bims-meract 2025-02-23 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–02–23
twenty-six papers selected by
Andrea Morandi, Università degli Studi di Firenze

Metformin combined with CB-839 specifically inhibits KRAS-mutant ovarian cancer.
AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer.
An integrative analysis of ASCL1 in breast cancer and inhibition of ASCL1 increases paclitaxel sensitivity by activating ferroptosis via the CREB1/GPX4 axis.
Hypoxia‑induced SREBP1‑mediated lipogenesis and autophagy promote cell survival via fatty acid oxidation in breast cancer cells.
RSK2-mediated phosphorylation and degradation of UBE2O inhibits hepatocellular carcinoma growth and resistance to radiotherapy.
CPT1A-mediated MFF succinylation promotes stemness maintenance in ovarian cancer stem cells.
Prexasertib exerts a synergistic effect on the antitumor activity of Lenvatinib through ALOX15-mediated ferroptosis in hepatocellular carcinoma.
CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia.
Targeting ELOVL6 to disrupt c-MYC driven lipid metabolism in pancreatic cancer enhances chemosensitivity.
The long noncoding RNA lncZBTB10 facilitates AR function via S-palmitoylation to promote prostate cancer progression and abiraterone resistance.
Heterogeneity in polyamine metabolism dictates prognosis and immune checkpoint blockade response in hepatocellular carcinoma.
KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.
Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of GPX4.
CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer.
Analysis of fatty acid metabolism in prostate cancer and discovery of a new programmed cell death-associated luminal cell subpopulation.
High-ammonia microenvironment promotes stemness and metastatic potential in hepatocellular carcinoma through metabolic reprogramming.
Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells.
Knockdown of VDAC1 Promotes Ferroptosis in Diffuse Large B-Cell Lymphoma.
IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3.
GABA regulates metabolic reprogramming to mediate the development of brain metastasis in non-small cell lung cancer.
Lactate Drives Senescence-Resistant Lineages in Hepatocellular Carcinoma via Histone H2B Lactylation of NDRG1.
Small molecule-mediated inhibition of the oxidoreductase ERO1A restrains aggressive breast cancer by impairing VEGF and PD-L1 in the tumor microenvironment.
KAT7-acetylated YBX1 promotes hepatocellular carcinoma proliferation by reprogramming nucleotide metabolism.
Etomidate Induces Mitochondrial Dysfunction in Glioma Cancer Cells by Inhibiting Mitochondrial Biogenesis Mediated by CREB/PGC-1α.
BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics.
CPEB4 modulates liver cancer progression by translationally regulating hepcidin expression and sensitivity to ferroptosis.

Sci Rep. 2025 Feb 19. 15(1): 6072

Metformin combined with CB-839 specifically inhibits KRAS-mutant ovarian cancer.

Han Wu, Jialin Zhang, Qiujie Wang, Zijiao Li, Linlin Li, Ya Xie.

  KRAS mutations can cause metabolic reprogramming in ovarian cancer, leading to an increased metastatic capacity. This study investigated the metabolic reprogramming changes induced by KRAS mutations in ovarian cancer and the mechanism of action of metformin combined with a glutaminase 1 inhibitor (CB-839). KRAS-mutant ovarian cancer accounted for 14% of ovarian cancers. The expression of glucose metabolism-related (PFKFB3, HK2, GLUT1, and PDK2) and glutamine metabolism-related enzymes (GLS1 and ASCT2) was elevated in KRAS-mutant ovarian cancer cells compared with that in wild-type cells. KRAS-mutant cells had a higher aerobic oxidative capacity than did wild-type cells. Metformin inhibited proliferation, the expression of glucose metabolism-related enzymes, and the aerobic oxidative capacity of KRAS-mutant cells compared with those of control cells. Furthermore, it enhanced the expression of glutamine metabolism-related enzymes in KRAS-mutant cells. Metformin combined with CB-839 inhibited the proliferation and aerobic oxidation of KRAS-mutant cells to a greater extent than that observed in wild-type cells. Additionally, the inhibitory effects of metformin and CB-839 in the KRAS-mutant ovarian cancer NOD-SCID mouse model were significantly stronger than those in the drug-alone group. KRAS mutations lead to enhanced glucose and glutamine metabolism in ovarian cancer cells, which was inhibited by metformin combined with CB-839.

