bims-meract 2025-04-20 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–04–20
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.
KAT3B Promotes the Glycolysis and Malignant Progression of Lung Cancer by Mediating the Succinylation Modification of PKM2.
SLC25A42 promotes gastric cancer growth by conferring ferroptosis resistance through enhancing CPT2-mediated fatty acid oxidation.
Jacaric Acid Empowers RSL3-Induced Ferroptotic Cell Death in Two- and Three-Dimensional Breast Cancer Cell Models.
Galectin-13 reduces membrane localization of SLC7A11 for ferroptosis propagation.
Targeting B7-H3 inhibition-induced activation of fatty acid synthesis boosts anti-B7-H3 immunotherapy in triple-negative breast cancer.
Peroxisomal membrane protein PMP70 confers drug resistance in colorectal cancer.
Therapeutic Targeting of the Pentose Phosphate Pathway in Colorectal Cancer Using 6-Aminonicotinamide and 5-Fluorouracil.
Inhibition of mitochondrial genome-encoded mitomiR-3 contributes to ZEB1 mediated GPX4 downregulation and pro-ferroptotic lipid metabolism to induce ferroptosis in breast cancer cells.
TMEM160 inhibits KEAP1 to suppress ferroptosis and induce chemoresistance in gastric cancer.
Iron overload mediates cytarabine resistance in AML by inhibiting the TP53 signaling pathway.
A novel role of exostosin glycosyltransferase 2 (EXT2) in glioblastoma cell metabolism, radiosensitivity and ferroptosis.
Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.
Inhibiting glycolysis facilitated checkpoint blockade therapy for triple-negative breast cancer.
BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma.
FADS2 inhibits colorectal cancer cell proliferation by regulating ferroptosis through SLC7A11/GPX4.
Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties.
CRISPR/Cas9-mediated SHP-1-knockout T cells combined with simvastatin enhances anti-tumor activity in humanized-PDX HCC model.
Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization.

Cell. 2025 Apr 08. pii: S0092-8674(25)00292-2. [Epub ahead of print]

ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1.

Jia-Shu Yang, Andrew J Morris, Koki Kamizaki, Jianzhong Chen, Jillian Stark, William M Oldham, Toshitaka Nakamura, Eikan Mishima, Joseph Loscalzo, Yasuhiro Minami, Marcus Conrad, Whitney S Henry, Victor W Hsu.

  Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.

Keywords:  aldehyde dehydrogenase 7A1; ferroptosis; ferroptosis suppressor protein 1; nicotinamide adenine dinucleotide reduced form

DOI:  https://doi.org/10.1016/j.cell.2025.03.019
J Biochem Mol Toxicol. 2025 Apr;39(4): e70259

KAT3B Promotes the Glycolysis and Malignant Progression of Lung Cancer by Mediating the Succinylation Modification of PKM2.

Zhifeng Guo, Yan Hui, Siqi Sun, Fanlong Kong.

  Lysine succinyltransferase KAT3B plays a critical role in the progression of various cancers by modulating key metabolic pathways, including glycolysis. However, the function and underlying mechanism of KAT3B in glycolysis and lung cancer (LC) progression remain to be further studied. We determined mRNA expression levels of lysine succinyl-modifying enzymes through qRT-PCR. Protein expression and succinylation status of glycolysis-related proteins PKM2, LDHA, and ENO1 were analyzed via Western blot. Co-immunoprecipitation and immunofluorescence microscopy were employed to verify the interaction between KAT3B and PKM2. Bioinformatics analysis predicted succinylation sites on PKM2, which were subsequently validated through site-directed mutagenesis. The effects of KAT3B and PKM2 on LC cell malignancy and glycolysis were evaluated using CCK-8, transwell migration, glucose uptake, lactate production, ECAR, and OCR assays. A xenograft tumor model was utilized to assess the impact of KAT3B on LC tumor growth. We confirmed the augmentation of KAT3B in LC, which also was correlated with advanced TNM stages and elevated T stages of LC patients. Conversely, KAT3B knockdown suppressed the growth, metastasis, and glycolytic activity of LC cells in vitro, while also inhibiting tumor growth in vivo. KAT3B mediated succinylation at PKM2 K298, and the suppression of LC cell malignancy and glycolysis upon KAT3B downregulation was largely reversed by upregulation of PKM2. The KAT3B/PKM2 axis may be a novel target for LC therapy.

Keywords:  KAT3B; PKM2; glycolysis; lung cancer; succinylation modification

DOI:  https://doi.org/10.1002/jbt.70259
Cell Death Dis. 2025 Apr 17. 16(1): 309

SLC25A42 promotes gastric cancer growth by conferring ferroptosis resistance through enhancing CPT2-mediated fatty acid oxidation.

