bims-meract 2025-05-04 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–05–04
24 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Lipid metabolism in cancer: Exploring phospholipids as potential biomarkers.
PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation.
Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis.
Lactylation-Driven NUPR1 Promotes Immunosuppression of Tumor-Infiltrating Macrophages in Hepatocellular Carcinoma.
GDF15 drives de novo lipogenesis and contributes to ovarian cancer metastasis.
ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27.
NCOA5 induces sorafenib resistance in hepatocellular carcinoma by inhibiting ferroptosis.
Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.
Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS.
MMP1-induced NF-κB activation promotes epithelial-mesenchymal transition and sacituzumab govitecan resistance in hormone receptor-positive breast cancer.
Alisertib impairs the stemness of hepatocellular carcinoma by inhibiting purine synthesis.
ALDOC promotes neuroblastoma progression and modulates sensitivity to chemotherapy drugs by enhancing aerobic glycolysis.
Kinesin-like protein KIFC2 stabilizes CDK4 to accelerate growth and confer resistance in HR+/HER2- breast cancer.
SETD5 facilitates stemness and represses ferroptosis via m6A-mediating PKM2 stabilization in non-small cell lung cancer.
PPARG Activation of Fatty Acid Metabolism Drives Resistance to Anti-HER2 Therapies in HER2-Positive Breast Cancer.
TAZ/NRF2 positive feedback loop contributes to proliferation in bladder cancer through antagonistic ferroptosis.
6-((1,4-naphthoquinone-2-yl)methyl)thio-glucose conjugates, a novel targeted approach for advanced prostate cancer.
A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC.
CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance.
NUDT16 enhances the resistance of cancer cells to DNA-damaging agents by regulating replication fork stability via reversing HMGA1 ADP-ribosylation.
Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
BTG2-deficient mast cells remodel the tumor and tumor-draining lymph node microenvironment leading to chemotherapy resistance in breast cancer.
Chemoresistome mapping in individual breast cancer patients unravels diversity in dynamic transcriptional adaptation.

Biomed Pharmacother. 2025 Apr 29. pii: S0753-3322(25)00289-6. [Epub ahead of print]187 118095

Lipid metabolism in cancer: Exploring phospholipids as potential biomarkers.

Dominique Delmas, Aurélie Mialhe, Alexia K Cotte, Jean-Louis Connat, Florence Bouyer, François Hermetet, Virginie Aires.

  Aberrant lipid metabolism is increasingly recognized as a hallmark of cancer, contributing to tumor growth, metastatic dissemination, and resistance to therapy. Cancer cells reprogram key metabolic pathways-including de novo lipogenesis, lipid uptake, and phospholipid remodeling-to sustain malignant progression and adapt to microenvironmental demands. This review summarizes current insights into the role of lipid metabolic reprogramming in oncogenesis and highlights recent advances in lipidomics that have revealed cancer type- and stage-specific lipid signatures with diagnostic and prognostic relevance. We emphasize the dual potential of lipid metabolic pathways-particularly those involving phospholipids-as sources of clinically relevant biomarkers and therapeutic targets. Enzymes and transporters involved in these pathways have emerged as promising candidates for both diagnostic applications and pharmacological intervention. We also examine persistent challenges hindering the clinical translation of lipid-based approaches, including analytical variability, insufficient biological validation, and the lack of standardized integration into clinical workflows. Furthermore, the review explores strategies to overcome these barriers, highlighting the importance of incorporating lipidomics into multi-omics frameworks, supported by advanced computational tools and AI-driven analytics, to decipher the complexity of tumor-associated metabolic networks. We discuss how such integrative approaches can facilitate the identification of actionable metabolic targets, improve the specificity and robustness of lipid-based biomarkers, and enhance patient stratification in the context of precision oncology.

Keywords:  Cancer metabolism; Lipid biomarkers; Lipidomics; Mass spectrometry; Metabolic reprogramming; Phospholipids

DOI:  https://doi.org/10.1016/j.biopha.2025.118095
Nat Chem Biol. 2025 Apr 25.

PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation.

Peixiang Zheng, Zhiqiang Hu, Yuli Shen, Lina Gu, Yuan Ouyang, Yuran Duan, Guimei Ji, Bofei Dong, Yanni Lin, Ting Wen, Qi Tian, Yueru Hou, Qimin Zhou, Xue Sun, Xiaohan Chen, Katherine L Wang, Shudi Luo, Shiqi Wu, Yuening Sun, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Zheng Wang, Xueli Bai, Shengzhong Duan, Yuan Ding, Yanli Bi, Yuhao Wang, Gaopeng Li, Xiaoguang Liu, Zhimin Lu, Xiaohong Wu, Zhiyuan Tang, Daqian Xu.

Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1's noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.

DOI: https://doi.org/10.1038/s41589-025-01887-3
Small. 2025 Apr 26. e2408996

Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis.