Keywords:  KRAS mutation; Metabolic reprogramming; Ovarian cancer

DOI:  https://doi.org/10.1038/s41598-025-90963-8
Adv Sci (Weinh). 2025 Feb 20. e2408106

AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer.

Zicheng Sun, Huazhen Xu, Guanming Lu, Ciqiu Yang, Xinya Gao, Jing Zhang, Xin Liu, Yongcheng Chen, Kun Wang, Jianping Guo, Jie Li.

  Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptosis and aerobic respiration but also promotes glycolysis. Consequently, the combination of AKT1 inhibitors and the copper ionophores synergistically alleviate TNBC tumorigenesis both in vitro and in vivo. In summary, the findings reveal a crucial mechanism underlying TNBC resistance to cuproptosis and suggest a potential therapeutic approach for TNBC.

Keywords:  AKT1; FDX1; breast cancer; cuproptosis; metabolic reprogramming

DOI:  https://doi.org/10.1002/advs.202408106
Front Immunol. 2025 ;16 1546794

An integrative analysis of ASCL1 in breast cancer and inhibition of ASCL1 increases paclitaxel sensitivity by activating ferroptosis via the CREB1/GPX4 axis.

Xiaolu Yang, Yilun Li, Yaqi Peng, Yuan Chang, Binglu He, Tianqi Zhang, Shiyu Zhang, Cuizhi Geng, Yunjiang Liu, Xiaolong Li, Jun Hao, Li Ma.

   Objective: Our previous study found that Achaete-scute complex homolog 1 (ASCL1) is involved in classifying BC subtypes with different prognostic and pathological characteristics. However, the biological role of ASCL1 in BC still remains largely unexplored. This study aims to elucidate the function of ASCL1 in BC using bioinformatics analyses, as well as in vitro and in vivo experimental approaches.
Methods: Data from the TCGA, GEO, and Human Protein Atlas databases were utilized to evaluate ASCL1 expression in BC and its association with patient prognosis. Genetic alterations in ASCL1 were assessed through the COSMIC and cBioPortal databases, while the TIMER2.0 database provided insights into the relationship between ASCL1 expression and key gene mutations in BC. The GDSC database was used to examine correlations between ASCL1 levels and sensitivity to standard chemotherapeutic agents. Associations between ASCL1 expression and cytokines, immunomodulatory factors, MHC molecules, and receptors were analyzed using Pearson and Spearman correlation methods. The TIP database was employed to investigate the connection between ASCL1 expression and immunoreactivity scores, and six computational approaches were applied to evaluate immune cell infiltration. Functional assays were conducted on BC cell lines MCF-7 and MDA-MB-231, and nude mouse models were used for in vivo studies.
Results: ASCL1 was found to be upregulated in BC and correlated with unfavorable prognosis and mutations in key oncogenes. Its expression was linked to immunomodulatory factors, immune cell infiltration, and immunoreactivity scores in the tumor microenvironment. Additionally, ASCL1 influenced tumor immune dynamics and chemosensitivity in BC. Overexpression of ASCL1 enhanced BC cell proliferation, migration and invasion, while its knockdown had the opposite effect. Notably, inhibition of ASCL1 increased BC cell sensitivity to paclitaxel both in vitro and in vivo. In addition, inhibition of ASCL1 activated ferroptosis in BC, including altered mitochondrial morphology, increased MDA and ROS levels, decreased GSH levels and reduced GSH/GSSG ratio. Mechanistically, inhibition of ASCL1 decreases the phosphorylation of CREB1, thus reducing the expression of GPX4. In summary, inhibition of ASCL1 increases paclitaxel sensitivity by activating ferroptosis via the CREB1/GPX4 axis.
Conclusions: ASCL1 exerts oncogenic effects in BC and represents a potential therapeutic target for intervention.

Keywords:  ASCL1; breast cancer; drug sensitivity; ferroptosis; therapeutic target

DOI:  https://doi.org/10.3389/fimmu.2025.1546794
Oncol Lett. 2025 Apr;29(4): 175

Hypoxia‑induced SREBP1‑mediated lipogenesis and autophagy promote cell survival via fatty acid oxidation in breast cancer cells.