Haoying Wang, Weijia Dou, Mengxiao Liu, Weifang Wang, Ying Yang, Jibin Li, Zhenxiong Liu, Nan Wang.

Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. Solute Carrier Family 25 Member 42 (SLC25A42) is a mitochondrial protein governing the transport of coenzyme A (CoA). However, the biological roles of SLC25A42 in human cancers are still unexplored. Here we uncovered that SLC25A42 is upregulated and correlated with a worse prognosis in GC patients. SLC25A42 promotes the proliferation of gastric cancer (GC) cells while suppresses apoptosis in vitro and in vivo. Mechanistically, SLC25A42 promotes the growth and inhibits apoptosis of GC cells by reprograming lipid metabolism. On the one hand, SLC25A42 enhances fatty acid oxidation-mediated mitochondrial respiration to provide energy for cell survival. On the other hand, SLC25A42 decreases the levels of free fatty acids and ROS to inhibit ferroptosis. Moreover, we found that SLC25A42 reprograms lipid metabolism in GC cells by upregulating the acetylation and thus the expression of CPT2. Collectively, our data reveal a critical oncogenic role of SLC25A42 in GCs and suggest that SLC25A42 represent a promising therapeutic target for GC.

DOI: https://doi.org/10.1038/s41419-025-07644-7
Int J Mol Sci. 2025 Apr 04. pii: 3375. [Epub ahead of print]26(7):

Jacaric Acid Empowers RSL3-Induced Ferroptotic Cell Death in Two- and Three-Dimensional Breast Cancer Cell Models.

Géraldine Cuvelier, Perrine Vermonden, Pauline Debisschop, Manon Martin, Françoise Derouane, Gerhard Liebisch, Josef Ecker, Marcus Hoering, Martine Berlière, Mieke Van Bockstal, Christine Galant, François Duhoux, Larissa Mourao, Colinda Scheele, Olivier Feron, René Rezsohazy, Cyril Corbet, Yvan Larondelle.

  Ferroptosis has recently emerged as a promising strategy to combat therapy-resistant cancers. As lipid peroxidation is a key trigger of ferroptotic cell death, enhancing cancer cell susceptibility through the supply of highly peroxidisable fatty acids represents a novel therapeutic approach. Conjugated linolenic acids (CLnAs) fulfill this requirement, exhibiting a peroxidation propagation rate eight times higher than their non-conjugated counterpart, α-linolenic acid. This study evaluates jacaric acid (JA), a plant-derived CLnA, as a ferroptotic inducer, both as a monotherapy and in combination with RAS-selective lethal 3 (RSL3), a canonical ferroptosis inducer, in 2D and 3D breast cancer cell models. JA treatment significantly reduced cell viability across all models, primarily through lipid peroxidation driven by JA incorporation into cellular lipids rather than alterations in anti-ferroptotic gene expression. Moreover, JA synergistically enhanced RSL3 cytotoxicity under 2D and several 3D conditions. Similar effects were observed with punicic acid, another plant-derived CLnA isomer. Our study exploits a common feature of cancer metabolism, increased fatty acid uptake, to turn it into a vulnerability. The incorporation of JA into breast cancer cells creates a highly peroxidisable environment that increases cancer cell sensitivity to RSL3, potentially reducing required doses and minimising side effects.

Keywords:  breast organoids; cancer; conjugated linolenic acids; ferroptosis; jacaric acid; lipid peroxidation

DOI:  https://doi.org/10.3390/ijms26073375
Nat Chem Biol. 2025 Apr 17.

Galectin-13 reduces membrane localization of SLC7A11 for ferroptosis propagation.

Hai-Liang Zhang, Yi-Qing Guo, Shan Liu, Zhi-Peng Ye, Li-Chao Li, Bing-Xin Hu, Zhi-Ling Li, Yu-Hong Chen, Gong-Kan Feng, Hui-Qi Shen, Rong Deng, Xiao-Feng Zhu.

The mechanism of ferroptosis propagation is still unclear. Here our results indicate that the cells undergoing ferroptosis secrete Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation. FOXK1 was phosphorylated by PKCβII and then facilitated the expression and secretion of Galectin-13 during ferroptotic cell death. Correlation analysis and functional analysis revealed that ferroptosis propagation ability was a previously unrecognized determinant of ferroptosis sensitivity in human cancer cells. A synthetic Galectin-13 mimetic peptide was shown to strongly enhance the sensitivity of tumors to the imidazole ketone erastin, radiotherapy and immunotherapy by boosting ferroptosis. In particular, cancer stem cells were vulnerable to the combination of Galectin-13 mimetic peptide and ferroptosis inducers. Our study provides new insights into ferroptosis propagation and highlights novel strategies for targeting ferroptosis to treat tumors.

