bims-meract 2025-04-13 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–04–13
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.
Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.
PPAR γ changing ALDH1A3 content to regulate lipid metabolism and inhibit lung cancer cell growth.
High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy.
From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.
Endogenous protein S100A14 stabilizes glutaminase to render hepatocellular carcinoma resistant to sorafenib.
PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair.
SCD1 Inhibition Blocks the AKT-NRF2-SLC7A11 Pathway to Induce Lipid Metabolism Remodeling and Ferroptosis Priming in Lung Adenocarcinoma.
FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.
Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.
Metformin inhibits the progression of castration resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation.
NAMPT Modulates Gemcitabine Resistance in Pancreatic Cancer via the p53 Signaling Pathway.
Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.
FMNL2/SRC-mediated androgen receptor translocation into the nucleus promotes enzalutamide resistance of prostate cancer.
Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.
Lipid metabolism associated PLPP4 gene drives oncogenic and adipogenic potential in breast cancer cells.
Reduced store operated calcium entry contributes to autophagy mediated escape of prostate cancer to oxaliplatin treatment.
Non-immune targeting of CXCR3 compromises mitochondrial function and suppresses tumor growth in glioblastoma.
MTCH2 regulates NRF2-mediated RRM1 expression to promote melanoma proliferation and dacarbazine insensitivity.
Potential role of CFLAR in enhancing 5-FU sensitivity and modulating immune cell infiltration in breast cancer.
Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance.

J Exp Clin Cancer Res. 2025 Apr 07. 44(1): 114

Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.

Su Jung Park, Claudia Cerella, Jin Mo Kang, Jinyoung Byun, David Kum, Barbora Orlikova-Boyer, Anne Lorant, Michael Schnekenburger, Ali Al-Mourabit, Christo Christov, Juyong Lee, Byung Woo Han, Marc Diederich.

   BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.
METHOD: This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.
RESULTS: TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.
CONCLUSION: TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.

Keywords:  Drug resistance; Glutathione; Glycolysis; Metabolic reprogramming; Monocytic myeloid leukemia; OXPHOS

DOI:  https://doi.org/10.1186/s13046-025-03372-0
Cell Death Dis. 2025 Apr 05. 16(1): 254

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.

Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07510-6
J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]

Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.

Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.

  Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.

Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation

DOI:  https://doi.org/10.1242/jcs.263688
Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00300-6. [Epub ahead of print]44(4): 115529

Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.

Linda K Do, Hyun Min Lee, Yun-Sok Ha, Chan-Hyeong Lee, Jiyeon Kim.

  Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.

Keywords:  CP: Cancer; CP: Metabolism; amino acids; cancer metabolism; metabolic heterogeneity

DOI:  https://doi.org/10.1016/j.celrep.2025.115529
Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Cell Death Dis. 2025 Apr 05. 16(1): 253

Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.

Nikita Markov, Sirina Sabirova, Gulnaz Sharapova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Marcel Egger, Albert Rizvanov, Hans-Uwe Simon.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

DOI: https://doi.org/10.1038/s41419-025-07596-y
Mol Genet Genomics. 2025 Apr 08. 300(1): 41

PPAR γ changing ALDH1A3 content to regulate lipid metabolism and inhibit lung cancer cell growth.

Xinyuan Tian, Xiaoping Bai, Yunqi Han, Yu Ye, Meiling Peng, Hongwei Cui, Kai Li.