Jae-Ha Jung, Yeseul Yang, Yongbaek Kim.

  In the hypoxic tumor microenvironment, cancer cells undergo metabolic reprogramming to survive. The present study aimed to assess the effects of hypoxic conditions on the lipid metabolism of breast cancer cells to elucidate the mechanisms by which cancer cells survive in an unfavorable environment. Cell viability was assessed by trypan blue staining, MTT and Annexin V-PI assays. Intracellular lipid levels were quantified using Nile red stain with immunofluorescence (IF). Autophagy was detected using LC3 antibody, Cyto-ID stain, IF, Western blotting, and flow cytometry. Fatty acid oxidation (FAO) and ATP production were analyzed using specific assays, while gene expression was assessed by reverse transcription-polymerase chain reaction. siRNA transfection was used for gene knockdown, and Kaplan-Meier analysis was performed for survival analysis. Fatostatin and rapamycin served as an inhibitor of sterol regulatory element-binding protein 1 (SREBP1) and an autophagy inducer, respectively. Under hypoxic conditions, triple-negative breast cancer (TNBC) MDA-MB-231 cells showed markedly increased survival and proliferation rates compared with normal cells (MCF-10A) and estrogen receptor-positive cells (MCF-7), with no change in apoptosis. Under hypoxic conditions, MDA-MB-231 cells showed increased expression of lipogenesis, autophagy and FAO-related enzymes and activation of SREBP1, a key transcription factor for lipogenic genes, whereas these changes were not observed in MCF-7 cells. When SREBP1 was inhibited with chemical inhibitors and siRNA, the expression of lipogenic, autophagic and FAO-related enzymes decreased, resulting in reduced ATP production and viability in hypoxic MDA-MB-231 cells; however, this effect was restored when an autophagy inducer was added. Kaplan-Meier analysis demonstrated that higher SREBP1 expression in patients with TNBC was associated with a worse prognosis, suggesting that SREBP1-mediated reprogramming of lipid metabolism and autophagy under hypoxia is essential for TNBC cell survival. The results of the present study indicate that strategies targeting SREBP1 could be exploited to treat TNBC and improve prognosis.

Keywords:  FAO; SREBP1; TNBC; autophagy; hypoxia; lipid

DOI:  https://doi.org/10.3892/ol.2025.14921
Cancer Lett. 2025 Feb 13. pii: S0304-3835(25)00122-3. [Epub ahead of print] 217558

RSK2-mediated phosphorylation and degradation of UBE2O inhibits hepatocellular carcinoma growth and resistance to radiotherapy.

Yumei Huang, Anchen Qiu, Yimei Meng, Ming Lin, Yunhong Xu, Liu Yang.

  Radioresistance poses the main challenge in radiation therapy (RT) for liver cancer, with the DNA Damage response (DDR) being a crucial component of this resistance. Ubiquitin-conjugating enzyme E2O (UBE2O) has been implicated in regulating tumor proliferation, cholesterol metabolism, and drug resistance. However, the role of the ubiquitin-conjugating enzyme E2O (UBE2O) in DDR of liver cancer remains to be fully explored. We discovered an elevated expression of UBE2O within liver cancer tissues, which was notably associated with unfavorable prognoses in hepatocellular carcinoma (HCC) patients. Furthermore, we found that the suppression of UBE2O can effectively reduce the growth and resistance to radiotherapy of HCC cells in vitro and in vivo. Moreover, p90 ribosomal S6 kinase2 (RSK2) was confirmed as a novel interacting kinase of UBE2O, which mediated the phosphorylation and degradation of UBE2O at the Thr838 site. RSK2 inhibition promotes tumor proliferation and resistance to radiotherapy of HCC cells in vitro and in vivo, and these effects are abrogated upon UBE2O knockdown. Collectively, our work revealed that UBE2O promotes tumor progression and resistance to radiotherapy, which was negatively regulated by RSK2 for phosphorylation and degradation, indicating that the RSK2/UBE2O axis provides a potential radiosensitization target for HCC patients.

Keywords:  HCC; RSK2; UBE2O; phosphorylation; radioresistance

DOI:  https://doi.org/10.1016/j.canlet.2025.217558
Commun Biol. 2025 Feb 16. 8(1): 250

CPT1A-mediated MFF succinylation promotes stemness maintenance in ovarian cancer stem cells.