Xiaohui Chen, Mairehaba Kadier, Mengting Shi, Kefeng Li, Hongtao Chen, Yongzhen Xia, Qiaohua Wang, Rongna Li, Yili Long, Jingbo Qin, Hao Wang, Guanmin Jiang.

  Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy, presenting a significant clinical challenge. Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation-targeted mitochondria-melatonin (Mito-Mel) significantly increases its potency by over 1000-fold. Mito-Mel selectively targets mitochondria, enhancing reactive oxygen species (ROS) generation and causing mitochondrial membrane potential disruption. This leads to the inhibition of mitochondrial respiration including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which, in turn, suppresses CRPC survival metabolic adaptations, such as glycolysis. In vitro and in vivo experiments reveal for the first time that natural small molecule compound with mitochondrial targeting via TPP exhibits excellent anticancer efficacy by inducing tumor cellular pyroptosis and facilitating the immune response, underlining the encouraging promise of this strategy for the effective treatment of CRPC.

Keywords:  castration‐resistant prostate cancer; immune response; mito–melatonin; pyroptosis; tumor metabolism

DOI:  https://doi.org/10.1002/smll.202408996
Adv Sci (Weinh). 2025 Apr 30. e2413095

Lactylation-Driven NUPR1 Promotes Immunosuppression of Tumor-Infiltrating Macrophages in Hepatocellular Carcinoma.

Jialiang Cai, Peiling Zhang, Yufan Cai, Guiqi Zhu, Shiping Chen, Lina Song, Junxian Du, Biao Wang, Weixing Dai, Jian Zhou, Jia Fan, Yiyi Yu, Zhi Dai.

  While checkpoint immunotherapy effectively mobilizes T-cell responses against tumors, its success in hepatocellular carcinoma (HCC) is frequently undermined by immunosuppressive myeloid cells within the tumor microenvironment. This study investigates the role of nuclear protein 1 (NUPR1), a gene prominently expressed in tumor-associated macrophages (TAMs), in mediating this suppression and influencing immunotherapy outcomes. Through comprehensive analysis of single-cell RNA sequencing (scRNA-seq) datasets and functional assays in vitro and in vivo, NUPR1 is identified as a critical regulator within TAMs. The upregulation of NUPR1 is associated with enhanced M2 macrophage polarization and increased expression of immune checkpoints PD-L1 and SIRPA, resulting in CD8+ T cell exhaustion and a diminished response to immunotherapy. Mechanistically, NUPR1 inhibits the ERK and JNK signaling pathways, thereby creating an immunosuppressive milieu conducive to tumor progression. Additionally, tumor-derived lactate is shown to upregulate NUPR1 expression in macrophages via histone lactylation, perpetuating a feedback loop that intensifies immune suppression. Pharmacological targeting of NUPR1 reverses M2 polarization, curtails tumor growth, and augments the efficacy of PD-1 blockade in preclinical models, positioning NUPR1 as both a potential biomarker for immunotherapy responsiveness and a therapeutic target to boost immunotherapy efficacy in HCC.

Keywords:  MAPK pathway; histone lactylation; immune checkpoint blockade; nuclear protein 1; tumor‐associated macrophages (TMA)

DOI:  https://doi.org/10.1002/advs.202413095
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 23. pii: S0925-4439(25)00216-9. [Epub ahead of print]1871(6): 167868

GDF15 drives de novo lipogenesis and contributes to ovarian cancer metastasis.

Chenxi Wang, Zhengjie Ou, Hongming Deng, Ying Zhang, Xiaoyang Li, Xiaobing Wang, Dan Zhao.

  Ovarian cancer is frequently diagnosed at an advanced stage, characterized by extensive metastasis. Recent studies indicate that metastatic and primary tumors exhibit similar mutational landscape, suggesting that non-mutational factors significantly contribute to the metastatic process. Enhanced lipid metabolism has been implicated across various stages of cancer progression, making the targeting of metabolic vulnerabilities a promising therapeutic strategy. In this study, we demonstrate that growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, which has been Indicated to be associated with several metabolic diseases, is significantly elevated in the serum of ovarian cancer patients, particularly in metastatic lesions compared to primary tumors. Elevated GDF15 levels correlate with reduced overall survival and progression-free survival. Furthermore, we found that GDF15 facilitates tumor metastasis by regulating de novo lipogenesis through the PI3K/AKT signaling pathway. These findings suggest that targeting GDF15-mediated lipid metabolism could provide a novel therapeutic approach to inhibit ovarian cancer metastasis.

Keywords:  GDF15; Lipogenesis; Ovarian cancer metastasis; PI3K/AKT pathway

DOI:  https://doi.org/10.1016/j.bbadis.2025.167868
Nat Commun. 2025 Apr 25. 16(1): 3908

ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27.