  PPAR γ, as a widely present receptor in tissues, plays a key role in lipid metabolism, energy balance, inflammatory response, and cell differentiation. It plays an important role in the occurrence and development of various tumors, including prostate cancer, gastric cancer, lung cancer, etc., by regulating lipid metabolism. However, the specific mechanism by which it affects lung cancer growth is not yet clear. To investigate how PPAR γ affects lung cancer cell growth by altering ALDH1A3 levels through its impact on lipid metabolism. Bioinformatics analysis was used to predict the correlation between PPAR γ, ALDH1A3 and lung cancer. Based on the results of bioinformatics analysis, PPAR γ activator (Pioglitazone, Pio) and ALDH1A3 inhibitor (diethylaminobenzaldehyde, DEAB) were used to act on lung cancer cells and observe their growth. After measuring the IC50 value of the drug in vitro experiments, lipid metabolomics analysis was conducted to identify the significant changes in differential metabolites and metabolic pathways under the combined influence of Pio and DEAB. Through bioinformatics analysis, it was found that there were significant differences in the levels of PPAR γ and ALDH1A3 between lung cancer and normal lung tissues, and ALDH1A3 was positively correlated with PPAR γ. AUC analysis found that PPAR γ and ALDH1A3 have good predictive value in the diagnosis and prognosis of lung cancer. GSEA enrichment analysis showed that PPAR γ and ALDH1A3 were significantly correlated with lipid oxidation. Combining relevant literature to demonstrate the inhibitory effect of PPAR γ receptors on lung cancer cells and the ability of PPAR γ activation to inhibit ALDH1A3 levels. Further in vitro CCK-8 and IC50 measurements of lung cancer cells A549 and H1299 were conducted, followed by non targeted lipidomics analysis. It was found that the metabolic pathways upregulated by activation of PPAR γ and inhibition of ALDH1A3 included glycerophospholipid metabolism, cholesterol metabolism, arachidonic acid metabolism, and fat digestion and absorption, with glycerophospholipid metabolism pathway accounting for the highest percentage. Conclusion: PPAR γ activation can inhibit the production of ALDH1A3, alter the glycerophospholipid metabolism pathway, and thus inhibit the proliferation of lung cancer cells. This study confirms that PPAR γ affects lung cancer proliferation by influencing the glycerophospholipid metabolism pathway.

Keywords:  ALDH1A3; Introduce; Lipid metabolism; Lung cancer; PPARγ

DOI:  https://doi.org/10.1007/s00438-025-02243-9
Cell Rep. 2025 Apr 09. pii: S2211-1247(25)00316-X. [Epub ahead of print]44(4): 115545

High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy.

Zhuo Xing, Tiejun Yang, Xurui Li, Haozhe Xu, Yulong Hong, Shuai Shao, Tao Li, Liefu Ye, Yuan Li, Xin Jin, Yongbao Wei.

  Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients with diabetes than in those with normoglycemia. The subsequent in vitro and in vivo experiments indicate that high glucose decreases the sensitivity of BC cells to EV. Mechanistically, lactate overproduction associated with high glucose promotes AARS1-mediated YTHDC1 lactylation and enhances RNF183-mediated YTHDC1 ubiquitination. Downregulated YTHDC1 reduces JUND mRNA stability in an m6A-dependent manner, subsequently decreasing NECTIN4 expression and EV responsiveness. Our study identifies a high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activators or β-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV.

Keywords:  CP: Cancer; NECTIN4; YTHDC1; bladder cancer; enfortumab vedotin

DOI:  https://doi.org/10.1016/j.celrep.2025.115545
Cancer Res. 2025 Apr 09.

From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.

Camille Attané, Catherine Muller.

Adipocytes from white adipose tissue support cancer progression by supplying fatty acids to tumor cells while cold-activated brown adipose tissue has been shown to inhibit tumor growth by disrupting cancer cell metabolism. In a groundbreaking study published in Nature Biotechnology, Nguyen and colleagues developed Adipose-Modified Therapy (AMT), a strategy that genetically reprograms white adipocytes to outcompete tumors for key nutrients. Using CRISPR activation technology, researchers enhanced adipocyte glucose and fatty acid consumption, by inducing a stable browning phenotype. In vitro, browned adipocytes reduced glycolysis and fatty acid oxidation in cancer cells, inhibiting their proliferation. Implantation of engineered adipose organoids adjacent to tumors suppressed tumor growth, reduced angiogenesis, and altered metabolic gene expression in xenograft models. AMT also prevented tumor development in genetic mouse models of cancer, suggesting a role in cancer prevention. Finally, modified human mammary adipocytes inhibited the growth of patient-derived breast cancer organoids. This therapy, based on autologous fat transplantation, could offer a reversible and patient-specific approach. Challenges remain, including metabolic plasticity in cancer cells and the fragility of mature adipocytes in cell culture. AMT represents a paradigm shift in cancer therapy, leveraging adipocytes as metabolic competitors rather than tumor facilitators, opening new avenues for metabolism-targeted cancer treatments.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1511
J Transl Med. 2025 Apr 11. 23(1): 435

Endogenous protein S100A14 stabilizes glutaminase to render hepatocellular carcinoma resistant to sorafenib.