DOI: https://doi.org/10.1038/s41589-025-01888-2
J Immunother Cancer. 2025 Apr 12. pii: e010924. [Epub ahead of print]13(4):

Targeting B7-H3 inhibition-induced activation of fatty acid synthesis boosts anti-B7-H3 immunotherapy in triple-negative breast cancer.

Ying Jiang, Zhiwen Qian, Cengzhu Wang, Danping Wu, Lu Liu, Xin Ning, Yilan You, Jie Mei, Xiaoqian Zhao, Yan Zhang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is the most malignant breast cancer, highlighting the need for effective immunotherapeutic targets. The immune checkpoint molecule B7-H3 has recently gained attention as a promising therapeutic target due to its pivotal role in promoting tumorigenesis and cancer progression. However, the therapeutic impact of B7-H3 inhibitors (B7-H3i) remains unclear.
METHODS: Transcriptomic and metabolomic analyses were conducted to explore the underlying mechanisms of B7-H3 inhibition in TNBC. The therapeutic efficacy of the combined treatment strategy was substantiated through comprehensive phenotypic assays conducted in vitro and validated in vivo using animal models.
RESULTS: B7-H3 blockade induces a "primed for death" stress state in cancer cells, leading to distinct alterations in metabolic pathways. Specifically, B7-H3 knockdown activated the AKT signaling pathway and upregulated sterol regulatory element-binding protein 1 (SREBP1), which in turn elevated FASN expression. The simultaneous inhibition of both B7-H3 and FASN more effectively attenuated the malignant progression of TNBC.
CONCLUSIONS: Our findings propose an "immune attack-metabolic compensation" dynamic model and suggest the feasibility of a dual-targeting strategy that concurrently inhibits both B7-H3 and FASN to enhance therapeutic efficacy in TNBC patients.

Keywords:  Breast Cancer; Immune Checkpoint Inhibitor; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-010924
Cell Death Dis. 2025 Apr 14. 16(1): 293

Peroxisomal membrane protein PMP70 confers drug resistance in colorectal cancer.

Jinwen Yin, Yu Shao, Fengxing Huang, Yuntian Hong, Wanhui Wei, Congqing Jiang, Qiu Zhao, Lan Liu.

Metabolic reprogramming is a key contributor to cancer therapeutic resistance. Peroxisomes are highly metabolic organelles essential for lipid metabolism and reactive oxygen species (ROS) turnover. Recent studies pointed out that targeting peroxisomal genes could be a promising strategy for treating therapy-resistant cells. However, the role of peroxisomes in CRC chemoresistance remains largely unexplored. This study aimed to investigate the function of peroxisomes in CRC chemoresistance and uncover the underlying mechanisms. Our results showed that the protein level of peroxisome marker PMP70 was strongly correlated with oxaliplatin (LOHP)-treated tumor recurrence in CRC. LOHP was confirmed to induce pexophagy in CRC cells, whereas LOHP-resistant cells maintained stable peroxisome levels and resisted this selective autophagy. Moreover, depletion of PMP70 significantly reduced the viability of resistant CRC cells in response to LOHP, both in vitro and in vivo. Mechanistically, PMP70 acted as a potential protector against excessive lipid peroxidation (LPO) in PMP70High and LOHP-resistant CRC cells. Additionally, PMP70-depleted cells exhibited an altered metabolic profile, characterized by reduced neutral lipids, fewer lipid droplets (LDs), and cell cycle arrest, indicating that PMP70 downregulation resulted in metabolic impairment. In conclusion, our study unveiled the pivotal role of PMP70-mediated peroxisomal functions in conferring chemoresistance, particularly in the context of LOHP resistance in CRC.

DOI: https://doi.org/10.1038/s41419-025-07572-6
Mol Carcinog. 2025 Apr 16.

Therapeutic Targeting of the Pentose Phosphate Pathway in Colorectal Cancer Using 6-Aminonicotinamide and 5-Fluorouracil.

Israa Ahmad Cheikh, Berthe Hayar, Noorhan Ghanem, Lara Al Saleh, Chirine El-Baba, Sadaf Al-Hadeethi, Riyad El-Khoury, Julnar Usta, Nadine Darwiche.