Yong Wang, Yanan Wang, Lei Bao, Goncalo Vale, Jeffrey G McDonald, Yisheng Fang, Yan Peng, Ashwani Kumar, Chao Xing, Fara Brasó-Maristany, Aleix Prat, Carlos L Arteaga, Yingfei Wang, Weibo Luo.

Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer.

DOI: https://doi.org/10.1038/s41467-025-59184-5
Cell Death Discov. 2025 May 02. 11(1): 215

NCOA5 induces sorafenib resistance in hepatocellular carcinoma by inhibiting ferroptosis.

Shuang Gao, Lulu Fan, Huiyan Wang, Anqi Wang, Mengyao Hu, Lei Zhang, Guoping Sun.

NCOA5 has been identified as a crucial factor in the progression of hepatocellular carcinoma (HCC). This study investigates the expression of NCOA5 in HCC, revealing its significant overexpression in tumor tissues compared to healthy liver tissues, as evidenced by analysis of the TCGA dataset and RT-qPCR in patient samples. Higher NCOA5 levels correlate with poor overall survival, highlighting its role as a prognostic indicator. Furthermore, our findings suggest that elevated NCOA5 is associated with resistance to sorafenib, a common chemotherapeutic agent for HCC, as shown through analysis of publicly available datasets and the establishment of sorafenib-resistant HCC cell lines. Mechanistically, NCOA5 appears to inhibit ferroptosis in HCC cells by modulating glutathione peroxidase 4 (GPX4) levels. Knockdown of NCOA5 sensitizes resistant cell lines to sorafenib and induces ferroptosis by decreasing GPX4 expression. Additionally, NCOA5 regulation of GPX4 is mediated through the transcription factor MYC. In vivo studies further validate that targeting NCOA5 enhances the efficacy of sorafenib in resistant HCC models by promoting ferroptosis. Collectively, these findings underscore the potential of NCOA5 as a therapeutic target to overcome drug resistance in HCC, providing insights into its role in modulating treatment responses and patient prognosis.

DOI: https://doi.org/10.1038/s41420-025-02473-1
Cancer Res. 2025 Apr 28. OF1-OF13

Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.

Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Fan Yang, Nabil F Saba, Yong Teng.

The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box-binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3477
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00390-0. [Epub ahead of print]44(5): 115619

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS.

Shilpa S Dhar, Calena Brown, Ali Rizvi, Lauren Reed, Sivareddy Kotla, Constantin Zod, Janak Abraham, Jun-Ichi Abe, Veena Rajaram, Kaifu Chen, Min Gyu Lee.

  The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in many cancers, including medulloblastoma (MB). Notably, heterozygous KMT2D loss frequently occurs in MB and other cancers. However, its oncogenic role remains largely uncharacterized. Here, we show that heterozygous Kmt2d loss in murine cerebellar regions promotes MB genesis driven by heterozygous loss of the MB-suppressor gene Ptch via the upregulation of tumor-promoting programs (e.g., oxidative phosphorylation [OXPHOS]). Downregulation of the transcription-repressive tumor suppressor NCOR2 by heterozygous Kmt2d loss, along with Ptch+/--increased MYCN, upregulated tumor-promoting genes. Heterozygous Kmt2d loss substantially diminished enhancer marks (H3K4me1 and H3K27ac) and the H3K4me3 signature, including those for Ncor2. Combinatory pharmacological inhibition of the enhancer-decommissioning H3K4 demethylase LSD1 and OXPHOS significantly reduced the tumorigenicity of MB cells bearing heterozygous Kmt2d loss. Our findings suggest the molecular and epigenetic pathogenesis underlying the MB-promoting effect of heterozygous KMT2D loss.

Keywords:  CP: Cancer; CP: Metabolism; KMT2D; LSD1; NCOR2; OXPHOS; enhancer; epigenetic modifier; heterozygous loss; histone methyltransferase; medulloblastoma; tumor suppressor

DOI:  https://doi.org/10.1016/j.celrep.2025.115619
Cell Death Dis. 2025 Apr 26. 16(1): 346

MMP1-induced NF-κB activation promotes epithelial-mesenchymal transition and sacituzumab govitecan resistance in hormone receptor-positive breast cancer.

Letian Chen, Yinghuan Cen, Keyang Qian, Wang Yang, Wenbin Zhou, Yaping Yang.

Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC), shows promise in the treatment of breast cancer (BC); however, drug resistance limits its clinical application. Matrix metalloproteinase 1 (MMP1), which is overexpressed in many tumor types, plays a key role in tumor metastasis and drug resistance. The involvement of MMP1 in SG resistance in metastatic hormone receptor-positive (HR + ) BC has not been previously reported. In this study, we employed various in vitro and in vivo approaches to investigate the role of MMP1 in SG resistance in BC. MMP1 expression was manipulated in different BC cell lines through lentiviral transfection and small interfering RNA techniques. Key methodologies included Western blot, quantitative reverse transcription PCR, and RNA sequencing to assess marker expression and identify differentially expressed genes. Functional assays were conducted to evaluate cell viability, proliferation, invasion, and migration. In vivo, a cell-derived xenograft model in nude mice was utilized to assess tumor growth and drug response. Bioinformatics analyses further explored MMP1 expression and its clinical relevance across different cancer types. Our findings indicate that MMP1 is overexpressed by approximately 30-fold in HR + BC tissues and is associated with poorer prognosis among HR + BC patients. Furthermore, our analysis reveals that HR + BC with high MMP1 expression displays resistance to SG, supporting the hypothesis that MMP1 plays a key role in regulating ADC resistance. Mechanistic studies demonstrate that MMP1 can activate the NF-κB pathway, which subsequently influences the epithelial-mesenchymal transition, thereby contributing to SG resistance. Ultimately, our research underscores the potential of MMP1 as a therapeutic target and biomarker, facilitating personalized treatment strategies that could enhance patient outcomes in BC therapy.

DOI: https://doi.org/10.1038/s41419-025-07615-y
J Biol Chem. 2025 Apr 29. pii: S0021-9258(25)00407-7. [Epub ahead of print] 108558

Alisertib impairs the stemness of hepatocellular carcinoma by inhibiting purine synthesis.

Zhuoran Qi, Jie Luo, Wenfeng Liu, Ye Xu, Yifan Ma, Sunkuan Hu, Xizhong Shen, Xiaojing Du, Wei Xiang.

  Hepatocellular carcinoma tumor-repopulating cells (HCC-TRCs) drive disease progression, yet their purine metabolism mechanisms remain poorly understood. This study revealed that the stemness index, strongly linked to poor HCC prognosis, exhibited a robust positive correlation with purine metabolism through single-sample gene set enrichment analysis (ssGSEA). Integrated drug screening across CTRP, GDSC, and PRISM databases identified alisertib, an Aurora kinase A inhibitor, as a potent agent targeting stemness. Using fibrin gel-based 3D-cultured HCC-TRCs, mechanistic studies demonstrated that alisertib suppresses xanthine and hypoxanthine production by inhibiting the AURKA/AKT signaling axis. This disruption markedly impaired tumor spheroid formation, migration, and invasion in vitro, while significantly suppressing tumor growth in vivo-effects reversible by the AKT agonist SC79. Our findings revealed a novel therapeutic strategy targeting purine metabolism through AURKA/AKT axis inhibition, effectively eliminating HCC-TRCs.

Keywords:  AURKA/AKT; Hepatocellular carcinoma; alisertib; purine metabolism; tumor-repopulating cells

DOI:  https://doi.org/10.1016/j.jbc.2025.108558
Front Immunol. 2025 ;16 1573815

ALDOC promotes neuroblastoma progression and modulates sensitivity to chemotherapy drugs by enhancing aerobic glycolysis.

Yunpeng Chen, Haixia Zhu, Yishu Luo, Tianyue Xie, Youyang Hu, Zhiwei Yan, Weichao Ji, YaXuan Wang, Qiyou Yin, Hua Xian.

   Introduction: Neuroblastoma (NB), a malignant extracranial solid tumor originating from the sympathetic nervous system, exhibits poor prognosis in high-risk cases, with a 5-year overall survival rate below 50%. Glycolysis has been implicated in NB pathogenesis, and targeting glycolysis-related pathways shows therapeutic potential. This study investigates the role of the glycolysis-associated gene ALDOC in NB pathogenesis and its impact on chemotherapy sensitivity.
Methods: Transcriptomic data from NB patients were analyzed to identify ALDOC as an independent risk factor for high-risk NB. Protein expression levels of ALDOC were assessed in NB cells versus normal cells using immunoblotting. Functional experiments, including proliferation and migration assays, were conducted in ALDOC-interfered NB cell lines. Glycolytic activity was evaluated by measuring glucose uptake, lactate production, and ATP generation. Additionally, the sensitivity of ALDOC-downregulated NB cells to cisplatin and cyclophosphamide was tested to explore its role in chemotherapy response.
Results: ALDOC was identified as a high-risk prognostic marker in NB, with elevated protein expression in NB cells compared to normal controls. Silencing ALDOC significantly inhibited NB cell proliferation and migration. Glycolytic activity was markedly reduced in ALDOC-downregulated cells, evidenced by decreased glucose uptake, lactate production, and ATP levels. Furthermore, ALDOC suppression enhanced NB cell sensitivity to cisplatin and cyclophosphamide, suggesting a glycolysis-dependent mechanism underlying chemotherapy resistance.
Discussion: Our findings highlight ALDOC as a critical driver of NB progression through glycolysis acceleration, with implications for therapeutic targeting. The observed increase in chemotherapy sensitivity upon ALDOC inhibition underscores its potential as a biomarker for treatment optimization. However, the complexity of glycolysis regulation, involving multiple genes and pathways, necessitates further mechanistic studies to clarify ALDOC's specific role. Despite this limitation, our work emphasizes the importance of aerobic glycolysis in NB pathogenesis and provides a foundation for developing novel therapeutic strategies targeting ALDOC or associated pathways. Future research should explore interactions between ALDOC and other glycolytic regulators to refine combinatorial treatment approaches.