Menghui Wang, Yueheng Li, Junhui Su, Xinjue Dong, Ao Liu, Yuqi Yang, Xinyi Tang, Ruijie Chen, QingQuan Li, Hongshan Wang, Hong Xiao.

   BACKGROUND: Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive.
METHODS: Single-cell lineage tracing and RNA sequencing were performed to identify primary sorafenib-resistant lineages in HCC. Differential gene expression analysis was employed to identify the biomarkers of drug-resistant lineage cells. Cell viability and colony formation assays were adopted to assess the involvement of S100A14 on sorafenib resistance. Co-immunoprecipitation (CO-IP) and mass spectrometry analysis were conducted to uncover the downstream targets and regulatory mechanisms of S100A14 in primary resistance to sorafenib. In vivo mouse xenograft experiments were carried out to assess the effect of S100A14 or its interacting protein glutaminase (GLS) on primary resistance to sorafenib in HCC.
RESULTS: Single-cell lineage tracing identified a cluster of sorafenib primary resistant cells, and S100A14, a Ca2+-binding protein, was determined to be a critical biomarker for primary resistance to sorafenib. Knockdown of S100A14 significantly increases sorafenib treatment sensitivity in HCC cells. Mechanistically, S100A14 binds to GLS and blocks its phosphorylation at residues Y308 and S314, which in turn inhibits its ubiquitination and subsequent degradation. By stabilizing GLS, S100A14 reduces oxidative stress in HCC cells, thereby antagonizing sorafenib-induced apoptosis. Inhibiting S100A14 or GLS significantly improved sorafenib efficacy against xenograft tumors in vivo.
CONCLUSIONS: Our results demonstrate that S100A14 plays a pivotal role in promoting primary resistance to sorafenib by stabilizing GLS to reduce oxidative stress, and acts as a potential therapeutic target to enhance the efficacy of sorafenib in HCC patients.

Keywords:  Glutaminase; Hepatocellular carcinoma; Lineage tracing; Primary resistance; S100A14; Sorafenib

DOI:  https://doi.org/10.1186/s12967-025-06333-5
Cell Death Dis. 2025 Apr 06. 16(1): 258

PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair.

Hui Shen, Jing Jin, Nanxi Yu, Tingting Liu, Yongzhan Nie, Zhijie Wan, Yuanyuan Chen, Kun Cao, Ying Xu, Yijuan Huang, Chao Feng, Ruixue Huang, Yanyong Yang, Fu Gao.

Neoadjuvant radiotherapy is the standard treatment for locally advanced rectal cancer, but resistance to this therapy remains a significant clinical challenge. Understanding the molecular mechanisms of radioresistance and developing strategies to enhance radiosensitivity are crucial for improving treatment outcomes. This study investigated the role of PRKCSH in colorectal cancer radioresistance and its underlying mechanisms. Our results demonstrate that PRKCSH is upregulated in colorectal cancer cells following ionizing radiation. Inhibiting PRKCSH sensitized these cells to radiation by reducing clonogenic survival, promoting apoptosis, and impairing DNA damage repair. Mechanistically, PRKCSH inhibition reduced p53 ubiquitination and degradation by activating the ER stress IRE1α/XBP1s pathway after radiation exposure, which enhanced DNA repair and contributed to radioresistance. In preclinical CRC models, PRKCSH depletion suppressed tumor growth and increased radiosensitivity. Similarly, in patient-derived organoid models, PRKCSH knockdown reduced organoid growth post-radiotherapy. In rectal cancer patients receiving neoadjuvant radiotherapy, higher PRKCSH expression in post-treatment samples correlated with reduced tumor regression. These findings suggest that targeting PRKCSH diminishes radioresistance by impairing DNA repair through the modulation of ER stress. Furthermore, PRKCSH expression may serve as a biomarker for evaluating radiotherapy efficacy and clinical outcomes in rectal cancer patients undergoing neoadjuvant therapy.

DOI: https://doi.org/10.1038/s41419-025-07582-4
Cancer Res. 2025 Apr 08.

SCD1 Inhibition Blocks the AKT-NRF2-SLC7A11 Pathway to Induce Lipid Metabolism Remodeling and Ferroptosis Priming in Lung Adenocarcinoma.