  Colorectal cancer (CRC) is a significant global health concern with rising incidence and mortality rates. 5-Fluorouracil (5-FU) is the standard chemotherapy for CRC but is often constrained by resistance and toxicity, highlighting the need for more efficient treatments. The pentose phosphate pathway (PPP), a glucose metabolic shunt, is significantly upregulated in CRC to support nucleotide synthesis and redox balance. Therefore, we hypothesized that targeting the PPP decreases CRC cell growth, reduces tumor progression, and improves 5-FU therapy. Consequently, we investigated the anti-tumor activities, cell death mechanism, and mode of action of the PPP inhibitor, 6-aminonicotinamide (6-AN), and 5-FU alone or in combination against CRC. We used human CRC cell lines with different p53 and 5-FU resistance statuses and a CRC xenograft model. Our findings show that 6-AN reduced the viability of human CRC cells independently of their p53 and 5-FU resistance profile, with its effect further enhanced in combination with 5-FU. The 6-AN/5-FU combination treatment synergized by reducing the total dehydrogenase activity of the PPP, inducing oxidative stress, and promoting senescence in CRC cells. Furthermore, 6-AN treatment significantly decreased tumor growth in a CRC xenograft mouse model. However, combining 6-AN with 5-FU did not reduce tumor volume significantly, highlighting the complexities of translating in vitro findings to animal models. These results suggest that interfering with the PPP activity suppresses CRC cell growth and may reduce 5-FU resistance. This study underscores targeting cancer metabolism as a novel therapeutic strategy to minimize drug resistance and to improve CRC therapeutic outcomes.

Keywords:  5‐fluorouracil; 6‐aminonicotinamide; cancer therapy; colorectal cancer; pentose phosphate pathway

DOI:  https://doi.org/10.1002/mc.23920
Free Radic Biol Med. 2025 Apr 14. pii: S0891-5849(25)00229-1. [Epub ahead of print]

Inhibition of mitochondrial genome-encoded mitomiR-3 contributes to ZEB1 mediated GPX4 downregulation and pro-ferroptotic lipid metabolism to induce ferroptosis in breast cancer cells.

Amoolya Kandettu, Joydeep Ghosal, Jesline Shaji Tharayil, Raviprasad Kuthethur, Sandeep Mallya, Rekha Koravadi Narasimhamurthy, Kamalesh Dattaram Mumbrekar, Yashwanth Subbannayya, Naveena An Kumar, Raghu Radhakrishnan, Shama Prasada Kabekkodu, Sanjiban Chakrabarty.

  Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a unique vulnerability in cancer cells. However, current ferroptosis-inducing therapies face clinical limitations due to poor cancer cell specificity, systemic toxicity, and off-target effects. Therefore, a deeper understanding of molecular regulators of ferroptosis sensitivity is critical for developing targeted therapies. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. While mitochondrial dysfunction contributes to metabolic reprogramming in cancer, its role in modulating ferroptosis remains poorly characterized. Previously, studies have identified that mitochondrial genome also encodes several noncoding RNAs. We identified 13 novel mitochondrial genome-encoded miRNAs (mitomiRs) that are aberrantly overexpressed in triple-negative breast cancer (TNBC) cell lines and patient tumors. We observed higher levels of mitomiRs in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Strikingly, 11 of these mitomiRs directly target the 3'UTR of ZEB1, a master regulator of epithelial-to-mesenchymal transition (EMT). Using mitomiR-3 mimic, inhibitor and sponges, we demonstrated its role as a key regulator of ZEB1 expression in TNBC cells. Inhibition of mitomiR-3 via sponge construct in basal-like TNBC, MDA-MB-468 cells, promoted ZEB1 upregulation and induced a mesenchymal phenotype. Further, mitomiR-3 inhibition in TNBC cells contributed to reduced cancer cell proliferation, migration, and invasion. Mechanistically, mitomiR-3 inhibition in TNBC cells promote metabolic reprogramming toward pro-ferroptotic pathways, including iron accumulation, increased polyunsaturated fatty acid (PUFA) metabolites, and lipid peroxidation, contributing to ferroptotic cell death via ZEB1-mediated downregulation of GPX4, a critical ferroptosis defense enzyme. We observed that mitomiR-3 inhibition significantly suppressed tumor growth in vivo. Our identified mitomiR-3 has low expression in normal breast cells, minimizing potential off-target toxicity, making them a promising target for pro-ferroptotic cancer therapy. Our study reveals a novel link between mitochondrial miRNAs and ferroptosis sensitivity in TNBC paving a way for miRNA-based therapeutics.