Keywords:  ALDOC; MYCN; aerobic glycolysis; drug sensitivity; neuroblastoma

DOI:  https://doi.org/10.3389/fimmu.2025.1573815
J Clin Invest. 2025 Apr 29. pii: e183531. [Epub ahead of print]

Kinesin-like protein KIFC2 stabilizes CDK4 to accelerate growth and confer resistance in HR+/HER2- breast cancer.

Shao-Ying Yang, Ming-Liang Jin, Lisa Andriani, Qian Zhao, Yun-Xiao Ling, Cai-Jin Lin, Min-Ying Huang, Jia-Yang Cai, Yin-Ling Zhang, Xin Hu, Zhi-Ming Shao, Fang-Lin Zhang, Xi Jin, A Yong Cao, Da-Qiang Li.

  Hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer (HR+/HER2- BC) is the most common subtype, with high risk of long-term recurrence and metastasis. Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is a standard treatment for advanced/metastatic HR+/HER2- BC, but resistance remains a major clinical challenge. We report that kinesin family member C2 (KIFC2) was amplified in approximately 50% HR+/HER2- BC, and its high expression was associated with poor disease outcome, increased tumor protein p53 (TP53) somatic mutation, and active pyrimidine metabolism. Function assays revealed that depletion of KIFC2 suppressed growth and enhanced sensitivity of HR+/HER2- BC cells to tamoxifen and CDK4/6 inhibitors. Mechanistically, KIFC2 stabilized CDK4 by enhancing its interaction with ubiquitin specific peptidase 9 X-linked (USP9X). Importantly, re-expression of CDK4 in KIFC2-depleted cells partially rescued the decreased growth and increased sensitivity to tamoxifen and CDK4/6 inhibitors caused by KIFC2 depletion. Clinically, high KIFC2 mRNA expression was negatively associated with survival rate of HR+/HER2- BC patients received adjuvant ET alone or in combination with CDK4/6 inhibitors. Collectively, these findings identify an important role for KIFC2 in HR+/HER2- BC growth and therapeutic resistance, and support its potential as a therapeutic target and predictive biomarker.

Keywords:  Breast cancer; Cell biology; Drug therapy; Molecular biology; Oncology; Therapeutics

DOI:  https://doi.org/10.1172/JCI183531
Oncogene. 2025 Apr 30.

SETD5 facilitates stemness and represses ferroptosis via m6A-mediating PKM2 stabilization in non-small cell lung cancer.

Xingzhe Liu, Yuzhen Cui, Jie Gong, Xinhui Yu, Yan Cui, Yanhua Xuan.

SETD5, an atypical member of the histone lysine methyltransferase family known for its association with cancer stemness, is a significant predictor of unfavorable survival outcomes in non-small cell lung cancer (NSCLC). However, the function of SETD5 in NSCLC stemness remains unclear, and whether it is an active H3K36me3 is controversial. Consequently, further investigation is required to clarify the pivotal role of SETD5 in NSCLC stemness and its related mechanism. Thus, this study employed the NSCLC tissue microarray and bioinformatics tools to analyze SETD5 expression and determine its effect on stemness and investigated the role of SETD5 in the metastasis of NSCLC using in vitro and in vivo analyses. The findings indicated high SETD5 expression in embryonic and NSCLC tissues, which was related to the pathological tumor stage, lymph node metastasis, and clinical stage, indicating that SETD5 could be used as a biomarker and prognostic factor in NSCLC. In addition, we found that SETD5 can promote glycolysis, thereby inhibiting ferroptosis and promoting the stemness of NSCLC, causing tumor metastasis and adverse prognosis in patients. In terms of mechanism, SETD5 as H3K36me3 facilitates the m6A modification of METTL14 and the recruitment of YTHDF1 and mediates PKM2 nuclear translocation and phosphorylation of p-PKM2 Tyr105, regulating GPX4 mediated ferroptosis resistance and SOX9 mediated stemness in NSCLC. The findings emphasize that SETD5 may serve as a promising indicator of stemness in NSCLC, which can help develop therapeutic targets for NSCLC and prognostic evaluation. This study provides evidence that SETD5 as H3K36me3 facilitates the m6A modification of METTL14 and the recruitment of YTHDF1 and mediates the nuclear translocation of PKM2, regulating GPX4 mediated ferroptosis resistance and SOX9 mediated stemness, causing tumor metastasis and adverse prognosis in patients.

DOI: https://doi.org/10.1038/s41388-025-03426-9
Int J Biol Sci. 2025 ;21(6): 2396-2414

PPARG Activation of Fatty Acid Metabolism Drives Resistance to Anti-HER2 Therapies in HER2-Positive Breast Cancer.