Utsav Sen, Charles Coleman, Nishant Gandhi, Vrinda Jethalia, Deniz Demircioglu, Andrew Elliott, Ari M Vanderwalde, Omar Hayatt, Elisa de Stanchina, Balazs Halmos, Patrick C Ma, Mirela Berisa, Dan Hasson, Triparna Sen.

Concurrent inactivating mutations in STK11 and KEAP1 drive primary resistance to therapies, lead to worse outcomes in KRAS-mutated lung adenocarcinoma (KRASmut-LUAD) and are associated with metabolic alterations. Elucidation of the underlying biology of this aggressive LUAD subset is needed to develop effective treatments to improve patient outcomes. Our transcriptomic analysis of 5498 "real-world" KRASmut-LUADs demonstrated that STK11/KEAP1 co-mutation led to upregulation of fatty acid and redox signaling pathways and considerable enrichment of the metabolic genes SCD1 and SLC7A11. High expression of SCD1 and SLC7A11 predicted poor prognosis in KRASmut-patients. Transcriptomics, lipidomics, and kinase arrays in preclinical models demonstrated that SCD1 inhibition promoted ferroptosis, altered fatty acid metabolism, and downregulated SLC7A11 via AKT-GSK3β-NRF2 signaling. SCD1 inhibition caused appreciable tumor regression in xenografts and augmented the efficacy of the ferroptosis inducer erastin. Overall, this study provides insights into the role of the SCD1-SLC7A11 axis in regulating metabolic programming and predicting poor patient outcomes in a genetically defined subset of KRASmut-LUAD.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2745
Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2411241122

FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis.

Shan-Shan Li, Baifeng Zhang, Cuicui Huang, Yuying Fu, Yuying Zhao, Lanqi Gong, Yanan Tan, Huali Wang, Wenqi Chen, Jie Luo, Yu Zhang, Stephanie Ma, Li Fu, Chenli Liu, Jiandong Huang, Huai-Qiang Ju, Anne Wing-Mui Lee, Xin-Yuan Guan.

  Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.

Keywords:  NRF2; esophageal cancer; lymph node metastasis; metabolic reprogramming; oxidative phosphorylation

DOI:  https://doi.org/10.1073/pnas.2411241122
Cancer Cell. 2025 Apr 01. pii: S1535-6108(25)00116-3. [Epub ahead of print]

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.

Yinghua Zhu, Ziwei Zhou, Xin Du, Xiaorong Lin, Zhi-Mei Liang, Si Chen, Yiwei Sun, Yue Wang, Zhenkun Na, Zhiyong Wu, Jiaxin Zhong, Beinan Han, Xiangping Zhu, Wenkui Fu, Hongde Li, Man-Li Luo, Hai Hu.

  Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.

Keywords:  arginine; breast cancer; metabolic communication; polyamine; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2025.03.015
Cancer Lett. 2025 Apr 09. pii: S0304-3835(25)00260-5. [Epub ahead of print] 217694

Metformin inhibits the progression of castration resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation.

Shanghua Cai, Yulin Deng, Zhihao Zou, Weicheng Tian, Zhenfeng Tang, Jinchuang Li, Zeheng Tan, Zhenjie Wu, Zhaodong Han, Biyan Wen, Yuanfa Feng, Ren Liu, Xuejin Zhu, Yongding Wu, Haiyin Xiao, Huichan He, Jianheng Ye, Weide Zhong.

  The castration-resistant prostate cancer (CRPC) remains an incurable disease. Metformin has demonstrated a potential therapeutic effect on CRPC. However, the poor clinical performance of metformin against cancer may be due to its clinical dose being much lower than the anticancer concentration used in pre-clinical experiments. The challenge is to determine a way to enhance sensitivity to metformin at an appropriate concentration on CRPC. In this study, a mouse model of low-dose metformin treatment for CRPC cells were established. Metabolomic-seq and transcriptomic-seq was used to investigate changes in CRPC xenografts. We discovered that low-dose metformin inhibits the progression of CRPC by regulating PDE6D, which induces alterations in purine metabolism and activates the cGMP/PKG pathway. Furthermore, we found that cells with high expression of PDE6D were more resistant to metformin. When combined with the PDE6D inhibitor TMX-4100, the inhibitory effect on tumors was enhanced, and TMX-4100 demonstrated favorable biosafety in animal models. In conclusion, we found that low-dose metformin inhibits the progression of CRPC by regulating PDE6D-induced alterations in purine metabolism and activating the cGMP/PKG pathway. Moreover, patients with high PDE6D expression may exhibit greater resistance to metformin. Combining metformin with TMX-4100 could further improve the inhibitory effects on tumors.