Yaqin Zhu, Shuting Chen, Hong Su, Yaning Meng, Chen Zang, Panjiao Ning, Lele Hu, Huanjie Shao.

Cancer stem cells (CSCs) play crucial roles in cancer progression, immune evasion, drug resistance, and recurrence. Understanding the mechanisms behind CSCs generation and stemness maintenance is vital for early cancer diagnosis and treatment. Here, we unveil that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer stem cells (OCSCs) and is essential for maintaining stemness by regulating lipid desaturation. Studies confirmed that CPT1A enhances SREBP1 activation, upregulating SCD1 expression, and promoting lipid desaturation in OCSCs. Mechanistic studies reveal that CPT1A promotes succinylation of mitochondrial fission factor (MFF) through its lysine succinyltransferase (LSTase) activity, crucial for mitochondria-associated membranes formation and SREBP1 activation. Inhibiting CPT1A's LSTase activity with Glyburide reduces OCSCs' stemness and enhances cisplatin's anti-tumor effects against ovarian cancer in vitro and in vivo. Together, our studies highlight the significance of CPT1A's LSTase activity in maintaining OCSCs' stemness, offering potential targets and therapeutic strategies for ovarian cancer treatment.

DOI: https://doi.org/10.1038/s42003-025-07720-w
Int Immunopharmacol. 2025 Feb 13. pii: S1567-5769(25)00268-1. [Epub ahead of print]150 114278

Prexasertib exerts a synergistic effect on the antitumor activity of Lenvatinib through ALOX15-mediated ferroptosis in hepatocellular carcinoma.

Shiyu Zhang, Mingcheng Guan, Tianyuan Ren, Na Li, Qian Ding, Di Sun, Hong Zhu.

  Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies worldwide. Lenvatinib, a potent multi-receptor tyrosine kinase inhibitor approved for the treatment of advanced HCC, demonstrates limited clinical efficacy. Therefore, there is an urgent need to investigate therapeutic strategies that combine Lenvatinib with other anticancer agents. Lenvatinib induces DNA damage in tumor cells, and the inhibition of the DNA damage response (DDR) pathway is hypothesized to enhance Lenvatinib-induced tumor cell death. In this study, we initially observed that Lenvatinib upregulated phosphorylated checkpoint kinase 1 (CHK1) protein levels, a key molecule in the DDR pathway, in HCC cells. This observation prompted us to investigate the antitumor efficacy of combining Lenvatinib with Prexasertib, a novel CHK1 inhibitor. The combination demonstrated synergistic anticancer effects in HCC cells. Mechanistically, treatment with Lenvatinib and Prexasertib resulted in cell death primarily through ferroptosis. Furthermore, we found that Lenvatinib and Prexasertib cooperatively upregulated ALOX15 expression, which culminated in the induction of ferroptosis. Taken together, our findings suggest the potential application of Prexasertib in combination with Lenvatinib as a promising therapeutic strategy for HCC treatment.

Keywords:  Ferroptosis; Hepatocellular carcinoma; Lenvatinib; Prexasertib; Synergistic therapy

DOI:  https://doi.org/10.1016/j.intimp.2025.114278
Cell Death Dis. 2025 Feb 18. 16(1): 107

CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia.

Lisa Scheiblecker, Thorsten Klampfl, Eszter Doma, Sofie Nebenfuehr, Omar Torres-Quesada, Sophie Strich, Gerwin Heller, Daniela Werdenich, Waltraud Tschulenk, Markus Zojer, Florian Bellutti, Alessia Schirripa, Sabine Zöchbauer-Müller, Peter Valent, Ingrid Walter, Eduard Stefan, Veronika Sexl, Karoline Kollmann.

Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. The cell cycle kinase CDK6 has recently been implicated in a wide range of hematopoietic malignancies. We here investigate the role of CDK6 in the regulation of cellular metabolism in BCR::ABL1+ leukemic cells. Our study, using gene expression data and ChIP-Seq analysis, highlights the contribution of CDK6 kinase activity in the regulation of oxidative phosphorylation. Our findings imply a competition for promoter interaction of CDK6 with the master regulator of mitochondrial respiration, NRF-1. In line, cells lacking kinase active CDK6 display altered mitochondria morphology with a defective electron transport chain. The enhanced cytoplasm/mitochondria ATP ratio paralleled by high pyruvate and lactate levels indicate a metabolic switch to glycolysis. Accordingly, combinatorial treatment of leukemic cells including imatinib resistant cells with the CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglucose (2-DG) enhanced apoptosis, while blocking cell proliferation in leukemic cells. These data may open a new therapeutic avenue for hematologic malignancies with high CDK6 expression by exploiting metabolic vulnerabilities unmasked by blocking CDK6 kinase activity that might even be able to overcome imatinib resistance.

DOI: https://doi.org/10.1038/s41419-025-07434-1
Nat Commun. 2025 Feb 16. 16(1): 1694

Targeting ELOVL6 to disrupt c-MYC driven lipid metabolism in pancreatic cancer enhances chemosensitivity.

Ana García García, María Ferrer Aporta, Germán Vallejo Palma, Antonio Giráldez Trujillo, Raquel Castillo-González, David Calzón Lozano, Alberto Mora Perdiguero, Raúl Muñoz Velasco, Miguel Colina Castro, Elena de Simone Benito, Raúl Torres-Ruiz, Sandra Rodriguez-Perales, Jonas Dehairs, Johannes V Swinnen, Juan Carlos Garcia-Cañaveras, Agustín Lahoz, Sandra Montalvo Quirós, Carlos Del Pozo-Rojas, Clara Luque Rioja, Francisco Monroy, Diego Herráez-Aguilar, Marina Alonso Riaño, José Luis Rodríguez Peralto, Víctor Javier Sánchez-Arévalo Lobo.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 12% survival rate, highlighting the need for novel therapies. c-MYC overexpression, driven by upstream mutations and amplifications, reprograms tumor metabolism and promotes proliferation, migration and metastasis. This study identifies ELOVL6, a fatty acid elongase regulated by c-MYC, as a potential therapeutic target. Using PDAC mouse models and cell lines, we show that c-MYC directly upregulates ELOVL6 during tumor progression. Genetic or chemical inhibition of ELOVL6 reduces proliferation and migration by altering fatty acid composition, affecting membrane rigidity, permeability and pinocytosis. These changes increase Abraxane uptake and show a synergistic effect when combined with ELOVL6 inhibition in vitro. In vivo, ELOVL6 interference significantly suppresses tumor growth and improves Abraxane response, prolonging survival. These findings position ELOVL6 as a promising target for improving PDAC treatment outcomes.

DOI: https://doi.org/10.1038/s41467-025-56894-8
Br J Cancer. 2025 Feb 16.

The long noncoding RNA lncZBTB10 facilitates AR function via S-palmitoylation to promote prostate cancer progression and abiraterone resistance.

Shin-Chih Lin, Yu-Sheng Cheng, Yi-Syuan Lin, Thi My Hang Nguyen, Wen-Tai Chiu, Ya-Chuan Tsai, Hsing-Yi Chen, Tsung-Yen Lin, Shih-Chieh Lin.

BACKGROUND: Activation of androgen receptor (AR) by androgen binding to its ligand-binding domain (LBD) has led to the development of clinical drugs that target androgen biosynthesis or the LBD of AR for the treatment of prostate cancer patients. While these drugs initially offer clinical benefits, the emergence of drug resistance is inevitable after a certain duration of treatment.
OBJECTIVES: Exploring alternative AR domains or identifying novel mechanisms for AR activation is crucial for advancing prostate cancer therapies.
METHODS: A systematic bioinformatic analysis identified novel androgen-responsive long noncoding RNAs (lncRNAs) in prostate cancer, which were verified using loss-of-function and gain-of-function strategies in vitro and in vivo.
RESULTS: lncZBTB10 or LINC02986 was overexpressed in prostate cancer specimens and correlated with poor clinical outcomes. Mechanistically, our findings elucidate the pivotal role of lncZBTB10 in facilitating AR function by inducing S-palmitoylation. Moreover, the interaction between lncZBTB10 and AR not only fosters but also orchestrates biomolecular condensates within the nucleus driven by a novel RNA-binding domain, particularly in prostate cancer cells. Notably, the overexpression of lncZBTB10 not only promotes tumor growth in vivo but also triggers abiraterone resistance in vitro by inducing AR expression.
CONCLUSIONS: These results collectively reveal a novel mechanism by which lncZBTB10 regulates AR function in prostate cancer cells.