Min Xiong, Douwaner Liu, Xuliren Wang, Hengyu Ren, Weiru Chi, Bingqiu Xiu, Qi Zhang, Jiayu Zhang, Liyi Zhang, Zehao Wang, Ming Chen, Jingyan Xue, Yayun Chi, Jiong Wu.

  HER2-positive breast cancer, which accounts for approximately 15-20% of all breast cancers, is characterized by its aggressive recurrence, metastasis and reduced survival. Despite advances in anti-HER2 therapies, many patients continue to face treatment resistance, either initially or after an initial positive response, resulting in relapse or disease progression. The primary focus of this research was to identify the peroxisome proliferator-activated receptor gamma (PPARG) as a contributing factor to decreased drug sensitivity by establishing anti-HER2 drug-resistant cell lines of HER2-positive breast cancer. We found that PPARG promotes fatty acid metabolism and activates the PI3K/Akt/mTOR signaling pathway. Inhibition of fatty acid synthesis (FASN) after overexpression of PPARG, effectively blocking the activation of the PI3K/Akt/mTOR pathway and enhancing cellular anti-HER2 drug sensitivity. Co-administration of the PPARG inhibitor GW9662 has emerged as a promising strategy to augment the efficacy of anti-HER2 therapies, offering potential for clinical applications.

Keywords:  Drug sensitivity; GW9662; HER2-positive breast cancer; PPARG

DOI:  https://doi.org/10.7150/ijbs.99275
Cell Death Discov. 2025 Apr 29. 11(1): 208

TAZ/NRF2 positive feedback loop contributes to proliferation in bladder cancer through antagonistic ferroptosis.

Zhen Song, Shikai Gui, Xuepeng Rao, Gan Zhang, Yu Cheng, Tao Zeng.

Bladder cancer (BLCA) is a prevalent malignancy characterized by high recurrence and metastasis rates. Emerging evidence suggests that the NRF2-GPX4 axis is closely associated with ferroptosis. The transcriptional coactivator with PDZ-binding motif (TAZ) plays a crucial role in regulating ferroptosis; however, its role in BLCA remains unclear. In our study, we found that TAZ was markedly upregulated in BLCA tissues and BLCA cell lines. Gene set enrichment analysis indicated that TAZ depletion was related to ferroptosis and glutathione metabolism. Our results demonstrated that TAZ promotes the malignant progression of BLCA cells both in vitro and in vivo. Moreover, TAZ enhances NRF2 transcriptional activity through interaction with NRF2. We further revealed that TAZ-TEAD4 regulates NRF2 expression at the transcriptional level. Additionally, NRF2 regulates TAZ transcription by binding to its promoter region, establishing a positive feedback loop between TAZ and NRF2 that sustains GPX4 activation and inhibits ferroptosis in BLCA. These insights provide novel molecular targets for therapeutic treatment in BLCA.

DOI: https://doi.org/10.1038/s41420-025-02506-9
Mol Cancer Ther. 2025 Apr 29.

6-((1,4-naphthoquinone-2-yl)methyl)thio-glucose conjugates, a novel targeted approach for advanced prostate cancer.

Tobias Busenbender, Dmitry N Pelageev, Jessica Hauschild, Moritz Kaune, Lukas Boeckelmann, Christoph Krisp, Mohamed E Elsesy, Alexandra Zielinski, Thomas Mair, Maria Riedner, Ayham Moustafa, Simone Venz, Malte Kriegs, Konstantin Hoffer, Yuri E Sabutski, Ksenia L Borisova, Nadja Strewinsky, Svetlana M Kovach, Ekaterina A Khmelevskaya, Hartmut Schlüter, Victor Ph Anufriev, Derya Tilki, Markus Graefen, Wael Y Mansour, Carsten Bokemeyer, Sergey A Dyshlovoy, Gunhild von Amsberg.

The Warburg effect is a shift from oxidative phosphorylation to anaerobic glycolysis, accompanied by an enormous increase in glucose uptake into cancer cells. We have utilized this effect to design a new group of targeted 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker, which are cytotoxic to prostate cancer cells. Compound PeS-9 revealed the highest efficacy and selectivity, which was conditioned by a GLUT-1-mediated uptake. PeS-9 induced androgen receptor degradation followed by downregulation of its signaling. In addition, it increased reactive oxygen species production and induced DNA double-strand breaks. Combinational therapy with PARP-inhibitor olaparib resulted in synergistic effects in homologous recombination deficient cells. The underlying mode of PeS-9's cytotoxic action involved mitochondrial targeting, leading to a loss of mitochondrial membrane potential, release of cytochrome C and AIF, activation of caspases-3 and -9, PARP cleavage, and apoptotic cell death. This process was stipulated by down-regulation of several antiapoptotic factors and induction of endoplasmic reticulum stress. Moreover, drug-induced activation of signaling pathway mediated by p38, JNK1/2, and ERK1/2 kinases was identified as an important factor of the cytotoxic activity. The anticancer activity of PeS-9 could be confirmed ex vivo using patients-derived tumoroids as well as in vivo in xenografts demonstrating suppression of tumor growth and decreased dissemination of prostate cancer cells to the lungs. No serious side effects were observed in animal models. This unique combination of anticancer properties makes PeS-9 an attractive candidate for targeted monotherapy against GLUT-1-overexpressing tumors and as a potential combination partner, especially with PARP inhibitors.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0955
Cancer Discov. 2025 Apr 29.