Keywords:  Apoptosis; CRPC; PDE6D; Precision medicine; Therapy sensitization

DOI:  https://doi.org/10.1016/j.canlet.2025.217694
Pancreas. 2025 Feb 14.

NAMPT Modulates Gemcitabine Resistance in Pancreatic Cancer via the p53 Signaling Pathway.

Jia Xu, Wenchao Xu, Jianzhou Liu, Ren Zheng, Xinmin Zhang, Xuanqi Wang, Li Yang, Li Zhou, Gary Guishan Xiao, Junchao Guo.

   OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage. Although gemcitabine (GEM) is commonly used as the first-line chemotherapy, many patients eventually develop resistance. This study aims to investigate the role of nicotinamide phosphoribosyltransferase (NAMPT) in mediating gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC), with a focus on identifying potential therapeutic targets within the nicotinate and nicotinamide metabolic pathways.
METHODS: We established the gemcitabine-resistant pancreatic cancer cell line BxPC-3-GR9 to simulate acquired resistance development. Subsequently, we conducted LC/MS metabolomics assays to identify altered metabolic pathways during gemcitabine resistance development. Additionally, molecular and functional experiments targeting key enzymes in KEGG-enriched metabolic pathways to identify genes exhibiting significant changes. Mechanistically, transcriptome sequencing and molecular assays were employed to elucidate the regulatory mechanisms governing these target genes.
RESULTS: Compared to parent BxPC-3 cell lines, significant alterations in the nicotinate and nicotinamide metabolic pathways were found in BxPC-3-GR9. Furthermore, nicotinamide was the only metabolite shared during the enrichment process; higher expression of NAMPT was also detected in gemcitabine-resistant cell lines. NAMPT knockdown increased gemcitabine sensitivity in gemcitabine-resistant cells, which validated in inherently resistant cell lines. Transcriptome analysis and molecular experiments demonstrated that NAMPT regulates the p53 signaling pathway via CCND1/2, contributing to gemcitabine resistance.
CONCLUSION: These findings suggest that NAMPT could serve as a promising therapeutic target to overcome gemcitabine resistance in PDAC, laying the groundwork for future clinical investigations aimed at modulating nicotinate and nicotinamide metabolism to improve treatment outcomes.

Keywords:  CCND1/2; NAMPT; gemcitabine resistance; nicotinate and nicotinamide metabolism; p53; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1097/MPA.0000000000002468
Cell Oncol (Dordr). 2025 Apr 07.

Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.

Chaoqun Li, Cun Ge, Qingwen Wang, Peng Teng, Heyuan Jia, Surui Yao, Zhaohui Huang.

   PURPOSE: Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.
METHODS: Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.
RESULTS: Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.
CONCLUSIONS: This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.

Keywords:  Cancer metabolism; Lactylation; ME2; Mitochondrion; Posttranslational modification; SIRT3

DOI:  https://doi.org/10.1007/s13402-025-01058-5
iScience. 2025 Apr 18. 28(4): 112205

FMNL2/SRC-mediated androgen receptor translocation into the nucleus promotes enzalutamide resistance of prostate cancer.

Jianpeng Yu, Yukui Gao, Mingpeng Zhang, Yue Gao, Chun Wang, Yuanjie Niu, Zhiqun Shang.

  Enzalutamide, a second-generation androgen receptor (AR) antagonist, has represented the association with improved overall survival in men with prostate cancer (PCa). However, PCa patients receiving enzalutamide will eventually develop resistance through various mechanisms without effective regimens. Here, we observed a higher level of formin-like 2 (FMNL2) in enzalutamide-resistant PCa cells. Functionally, FMNL2 knockdown partially re-sensitized enzalutamide-resistant PCa cells. Mechanistically, FMNL2 directly interacted with SRC kinase through FMNL2-FH1 and SRC-SH3 domain, which induced AR translocation from the cytoplasm to the nucleus, resulting in increased expression of the AR-targeted genes and leading to resistance to enzalutamide. Consistently, SRC inhibitor dasatinib rescued enzalutamide sensitivity and inhibited the proliferation of enzalutamide-resistant cancer cells. Taken together, our findings demonstrate a substantial role for FMNL2/SRC interaction in the regulation of AR translocation, suggesting that targeting FMNL2-mediated SRC activation might be a potential therapeutic strategy for enzalutamide-resistant PCa and dasatinib could be an option.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112205
Commun Biol. 2025 Apr 04. 8(1): 562

Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.