Keywords:  GPX4; PUFA; TNBC; ZEB1; ferroptosis; lipid peroxidation; miRNA; mitochondria

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.019
Cell Death Dis. 2025 Apr 13. 16(1): 287

TMEM160 inhibits KEAP1 to suppress ferroptosis and induce chemoresistance in gastric cancer.

Chunye Huang, Qinru Zeng, Jingyi Chen, Qin Wen, Weilun Jin, Xiaofeng Dai, Ruiwen Ruan, Hongguang Zhong, Yang Xia, Zhipeng Wu, Ruixuan Huang, Jianxi Zhang, Yangyang Yao, Li Li, Wan Lei, Jianping Xiong, Jun Deng.

Chemoresistance is the most significant challenge affecting the clinical efficacy of the treatment of patients with gastric cancer (GC). Here we reported that transmembrane protein 160 (TMEM160) suppressed ferroptosis and induced chemoresistance in GC cells. Mechanistically, TMEM160 recruited the E3 ligase TRIM37 to promote K48-linked ubiquitination and degradation of KEAP1, thereby activating NRF2 and transcriptionally upregulating the target genes GPX4 and SLC7A11 to inhibit ferroptosis. Further in vitro and in vivo experiments demonstrated that the combination of TMEM160 targeting and chemotherapy had a synergistic inhibitory effect on the growth of GC cells, which was partially NRF2-dependent. Moreover, TMEM160 and NRF2 protein levels were markedly overexpressed in GC tissues, and their co-overexpression was an independent factor for poor prognosis. Collectively, these findings indicate that TMEM160, as a pivotal negative regulator of ferroptosis, exerts a crucial influence on the chemoresistance of GC through the TRIM37-KEAP1/NRF2 axis, providing a potential new prognostic factor and combination therapy strategy for patients with GC.

DOI: https://doi.org/10.1038/s41419-025-07621-0
Acta Biochim Biophys Sin (Shanghai). 2025 Feb 28. 57(4): 646-655

Iron overload mediates cytarabine resistance in AML by inhibiting the TP53 signaling pathway.

Yan Jia, Ling Li, Ying Li, Xunxun Zhu, Haiyan Wang, Bin Xu, Qiuping Li, Hao Zhang.

  Currently, chemotherapy remains the primary treatment for acute myeloid leukemia (AML). Drug resistance in AML cells is a critical factor contributing to the failure of chemotherapy remission and subsequent relapse. Iron overload frequently occurs in AML patients because of hematopoietic suppression or supportive blood transfusion therapy. Previous studies have indicated that iron overload may promote the progression of AML; however, the underlying mechanisms remain unclear. Our results demonstrate that, compared with TP53-wild-type AML cells, TP53-mutant AML cells exhibit increased resistance to cytarabine-induced cytotoxicity. Moreover, reducing TP53 expression in wild-type AML cells diminishes their sensitivity to cytarabine. The TP53 signaling pathway is essential for mediating cytarabine-induced apoptosis in AML cells. In this study, an iron overload model in AML cells via the use of ferric citrate is constructed. Our data indicate that iron overload can suppress the TP53/BCL2/BAX signaling pathway, counteracting cytarabine-induced apoptosis. In TP53 wild-type AML cells, TFR1 participates in iron-mediated resistance to cytarabine by regulating the entry of iron into the cells. These findings provide a foundation for further exploration of the molecular mechanisms involved in AML resistance to cytarabine.

Keywords:  TFR1; TP53; acute myeloid leukemia; iron overload

DOI:  https://doi.org/10.3724/abbs.2025027
Cell Death Differ. 2025 Apr 15.

A novel role of exostosin glycosyltransferase 2 (EXT2) in glioblastoma cell metabolism, radiosensitivity and ferroptosis.

Rocío Matesanz-Sánchez, Mirko Peitzsch, Inga Lange, Jovan Mircetic, Michael Seifert, Nils Cordes, Anne Vehlow.

