knocked down. Moreover, BenZ suppressed NF-κB activation and downregulated inflammatory gene expressions, including IκB and RELA phosphorylation, TNF-α, BCL-2, and IL-1β. These effects were attributed to inhibition of HK2 by BenZ leading to the suppression of IκBα phosphorylation. It has been shown that combined use of DDP and BenZ significantly inhibited tumor growth in NSCLC cell xenograft mouse models, while BenZ alleviated the DDP-induced nephrotoxicity. Our findings demonstrate that BenZ inhibits the kinase activity of HK2, reduces ATP level and cisplatin efflux, as well as alleviates NF-κB activation. These multifaceted actions enhance the anticancer efficacy of cisplatin in NSCLC cell models, indicating its potential as an effective adjunct therapy.

Keywords:  Benserazide (BenZ); Glycolysis; Hexokinase 2 (HK2); NF-κB pathway; Non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.1016/j.bcp.2025.117071
Blood Neoplasia. 2024 Dec;1(4): 100037

Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.

Sara H Small, Ricardo E Perez, Elspeth M Beauchamp, Aneta H Baran, Stephen D Willis, Mariafausta Fischietti, Michael Schieber, Masha Kocherginsky, Diana Saleiro, Leonidas C Platanias.

Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML), and a better understanding of the resistance mechanisms can lead to the development of novel AML therapies. Here, we demonstrated that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with poor overall survival and worse prognosis in patients with AML. Moreover, we showed that SLFN11 plays an essential role in regulating chemotherapy sensitivity in AML. AML cells with suppressed levels of SLFN11 do not undergo apoptosis in response to cytarabine because of aberrant activation of the Ataxia telangiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk1) pathway, allowing for DNA damage repair, whereas sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, SLFN11 knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal SLFN11 as an important regulator and predictor of chemotherapy sensitivity in AML and suggest that targeting pathways suppressed by SLFN11 may offer potential combination therapies to enhance and optimize chemotherapy responses in AML.

DOI: https://doi.org/10.1016/j.bneo.2024.100037
Nat Rev Drug Discov. 2025 Jun 26.

Metabolites as agents and targets for cancer immunotherapy.

Marcel P Trefny, Guido Kroemer, Laurence Zitvogel, Sebastian Kobold.

The depletion or accumulation of metabolites in the tumour microenvironment is one of the hallmarks of cancer, but targeting cancer cell metabolism therapeutically must also take into account the impact on metabolic pathways in immune cells. As we understand more about immunometabolism, opportunities arise for synergies between agents that modulate metabolism and immunotherapy. In this Review, we discuss the pivotal role of metabolic pathways in both cancer and immune cells in shaping the tumour microenvironment. We survey major anabolic and catabolic pathways and discuss how metabolic modulators and dietary nutrients can improve the anticancer immune response and overcome drug resistance mechanisms. Agents in the clinic include inhibitors of the adenosine and tryptophan pathways, and we discuss opportunities and challenges for successful drug development in the context of immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapies.

DOI: https://doi.org/10.1038/s41573-025-01227-z
Sci Immunol. 2025 Jun 27. 10(108): eado3485

Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti-PD-1 resistance in hepatocellular carcinoma.

Junnan Liang, Jingyu Liao, Ruizhi Chang, Wenlong Jia, Ganxun Li, Zeyu Chen, Hang Wu, Chang Zhu, Jingyuan Wen, Qibo Huang, Han Gao, Zichen Gui, Weiqi Xu, Huifang Liang, Qiumeng Liu, Dafeng Xu, Zifu Li, Limin Xia, Xiaoping Chen, Zhao Huang, Wanguang Zhang, Zeyang Ding, Bixiang Zhang.

The overall response rate to immunotherapy is modest in hepatocellular carcinoma (HCC), and immunotherapy resistance mechanisms are incompletely understood. We report that the E3 ubiquitin ligase Riplet is universally silenced by promoter hypermethylation in HCC. Loss of Riplet modulates fatty acid metabolism to promote terminal exhaustion of CD8 T cells. Riplet loss impedes K48-linked polyubiquitination of fatty acid synthase (FASN), consequently accelerating fatty acid production in HCC. Tumor cell-derived free fatty acids, especially palmitic acid (PA/C16:0), activate STAT3 (signal transducers and activators of transcription 3) by enhancing its palmitoylation in T cells, consequently triggering terminal CD8 T cell exhaustion. HCC cells with Riplet deficiency are resistant to anti-PD-1 therapy, and treatment with an FASN inhibitor overcomes resistance. Our study shows how Riplet can alter lipid metabolism and induce CD8 T cell exhaustion and anti-PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.

DOI: https://doi.org/10.1126/sciimmunol.ado3485
Cell Signal. 2025 Jun 17. pii: S0898-6568(25)00362-6. [Epub ahead of print] 111947

USP7-DDX5-FASN axis drives fatty acid metabolism and supports hepatocellular carcinoma progression.

Jiawei Wang, Lihua Zhou, Yujia Pan, Cai Li, Shuxian Huang, Zhaofang Yan, Haipeng Wang, Guangying Qi, Jinfeng Gan.

  Lipid metabolism plays a critical role in meeting the biosynthetic demands of rapidly proliferating tumor cells and is a major driver in the development of hepatocellular carcinoma (HCC). However, the precise molecular mechanisms underlying this process remain unclear. In this study, we identified DEAD box protein 5 (DDX5) as a key regulator of fatty acid synthesis in HCC. Analysis of multiple HCC cohorts revealed a marked elevation in DDX5 expression, which is closely correlates with poorer clinical outcomes. Functional studies demonstrated that DDX5 facilitates HCC cell proliferation, enhances colony formation, and promotes fatty acid synthesis through the upregulation fatty acid synthetase (FASN). In vivo studies showed that inhibition of DDX5 effectively suppressed tumor growth. Further investigation identified an interaction between DDX5 and ubiquitin-specific peptidase 7 (USP7), whereby USP7 stabilizes DDX5 by removing ubiquitin chains through deubiquitination. Collectively, these findings highlight the USP7-DDX5-FASN axis as a critical regulator of fatty acid metabolism in HCC progression, offering potential avenues for therapeutic intervention.

Keywords:  DDX5; FASN; Fatty acid metabolism; Hepatocellular carcinoma; USP7

DOI:  https://doi.org/10.1016/j.cellsig.2025.111947