Alessandro Sammarco, Giorgia Guerra, Katharina M Eyme, Kelly Kennewick, Yu Qiao, Joelle El Hokayem, Kevin J Williams, Baolong Su, Cagri Cakici, Hayk Mnatsakanyan, Valentina Zappulli, Steven J Bensinger, Christian E Badr.

Breast cancer brain metastases (BCBM) are incurable, and new therapies are urgently needed. BCBM upregulates stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability. Here, we test the effect of a brain-penetrant, clinical-stage SCD inhibitor (SCDi) on breast cancer cells and mouse models of BCBM. We show that SCDi markedly reshapes the lipidome of breast cancer cells, resulting in endoplasmic reticulum stress, DNA damage, impaired DNA damage repair, and cytotoxicity. Importantly, SCDi alone or combined with a PARP inhibitor prolongs the survival of BCBM-bearing mice. Furthermore, pharmacological inhibition of SCD enhances antigen presentation by dendritic cells, increases interferon signaling, promotes the infiltration of cytotoxic T cells, and decreases the proportion of exhausted T cells and regulatory T cells (Tregs) in the tumor microenvironment (TME) in a syngeneic mouse model of BCBM. Additionally, SCDi reduces the engagement of immunosuppressive pathways, including the PD-1:PD-L1/PD-L2 and PVR/TIGIT axes in the TME. These findings suggest that SCD inhibition could be an effective strategy to both intrinsically reduce tumor growth and reprogram anti-tumor immunity in the brain microenvironment to treat BCBM.

DOI: https://doi.org/10.1038/s42003-025-07977-1
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Apr 03. pii: S1388-1981(25)00017-4. [Epub ahead of print] 159609

Lipid metabolism associated PLPP4 gene drives oncogenic and adipogenic potential in breast cancer cells.

Sneha Soni, Sweta H Makwana, Shivani Bansal, Monika Kumari, Chandi C Mandal.

  Lipid metabolic reprogramming plays a pivotal role in cancer cell evolution and causing subsequent cancer growth, metastasis and therapy resistance. Cancer associated adipocyte and/or cancer derived adipocyte-like cells often supply fuels and various factors to fulfill the cells bioenergetics to enhance oncogenic potential. This study intends to find out a set of dysregulated genes involved in lipid metabolism in breast cancer studies and uncovers the role of unexplored dysregulated gene in cancer potential. Cancer database analysis determines seven seed signature genes (PLPP2, PLPP4, CDS1, ASAH2, LCLAT1, LPCAT1 and LASS6/CERS6) concluded from relative expression and survival analysis. Furthermore, experimental analysis unveils the gene PLPP4 (Phospholipid Phosphatase 4) as oncogene confirmed by knockdown and overexpression studies in MDA-MB 231 and MCF-7 breast cancer cells. PLPP4 enzyme is involved in regulation of triacyl glycerol metabolism. Lipid accumulation along with other studies documented enhanced lipid droplets, TAG formation and glycerol release with concomitant increased expressions of various adipogenic markers (e.g., PPARγ, perilipin 1 and leptin) in breast cancer cells transfected with PLPP4 gene expressing plasmid whereas downregulation of PLPP4 gene diminished lipid accumulation and adipocyte marker gene expressions. Our findings also revealed that BMP2 induced adipogenic potential in breast cancer cells was mitigated in response to downregulation of PLPP4 gene expression. All these findings together, for first time, demonstrated that BMP2 drives PLPP4 to enhance both oncogenic and adipogenic potential in breast cancer cells. This article uncovers the perturbed lipid metabolism associated PLPP4 acts as oncogene presumably by modulating adipogenic activity in cancer cells.