Glioblastoma (GBM) employs various strategies to resist therapy, resulting in poor patient survival. A key aspect of its survival mechanisms lies in metabolic regulation, maintaining rapid growth and evading cell death. Recent studies revealed the connection between therapy resistance and ferroptosis, a lipid peroxidation-dependent cell death mechanism triggered by metabolic dysfunction. Our aim was to identify novel regulators of therapy resistance in GBM cells. We conducted a comprehensive analysis combining RNA-sequencing data from a panel of human GBM cell models and TCGA GBM patient datasets. We focused on the top-12 differentially expressed gene candidates associated with poor survival in GBM patients and performed an RNA interference-mediated screen to uncover the radiochemosensitizing potential of these molecules and their impact on metabolic activity, DNA damage, autophagy, and apoptosis. We identified exostosin glycosyltransferase 2 (EXT2), an enzyme previously described in heparan sulfate biosynthesis, as the most promising candidate. EXT2 depletion elicited reduced cell viability and proliferation as well as radiochemosensitization in various GBM cell models. Mechanistically, we explored EXT2 function by conducting untargeted and targeted metabolomics and detected that EXT2-depleted GBM cells exhibit a differential abundance of metabolites belonging to S-adenosylmethionine (SAM) metabolism. Considering these metabolic changes, we determined lipid peroxidation and found that the diminished antioxidant capacity resulting from decreased levels of metabolites in the transsulfuration pathway induces ferroptosis. Moreover, modifications of specific SAM and transsulfuration metabolism associated enzymes revealed a prosurvival and ferroptosis-reducing function when EXT2 is depleted. Collectively, our results uncover a novel role of EXT2 in GBM cell survival and response to X-ray radiation, which is controlled by modulation of ferroptosis. These findings expand our understanding of how GBM cells respond to radio(chemo)therapy and may contribute to the development of new therapeutic approaches.

DOI: https://doi.org/10.1038/s41418-025-01503-w
J Microbiol Biotechnol. 2025 Apr 10. 35 e2412032

Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.

Dong-Hwan Kim, Dong Joon Kim, Seong-Jun Park, Won-Jun Jang, Chul-Ho Jeong.

  Pancreatic cancer, a leading cause of cancer-related deaths, is characterized by increased dependence on glutamine metabolism. Telaglenastat (CB-839), a glutaminase (GLS) inhibitor targets glutamine metabolism; however, its efficacy as monotherapy is limited owing to metabolic adaptations. In this study, we demonstrated that CB-839 effectively inhibited cell growth in pancreatic cancer cells, but activated the general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) signaling pathway. ATF4 knockdown reduced glutamine transporter alanine, serine, and cysteine transporter 2 (ASCT2) expression, glutamine uptake, and cell viability under glutamine deprivation-recovery conditions, confirming its protective role in mitigating glutamine-related metabolic stress. Notably, the combination of CB-839 and the ASCT2 inhibitor V-9302 demonstrated a synergistic effect, significantly suppressing pancreatic cancer cell survival. These findings highlight ATF4 and ASCT2 as crucial therapeutic targets and indicate that dual inhibition of GLS and ASCT2 may enhance treatment outcomes for pancreatic cancer.

Keywords:  ATF4; CB-839; Pancreatic cancer; V-9302; glutamine metabolism

DOI:  https://doi.org/10.4014/jmb.2412.12032
Discov Oncol. 2025 Apr 17. 16(1): 550

Inhibiting glycolysis facilitated checkpoint blockade therapy for triple-negative breast cancer.

Chong Li, Yu Tang, Ruizhi Zhang, Liang Shi, Jianying Chen, Peng Zhang, Ning Zhang, Wei Li.

  Cancer cells are characterized by their altered energy metabolism. A hallmark of cancer metabolism is aerobic glycolysis, also called the Warburg effect. Hexokinase 2 (HK2), a crucial glycolytic enzyme converting glucose to glucose-6-phosphate, has been identified as a central player in the Warburg effect. Deletion of HK2 decreases cancer cell proliferation in animal models without explicit side effects, suggesting that targeting HK2 is a promising strategy for cancer therapy. In this study, we discovered a correlation between HK2 and the tumor immune response in triple-negative breast cancer. Inhibition of HK2 led to a reduction in G-CSF expression in 4T1 cells and a decrease in the development of myeloid-derived suppressor cells which, in turn, enhanced T cell immunity and prolonged the survival of 4T1 tumor-bearing mice. Furthermore, the HK2 inhibitor 3-BrPA improved the therapeutic efficacy of anti-PD-L1 therapy in 4T1 tumor-bearing mouse models. This study highlights the potential of glycolysis-targeting interventions as a novel treatment strategy, which can be combined with immunotherapy for the treatment of triple-negative breast cancer.

Keywords:  3-Bromopyruvate; Glycolysis; Hexokinase 2; Immunotherapy; Triple-negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-02320-w
Mol Cancer. 2025 Apr 14. 24(1): 113

BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma.

Lingyi Fu, Shuo Li, Jie Mei, Ziteng Li, Xia Yang, Chengyou Zheng, Nai Li, Yansong Lin, Chao Cao, Lixuan Liu, Liyun Huang, Xiujiao Shen, Yuhua Huang, Jingping Yun.