A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC.

Caroline Broderick, Riccardo Mezzadra, Exequiel M Sisso, Felix Mbuga, Rashi Raghulan, Almudena Chaves Perez, Amanda Kulick, Lingyan Jiang, Jingjing Jiang, Yu-Jui Ho, Janelle Simon, Eric Rosiek, Eric Chan, Aveline Filliol, Ronan Chaligne, Elisa de Stanchina, Ximo Pechuan-Jorge, Andrea Schietinger, Mallika Singh, Scott W Lowe.

Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these 'persister' cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrate a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1425
Adv Sci (Weinh). 2025 Apr 30. e2503009

CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance.

Tian He, Zi-Yi Wang, Bin Xu, Cheng-Jie Zhong, Lu-Na Wang, Huan-Chen Shi, Zi-Yue Yang, Shi-Qi Zhou, Hui Li, Bo Hu, Xiao-Dong Zhu, Ying-Hao Shen, Jian Zhou, Jia Fan, Hui-Chuan Sun, Cheng Huang.

  The chemokine CXCL6 is identified as a pivotal regulator of biological processes across multiple malignancies. However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for CXCL6 is performed using a public database. Both in vitro and in vivo experiments are utilized to evaluate the oncogenic effects of CXCL6 on CCA. Additionally, RNA-Seq is employed to detect transcriptomic changes related to CXCL6 expression in CCA cells and neutrophils. Molecular docking, fluorescence colocalization, and Co-IP are used to elucidate a direct interaction between JAKs and CXCR1/2. Additionally, LC-MS lipidomics and explored the impact of CXCL6 on immunotherapy in vivo. CXCL6 is upregulated in CCA tissues and promoted the proliferation and metastasis of CCA. Mechanistically, CXCL6 regulated the CXCR1/2-JAK-STAT/PI3K axis in CCA via autocrine signaling, leading to lipid metabolic reprogramming, and promoted neutrophil extracellular traps (NETs) formation by activating the RAS/MAPK pathway in neutrophils. Eventually, NETs formation induced immunotherapy resistance in CCA by blocking CD8+T cell infiltration. CXCL6 modulates CCA progression through the CXCR1/2-JAK-STAT/PI3K axis and reshaping its lipid metabolism. CXCL6 also mediates immunotherapy resistance through NETs, which may be a potential therapeutic target and biomarker for CCA.

Keywords:  CXCL6; Cholangiocarcinoma; Immunotherapy; Lipid metabolism; Neutrophil extracellular traps

DOI:  https://doi.org/10.1002/advs.202503009
J Biol Chem. 2025 Apr 25. pii: S0021-9258(25)00400-4. [Epub ahead of print] 108551

NUDT16 enhances the resistance of cancer cells to DNA-damaging agents by regulating replication fork stability via reversing HMGA1 ADP-ribosylation.

Yingshi Zhou, Zhihuai Deng, Shiyu Xiong, Wenjia Li, Wanrong Luo, Man Luo, Haifeng Tang, Wenjing Wu, Carmen Chak-Lui Wong, Dong Yin, Kaishun Hu, Baoming Luo.

  Precise DNA replication is the basis for maintaining cell proliferation and genome stability. Current chemotherapy drugs and radiotherapy induce cell death by aggravating replication stress, albeit with poor efficacy. The replication stress response has been shown to play fundamental roles in resistance to radiotherapy and chemotherapy. High mobility group A1 (HMGA1) promotes tumor progression by regulating autophagy, angiogenesis, and chemoresistance; however, its role in coordinating replication stress and cell cycle progression remains elusive. Our results indicated that HMGA1 recruited FANCD2 to promote DNA replication and cell cycle progression both by attenuating R-loop-induced replication stress and by protecting stalled replication forks from degradation, ultimately enhancing tumor resistance to chemotherapy and irradiation (IR) treatment. We also identified HMGA1 as a novel substrate for the dePARylase NUDT16. NUDT16 was found to suppress the binding of HMGA1 to the E3 ubiquitin ligase CHFR by removing its PARylation at Glu 50, thereby reducing its ubiquitin-proteasome pathway-mediated degradation and enhancing HMGA1 protein stability. NUDT16-HMGA1 inhibition can significantly improve the sensitivity of tumor cells to chemotherapy and IR treatment. Collectively, these data suggest that NUDT16 enhances the ability of tumor cells to cope with replication stress by reversing the PARylation and positively regulating the protein expression of HMGA1. Therefore, targeting the NUDT16-HMGA1 pathway may be a novel strategy to enhance the sensitivity of radiotherapy and chemotherapy.