Keywords:  Adipogenic potential; Breast cancer; Lipid metabolism; Phospholipid Phosphatase 4

DOI:  https://doi.org/10.1016/j.bbalip.2025.159609
Biochim Biophys Acta Mol Cell Res. 2025 Apr 04. pii: S0167-4889(25)00058-8. [Epub ahead of print] 119953

Reduced store operated calcium entry contributes to autophagy mediated escape of prostate cancer to oxaliplatin treatment.

Dheeraj Kannancheri Puthooru, Maya Yassine, Dmitri Gordienko, Nathalie Ziental-Gelus, Emilie Desruelles, Valerio Farfariello, Loïc Lemonnier, Natalia Prevarskaya.

  Oxaliplatin, a third-generation platinum-based chemotherapeutic drug, induces cell cycle arrest and apoptosis in prostate cancer treatment. However, both intrinsic and acquired resistance mechanisms limit its therapeutic efficacy. Notably, chemotherapeutic agents often induce autophagy-a cellular recycling process-that can contribute to drug resistance. Calcium (Ca2+) signalling plays a pivotal role in regulating cell fate. However, the involvement of Ca2+ and Ca2+ channels in oxaliplatin resistance within prostate cancer cells remains controversial and poorly understood. In this study, we demonstrate that oxaliplatin treatment enhances autophagy in prostate cancer cells. Concurrently, oxaliplatin modulates the expression of key proteins involved in store-operated calcium entry (SOCE): it upregulates Orai3 channels while downregulating Orai1 and Stim1. These alterations result in diminished SOCE activity, contributing to an apoptosis-resistant phenotype. Importantly, we found that targeting Orai3 expression and inhibiting autophagy sensitizes prostate cancer cells to oxaliplatin-induced apoptosis. Our findings suggest that combining Orai3 downregulation with autophagy inhibition may enhance the efficacy of oxaliplatin in treating prostate cancer. This combinatorial approach could hold potential for overcoming resistance and improving therapeutic outcomes.

Keywords:  Autophagy; Chemoresistance; ER stress; Orai3; Oxaliplatin; Prostate Cancer; SOCE

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119953
Cell Death Discov. 2025 Apr 04. 11(1): 143

Non-immune targeting of CXCR3 compromises mitochondrial function and suppresses tumor growth in glioblastoma.

Travis Yui Hei Chan, Bo Chen, Wanjun Tang, Henry Hei Chan, Yogesh K H Wong, Ethan C L Wong, Junbo Liao, Anson Cho-Kiu Ng, Jenny Sum Yee Wong, Gilberto Ka-Kit Leung, Karrie M Kiang.

The chemokine receptor CXCR3 is traditionally recognized for its role in immune cell trafficking. However, emerging evidence suggests that its functions may extend beyond the immune system, particularly in cancer, where its roles remain to be elucidated. In this study, we demonstrated that CXCR3 expression correlates with glioblastoma (GBM) grading, with CXCR3-A isoform being associated with poorer patient prognosis compared to CXCR3-B. Ablation of both CXCR3 isoforms significantly impaired GBM cell proliferation, migration, and tumor growth both in vitro and in immunodeficient mice. To elucidate the mechanistic role of CXCR3, we conducted transcriptomic profiling of tumor xenografts, revealing that CXCR3 depletion would disrupt mitochondrial homeostasis. This was further supported by our findings that CXCR3 would localize to the mitochondrial membrane, and that inhibition of CXCR3 would lead to mitochondrial depolarization and increased reactive oxygen species production. Notably, activation of phosphorylated-STAT3 rescued cell viability in CXCR3-depleted cells, suggesting that CXCR3 may modulate mitochondrial function through a STAT3-dependent mechanism, consistent with the known functional role of STAT3 in maintaining mitochondrial redox balance. Furthermore, treatment with the selective CXCR3 antagonist AMG487 reduced tumor growth and disrupted mitochondrial function in vitro, in vivo, and in patient-derived GBM stem cells. Our findings reveal CXCR3 as a previously unrecognized regulator of mitochondrial function in cancer cells, positioning the CXCR3-mitochondrial signaling axis as a promising therapeutic target for GBM. Chemokine receptors are well-established mediators of inflammatory responses, emerging evidence suggests that these receptors may play roles beyond the immune system. In this study, we have demonstrated that CXCR3 would localize to the mitochondrial membrane and exert a previously unrecognized function in regulating cancer metabolism and mitochondrial function. Figure created using BioRender ( https://biorender.com ).