   BACKGROUND: The effectiveness of immunotherapy in hepatocellular carcinoma (HCC) is limited, however, the molecular mechanism remains unclear. In this study, we identified baculoviral IAP repeat-containing protein 2 (BIRC2) as a key regulator involved in immune evasion of HCC.
METHODS: Genome-wide CRISPR/Cas9 screening was conducted to identify tumor-intrinsic genes pivotal for immune escape. In vitro and in vivo models demonstrated the role of BIRC2 in protecting HCC cells from immune killing. Then the function and relevant signaling pathways of BIRC2 were explored. The therapeutic efficacy of BIRC2 inhibitor was examined in different in situ and xenograft HCC models.
RESULTS: Elevated expression of BIRC2 correlated with adverse prognosis and resistance to immunotherapy in HCC patients. Mechanistically, BIRC2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to the inactivation of the non-canonical NFκB signaling pathway. This resulted in the decrease of major histocompatibility complex class I (MHC-I) expression, thereby protecting HCC cells from T cell-mediated cytotoxicity. Silencing BIRC2 using shRNA or inhibiting it with small molecules increased the sensitivity of HCC cells to immune killing. Meanwhile, BIRC2 blockade improved the function of T cells both in vitro and in vivo. Targeting BIRC2 significantly inhibited tumor growth, and enhanced the efficacy of anti-programmed death protein 1 (PD-1) therapy.
CONCLUSIONS: Our findings suggested that BIRC2 blockade facilitated immunotherapy of HCC by simultaneously sensitizing tumor cells to immune attack and boosting the anti-tumor immune response of T cells.

Keywords:  BIRC2; Hepatocellular carcinoma; Immunotherapy; MHC-I; NIK

DOI:  https://doi.org/10.1186/s12943-025-02319-5
Mol Biol Rep. 2025 Apr 15. 52(1): 394

FADS2 inhibits colorectal cancer cell proliferation by regulating ferroptosis through SLC7A11/GPX4.

Qinghui Yang, Hao Zhang, Jing Luo, Hongmei Yu, Xiaodi Yang, Chen Wang.

   BACKGROUND: Colorectal cancer (CRC) is a leading factor in cancer mortality globally. Ferroptosis, a regulated cell death described via lipid peroxidation, is crucial in cancer biology. This study explores the link between ferroptosis, FADS2, and CRC, focusing on the prognostic significance and therapeutic potential of targeting FADS2.
METHODS: The differential expression analysis of the Cancer Genome Atlas-colon adenocarcinoma (TCGA-COAD) and GSE36400 datasets was conducted to determine key ferroptosis-related genes, followed by functional enrichment analysis. Prognosis-related genes were assessed utilizing Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. Genetic variation analysis and immune analysis were employed to evaluate the clinical significance of FADS2. The impacts of FADS2 knockdown on CRC cell migration, proliferation, invasion, and ferroptosis were evaluated by in vitro cell experiments.
RESULTS: 64 key ferroptosis-related genes in CRC were highly enriched in pathways such as glutathione metabolism and peroxisome. Eleven prognosis-associated genes were identified, with TP53 showing the highest mutation frequency. High FADS2 expression was linked to poorer prognosis and higher immune cell infiltration. FADS2 knockdown significantly decreased glutathione (GSH) levels, SLC7A11, and GPX4 expression, increased malondialdehyde (MDA) levels, indicating the promotion of ferroptosis. Functional tests revealed knockdown FADS2 repressed CRC cell proliferation, migration, and invasion. SLC7A11 or GPX4 overexpression partially rescued the effects of FADS2 knockdown. Additionally, FADS2 knockdown enhances the chemosensitivity of CRC cells to oxaliplatin.
CONCLUSION: FADS2 is essential for encouraging CRC cell proliferation and tumor growth by preventing ferroptosis. Targeting FADS2 may enhance ferroptosis and suppress CRC progression, offering a possible course of treatment for CRC patients. The knockdown of FADS2 enhances the chemosensitivity of CRC cells to oxaliplatin, providing valuable insights for future clinical applications.

Keywords:   FADS2 ; Cell proliferation; Colorectal cancer; Ferroptosis; Prognosis

DOI:  https://doi.org/10.1007/s11033-025-10395-5
Adv Ther (Weinh). 2024 Oct;pii: 2400041. [Epub ahead of print]7(10):

Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties.

Edward R Neves, Achal Anand, Joseph Mueller, Roddel A Remy, Hui Xu, Kim A Selting, Jann N Sarkaria, Brendan Ac Harley, Sara Pedron-Haba.