Keywords:  HMGA1; NUDT16; PARylation; replication stress; ubiquitination

DOI:  https://doi.org/10.1016/j.jbc.2025.108551
Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]

Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.

Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.

  Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.

Keywords:  CCN1; cell death; mitochondria

DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
Nat Commun. 2025 Apr 29. 16(1): 4029

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.

DOI: https://doi.org/10.1038/s41467-025-59427-5
Front Immunol. 2025 ;16 1562700

BTG2-deficient mast cells remodel the tumor and tumor-draining lymph node microenvironment leading to chemotherapy resistance in breast cancer.

Xiaoqian Zhang, Jiayi Wang, Ziyu Liu, Jiahuai Wen, Mengling Kang, Chen Fang, Liping Ren.

   Background: Breast cancer is currently the most frequently diagnosed malignancy worldwide, with chemotherapy resistance being a major contributor to breast cancer-related mortality and distant metastasis. The role of lymph nodes as the initial site of immune defense remains controversial, particularly regarding whether complete dissection or preservation is necessary during breast cancer surgery.
Methods: We performed single-cell RNA sequencing (scRNA-seq) on cells derived from metastatic tumor draining lymph nodes and tumor tissue of four breast cancer patients exhibiting either sensitivity or resistance to neoadjuvant chemotherapy (NAC).
Results: Mast cells with low BTG2 expression were identified in the metastatic lymph nodes and in situ tumor of the NAC-resistant group. Mast cells with low BTG2 expression have enhanced migratory capacity and are preferentially recruited to lymph nodes by cytokines such as CCL5, secreted by tumor cells during metastasis. Mechanistically, the mast cells with low BTG2 suppress anti-tumor immunity by inducing Treg cell production through IL-2 secretion, particularly within tumor-draining lymph nodes. Furthermore, the mast cells with low BTG2 promote NAC resistance by inducing fibroblast precursor cells to differentiate into α-SMA-positive fibroblasts via the Tryptase-PAR-2-pERK signaling pathway, leading to excessive collagen fiber production. Finally, we demonstrated that combining radiotherapy upregulating the expression of BTG2 in mast cells with chemotherapy enhances therapeutic efficacy in a murine model.
Conclusions: This study highlights the immunoregulatory role of mast cells in the breast cancer tumor microenvironment and establishes a link between BTG2 expression in mast cells and neoadjuvant chemotherapy response. These findings provide a foundational basis for preserving functional lymph nodes and optimizing combined radiotherapy treatment strategies.

Keywords:  BTG2 gene; anti-tumor immunity; mast cells; metastatic lymph nodes; αSMA+ fibroblasts

DOI:  https://doi.org/10.3389/fimmu.2025.1562700
Mol Oncol. 2025 Apr 28.

Chemoresistome mapping in individual breast cancer patients unravels diversity in dynamic transcriptional adaptation.

Maya Dadiani, Gilgi Friedlander, Gili Perry, Nora Balint-Lahat, Shlomit Gilad, Dana Morzaev-Sulzbach, Anjana Shenoy, Noa Bossel Ben-Moshe, Anya Pavlovsky, Rinat Bernstein-Molho, Eytan Domany, Iris Barshack, Tamar Geiger, Bella Kaufman, Einav Nili Gal-Yam.

  Nongenetic adaptive resistance to chemotherapy, driven by transcriptional rewiring, is emerging as a significant mechanism in tumor survival. In this study we combined longitudinal transcriptomics with temporal pattern analysis to investigate patient-specific mechanisms underlying acquired resistance in breast cancer. Matched tumor biopsies (pretreatment, posttreatment, and adjacent normal) were collected from breast cancer patients who received neoadjuvant chemotherapy. Transcriptomes were analyzed by longitudinal gene-pattern classification to track patient-specific gene expression alterations that occur during treatment. Our findings reveal that resistance-associated genes were already dysregulated in primary tumors, suggesting the presence of a preexisting drug-tolerant state. While each patient displayed unique resistance-associated gene rewiring, these alterations converged into a limited number of dysregulated functional modules. Notably, patients receiving the same treatment exhibited distinct rewiring of genes and pathways, revealing parallel, individualized routes to resistance. In conclusion, we propose that tumor cells survive chemotherapy by sustaining or amplifying a preexisting drug-tolerant state that circumvents drug action. We suggest that individualized "chemoresistome maps" could identify cancer vulnerabilities and inform personalized therapeutic strategies to overcome or prevent resistance.

Keywords:  breast cancer; chemotherapy; resistance; transcriptional adaptation

DOI:  https://doi.org/10.1002/1878-0261.70030