DOI: https://doi.org/10.1038/s41416-025-02938-1
Front Immunol. 2025 ;16 1516332

Heterogeneity in polyamine metabolism dictates prognosis and immune checkpoint blockade response in hepatocellular carcinoma.

Jianyan Pan, Zhong Lin, Qinchun Pan, Tao Zhu.

  Immune checkpoint blockade holds promise in hepatocellular carcinoma (HCC) treatment, but its efficacy remains limited. Dysregulated polyamine metabolism and its interaction with oncogenic pathways promote tumor progression. However, the heterogeneity of polyamine metabolism and its effects on the immune microenvironment and response to immunotherapy in HCC remain unclear. Here, we aimed to investigate the prognostic and immunotherapeutic implications of polyamine metabolism in HCC. Based on polyamine-related genes, HCC patients were categorized into two clusters with distinct survival outcomes. We developed a polyamine-related signature, termed PAscore, which was found to be a strong predictor of both poor prognosis and reduced immunocyte infiltration. Notably, a high PAscore was also associated with decreased sensitivity to immunotherapy. Within the HCC microenvironment, malignant cells exhibited polyamine metabolic heterogeneity, those with high polyamine metabolic activity showed altered hallmark pathway signatures and increased communication with myeloid cells. In vitro experiments suggested that FIRRE, the gene with the greatest impact on the PAscore, significantly contributed to HCC proliferation and metastasis. This study underscores the potential of our polyamine-related signature in predicting the prognosis and immunotherapy response in HCC patients, and also reveals the polyamine metabolic heterogeneity among HCC cells that influences their crosstalk with infiltrating myeloid cells.

Keywords:  hepatocellular carcinoma; immunotherapy; metabolic heterogeneity; polyamine; prognosis

DOI:  https://doi.org/10.3389/fimmu.2025.1516332
Cell Rep Med. 2025 Feb 18. pii: S2666-3791(25)00039-4. [Epub ahead of print]6(2): 101966

KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.

Xiangyan Jiang, Tao Wang, Bin Zhao, Haonan Sun, Yuman Dong, Yong Ma, Zhigang Li, Yuxia Wu, Keshen Wang, Xiaoying Guan, Bo Long, Long Qin, Wengui Shi, Lei Shi, Qichen He, Wenbo Liu, Mingdou Li, Lixia Xiao, Chengliang Zhou, Hui Sun, Jing Yang, Junhong Guan, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao.

  The KRASG12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRASG12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRASG12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRASG12D-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRASG12D-mutated PDAC.

Keywords:  KRAS(G12D); MRTX1133; metabolic reprogramming; pancreatic ductal adenocarcinoma; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.xcrm.2025.101966
J Med Chem. 2025 Feb 19.

Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of GPX4.

Lingling Wang, Xiaoyan Ma, Ling Zhou, Miao Luo, Yunlong Lu, Yawen Wang, Pengdou Zheng, Huiguo Liu, Xiansheng Liu, Wukun Liu, Shuang Wei.

Gefitinib exhibits significant clinical efficacy in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) sensitive mutations. However, its efficacy is severely limited by acquired resistance. Herein, we designed and synthesized a series of dual-targeting thioredoxin reductase (TrxR)-EGFR gold complexes by attaching a gold ligand to the parent structure of gefitinib, 4-anilinoquinazoline. Among them, L1Au2 exhibited significant activity against both gefitinib-sensitive and resistant lung cancers, effectively inhibiting tumor proliferation and promoting apoptosis. Mechanistically, L1Au2 effectively inhibits TrxR and EGFR both in vitro and in vivo. Additionally, L1Au2 promotes the degradation of GPX4 protein via autophagolysosomal and proteasomal pathways, leading to ferroptosis. Notably, L1Au2 also induces endoplasmic reticulum stress (ERS) and triggers immunogenic cell death (ICD). In conclusion, this study provides an innovative strategy for overcoming gefitinib resistance in lung cancer by utilizing dual-targeting TrxR-EGFR alkynyl-Au(I) gefitinib derivatives, thereby offering a new approach for treating gefitinib-resistant lung cancer.