  Despite extensive advances in cancer research, glioblastoma (GBM) still remains a very locally invasive and thus challenging tumor to treat, with a poor median survival. Tumor cells remodel their microenvironment and utilize extracellular matrix to promote invasion and therapeutic resistance. We aim here to determine how GBM cells exploit hyaluronan (HA) to maintain proliferation using ligand-receptor dependent and ligand-receptor independent signaling. We use tissue engineering approaches to recreate the three-dimensional tumor microenvironment in vitro, then analyze shifts in metabolism, hyaluronan secretion, HA molecular weight distribution, as well as hyaluronan synthetic enzymes (HAS) and hyaluronidases (HYAL) activity in an array of patient derived xenograft GBM cells. We reveal that endogenous HA plays a role in mitochondrial respiration and cell proliferation in a tumor subtype dependent manner. We propose a tumor specific combination treatment of HYAL and HAS inhibitors to disrupt the HA stabilizing role in GBM cells. Taken together, these data shed light on the dual metabolic and ligand - dependent signaling roles of hyaluronan in glioblastoma.

Keywords:  brain cancer; engineered disease models; glioblastoma; hyaluronan metabolism; hydrogel; tumor microenvironment

DOI:  https://doi.org/10.1002/adtp.202400041
iScience. 2025 Apr 18. 28(4): 112266

CRISPR/Cas9-mediated SHP-1-knockout T cells combined with simvastatin enhances anti-tumor activity in humanized-PDX HCC model.

Huaping Liu, Wu Ge, Xiaoping Yu, Jianwei Luo, Juan Zhang, Min Yang, Lu Cao, Yangnan Zhang, Ruike Wang, Cejun Yang, Pei Li, Mengyu Tian, XiaoPei Peng, Lei Peng, Di Wu, Muqi Liu, Qi Liang, Shengwang Zhang, Wei Li, Pengfei Rong, Hailan Li, Xiaoqian Ma, Wei Wang.

  Hepatocellular carcinoma (HCC) resists immunotherapy due to its immunosuppressive microenvironment. Sarcoma homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) inhibits T cell receptor signaling, and its pharmacological inhibition is limited by poor selectivity and membrane permeability. Here, we generated CRISPR-edited SHP-1-knockout (KO) CD8+ T cells to enhance adoptive therapy against HCC. Single-cell RNA sequencing of HCC patient T cells revealed elevated SHP-1 in exhausted subsets. SHP-1-KO T cells exhibited increased effector memory T cells (TEM) proportions and enhanced IFN-γ/Granzyme B/perforin secretion, improving cytotoxicity against HCC lines. In humanized PDX models, SHP-1-KO T cells demonstrated superior tumor-killing activity. Transcriptomics identified upregulated lipid metabolism pathways, with HMGCR as a hub gene. Combining SHP-1-KO T cells with simvastatin (HMGCR inhibitor) synergistically amplified anti-HCC efficacy. This study proposes a dual strategy combining SHP-1-targeted cell therapy and metabolic modulation to overcome immunotherapy resistance, offering a translatable approach for HCC treatment.

Keywords:  Biological sciences; Cancer; Cancer systems biology; Natural sciences; Systems biology

DOI:  https://doi.org/10.1016/j.isci.2025.112266
Nat Commun. 2025 Apr 15. 16(1): 3554

Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization.

Yuma Saimoto, Daiki Kusakabe, Kazushi Morimoto, Yuta Matsuoka, Eisho Kozakura, Nao Kato, Kayoko Tsunematsu, Tomohiro Umeno, Tamiko Kiyotani, Shota Matsumoto, Mieko Tsuji, Tasuku Hirayama, Hideko Nagasawa, Koji Uchida, Satoru Karasawa, Mirinthorn Jutanom, Ken-Ichi Yamada.

Ferroptosis, a form of cell death instigated by iron-dependent lipid peroxidation reactions (LPO), is emerging as a promising therapeutic target for cancer. While the mechanisms governing LPO induction and suppression have gradually been unveiled, questions persist regarding the specific cellular location of LPO and the utilization of iron in driving cell death. A comprehensive understanding of these aspects holds significant potential for advancing therapeutic applications in disease management. Here, we show lysosomal LPO in the initiation of ferroptosis, leveraging the hidden abilities of fluorescent detection probes. Intra-lysosomal LPO triggers iron leakage, fostering cell-wide LPO by augmenting lysosomal membrane permeabilization (LMP). Conversely, cell lines with low susceptibility to ferroptosis do not exhibit LMP. This deficiency is rectified by the concurrent administration of chloroquine, leading to LMP induction and subsequent cell death. These findings underscore enhancing LMP induction efficacy as a strategic approach to surmount resistance to therapies in cancer.

DOI: https://doi.org/10.1038/s41467-025-58909-w