DOI: https://doi.org/10.1038/s41420-025-02449-1
Cell Death Dis. 2025 Apr 09. 16(1): 268

MTCH2 regulates NRF2-mediated RRM1 expression to promote melanoma proliferation and dacarbazine insensitivity.

Xuedan Zhang, Enjiang Li, Yingmin Kuang, Yanlong Gai, Yu Feng, Yu Huang, Zhenyan Wei, Junzi Niu, Song Yu, Zhe Yang, Qiao Zhang, Buqing Sai, Yuechun Zhu.

Melanoma is among the 10 most prevalent malignant tumors, posing a significant threat to human health. A detailed understanding of the molecular mechanisms driving its progression is crucial for advancing treatment strategies and outcomes. Based on bioinformatic analysis and experimental validation, this study identified mitochondrial carrier homolog 2 (MTCH2) as a key regulator of melanoma proliferation. Mechanistically, MTCH2 enhanced the expression and nuclear translocation of nuclear factor (erythroid-derived-2)-like 2 (NRF2), which up-regulated ribonucleotide reductase subunit M1 (RRM1) expression, thereby promoting melanoma cell proliferation. Targeting RRM1 in combination with dacarbazine significantly inhibited tumor growth in nude mouse xenograft models. These findings elucidate a mechanistic link between MTCH2 and the NRF2-RRM1 axis in melanoma proliferation and highlight potential therapeutic targets for intervention.

DOI: https://doi.org/10.1038/s41419-025-07618-9
Eur J Med Res. 2025 Apr 10. 30(1): 265

Potential role of CFLAR in enhancing 5-FU sensitivity and modulating immune cell infiltration in breast cancer.

Yuwei Sun, Weilun Fang, Jinwu Peng, Xingling Liu, Chunjiang Wang, Liying Song, Zhenzhen Deng.

   BACKGROUND: Breast cancer (BRCA), the most common malignancy among women, is a highly heterogeneous disease. Chemoresistance is a major factor leading to treatment failure in BRCA. However, mechanisms underlying the development of chemoresistance remain unclear.
METHODS: In this study, we performed a comprehensive bioinformatic analysis to examine the role of cell death-associated genes in BRCA treatment. Specifically, we focused on caspase 8 and Fas-associated protein with death domain-like apoptosis regulator (CFLAR), which was identified as a co-differentially expressed cell death-associated molecule with potential prognostic values. We then validated these findings through in vitro experiments in BT- 549 and MDA-MB- 231 breast cancer cells.
RESULTS: Based on bioinformatics analysis, CFLAR expression was found to be downregulated in patients with BRCA, whereas its high expression was significantly associated with improved prognosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that aberrantly expressed CFLAR was potentially associated with oxidative phosphorylation, T cell receptor signaling, and NADH dehydrogenase (ubiquinone) activity. In vitro experiments demonstrated that overexpression of CFLAR inhibited the generation of reactive oxygen species (ROS), consequently promoting 5-fluorouracil (5-FU) sensitivity in BT- 549 and MDA-MB- 231 breast cancer cells. The expression of CFLAR was positively correlated with the abundance of several tumor-infiltrating immune cells, especially CD8 + T cells, further supporting the role of CFLAR in immune regulation.
CONCLUSION: In conclusion, this study reveals the novel roles of CFLAR in enhancing chemotherapy sensitivity and patient outcome in BRCA and underscores its potential as a therapeutic target. These results supported CFLAR as a therapeutic target and prognostic biomarker in BRCA patients.

Keywords:  5-Fluorouracil; Breast cancer; CFLAR; Chemoresistance; Immune infiltration; ROS

DOI:  https://doi.org/10.1186/s40001-025-02532-4
Cancer Cell. 2025 Apr 07. pii: S1535-6108(25)00132-1. [Epub ahead of print]

Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance.

Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Jack A Roth, Nicholas Navin, Albert C Koong, Mingjian James You, Steven H Lin, Boyi Gan.

  Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins-both hallmarks of cuproptosis-in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.

Keywords:  copper; cuproptosis; metallothionein; radioresistance; radiotherapy

DOI:  https://doi.org/10.1016/j.ccell.2025.03.031