DOI: https://doi.org/10.1021/acs.jmedchem.4c02252
Cell Death Dis. 2025 Feb 21. 16(1): 122

CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer.

Da Qi, Yan Lu, Huinan Qu, Yuan Dong, Qiu Jin, Minghao Sun, Chengshi Quan.

We previously identified CLDN6 as a pivotal tumor suppressor in breast cancer and unexpectedly discovered that overexpression of CLDN6 resulted in characteristic ultrastructural alterations of ferroptosis. However, the exact mechanism by which CLDN6 triggers ferroptosis is still elusive in breast cancer. Our study showed that CLDN6 was associated with ferroptosis in breast cancer patients. The integration of CLDN6 and ferroptosis demonstrated remarkable predictive prognostic performance. We observed that CLDN6 triggers NRF2-mediated ferroptosis in vitro and in vivo. Mechanistically, CLDN6 enhanced nuclear export of NRF2 by regulating the PBK-dependent AKT/GSK3β/FYN axis. Further CLDN6 recruited PBK to the cell membrane through the endosomal pathway and bound with the DLG1/PBK complex, thereby promoted the degradation of PBK by the UPS. This study elucidates the previously unrecognized mechanism of CLDN6 triggering NRF2-mediated ferroptosis through recruiting DLG1/PBK complex. This study provides a reliable biomarker for predicting prognosis and is anticipated to guide the selection of therapies targeting ferroptosis in breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07448-9
Discov Oncol. 2025 Feb 17. 16(1): 194

Analysis of fatty acid metabolism in prostate cancer and discovery of a new programmed cell death-associated luminal cell subpopulation.

Yan Zeng, Zhaolin Jiang.

   INTRODUCTION: This study focuses on the role of fatty acid metabolism in prostate cancer, particularly in oncogenic luminal cells associated with programmed cell death under the influence of metabolic reprogramming.
MATERIALS AND METHODS: Prostate cancer was analyzed using single-cell transcriptomics and spatial transcriptomics data. Fatty acid metabolism levels in the tumor microenvironment were quantified by multiple gene set scoring methods, and data were processed using NMF and deconvolution methods to identify different cell populations and their interactions in the tumor microenvironment.
RESULTS: Luminal cells have significantly increased activity in fatty acid metabolism, which is associated with the aggressiveness and metastatic capability of tumors. Luminal cell subpopulations have been found to play a key role in the development of prostate cancer, especially their close association with programmed cell death.
CONCLUSION: This study deepens the understanding of the role of fatty acid metabolism in prostate cancer, identifies fatty acid metabolism-related luminal cell subtypes, and proposes new therapeutic targets, providing new insights into prostate cancer treatment.

Keywords:  Fatty acid metabolism; Luminal cells; Programmed cell death; Prostate cancer; Therapeutic targets; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-01982-w
Discov Oncol. 2025 Feb 14. 16(1): 182

High-ammonia microenvironment promotes stemness and metastatic potential in hepatocellular carcinoma through metabolic reprogramming.

Renchao Zou, Sicong Jiang, Jiaqi Mei, Chen Chen, Jia Yu, Yanqiu Fu, Siyu Chen.

   BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent and aggressive form of liver cancer, characterized by frequent recurrence and metastasis, which remain significant obstacles to effective treatment. Ammonia accumulates in the tumor microenvironment of HCC due to dysfunction in the urea cycle, but the detailed impact of ammonia on HCC cells remains insufficiently understood.
METHODS: We exposed HCC cell lines to high concentrations of ammonium chloride to evaluate alterations in proliferation, stemness, and migratory potential. After ammonia removal, changes in cellular behavior were assessed using colony formation, and spheroid assays. Transcriptomic and metabolomic analyses were conducted to investigate ammonia-induced metabolic reprogramming and alterations in gene expression. Additionally, animal models were employed to validate the impact of ammonia on tumor growth and metastasis.
RESULTS: Exposure to high-ammonia conditions transiently suppressed HCC cell proliferation without inducing apoptosis. However, following ammonia removal, cells demonstrated increased proliferation, enhanced spheroid formation, and elevated migratory capacity. Transcriptomic analysis revealed the upregulation of genes associated with cell adhesion, migration, and glycolysis. Concurrently, metabolomic profiling indicated increased lactate production, facilitating the aggressive behavior of HCC cells after ammonia withdrawal. Animal experiments confirmed that high-ammonia exposure accelerated tumor growth and metastasis.
CONCLUSION: Ammonia exerts a dual effect on HCC progression: it initially suppresses cell growth but later promotes stemness, proliferation, and metastasis through metabolic reprogramming. Targeting ammonia metabolism or glycolysis in the tumor microenvironment may represent a promising therapeutic strategy for mitigating HCC recurrence and metastasis. Future studies utilizing clinical samples are required to validate these findings and identify potential therapeutic strategies targeting ammonia metabolism.

Keywords:  Ammonia metabolism; Hepatocellular carcinoma (HCC); Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-01922-8
Cell Death Dis. 2025 Feb 20. 16(1): 118

Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells.

Peijia Jiang, Sandhya Chipurupalli, Byong Hoon Yoo, Xiaoyang Liu, Kirill V Rosen.

Mortality from colorectal cancer (CRC) is significant, and novel CRC therapies are needed. A pseudokinase MLKL typically executes necroptotic cell death, and MLKL inactivation protects cells from such death. However, we found unexpectedly that MLKL gene knockout enhanced CRC cell death caused by a protein synthesis inhibitor homoharringtonine used for chronic myeloid leukemia treatment. In an effort to explain this finding, we observed that MLKL gene knockout reduces the basal CRC cell autophagy and renders such autophagy critically dependent on the presence of VPS37A, a component of the ESCRT-I complex. We further found that the reason why homoharringtonine enhances CRC cell death caused by MLKL gene knockout is that homoharringtonine activates p38 MAP kinase and thereby prevents VPS37A from supporting autophagy in MLKL-deficient cells. We observed that the resulting inhibition of the basal autophagy in CRC cells triggers their parthanatos, a cell death type driven by poly(ADP-ribose) polymerase hyperactivation. Finally, we discovered that a pharmacological MLKL inhibitor necrosulfonamide strongly cooperates with homoharringtonine in suppressing CRC cell tumorigenicity in mice. Thus, while MLKL promotes cell death during necroptosis, MLKL supports the basal autophagy in CRC cells and thereby protects them from death. MLKL inactivation reduces such autophagy and renders the cells sensitive to autophagy inhibitors, such as homoharringtonine. Hence, MLKL inhibition creates a therapeutic vulnerability that could be utilized for CRC treatment.

DOI: https://doi.org/10.1038/s41419-025-07436-z
Hematol Oncol. 2025 Mar;43(2): e70054

Knockdown of VDAC1 Promotes Ferroptosis in Diffuse Large B-Cell Lymphoma.

Chuanming Lin, Liuyan Xin, Shuiling Xie.

  Diffuse large B-cell lymphoma (DLBCL) is a prevalent subtype of non-Hodgkin's lymphoma (NHL). Ferroptosis is a novel form of cell death involved in multiple tumor development. However, the relationship between ferroptosis-related genes and DLBCL has not been extensively studied. The GSE95290 dataset was downloaded from the Gene Expression Omnibus (GEO) database and merged with genes associated with ferroptosis to screen differentially expressed genes (DEGs). Hub genes were identified by constructing a protein-protein interaction (PPI) network. The messenger RNA (mRNA) expressions of hub genes were subsequently detected in vitro using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). The impact of voltage dependent anion channel 1 (VDAC1) on the proliferation, apoptosis, and ferroptosis of DLBCL was evaluated using Cell Counting Kit-8, flow cytometry, and relevant ferroptosis assays, respectively. Six highly expressed hub genes were identified, all of which could be used as diagnostic biomarkers for DLBCL. In vitro studies revealed that suppressing VDAC1 expression inhibited DLBCL cell proliferation and promoted apoptosis. Furthermore, knockdown of VDAC1 promoted ferroptosis in DLBCL cells and xenograft tumor models, resulting in elevated levels of malondialdehyde (MDA) and iron and increased protein levels of Acyl-CoA synthetase long-chain family 4 (ACSL4) and cyclooxygenase-2 (COX2). Conversely, glutathione (GSH) and superoxide dismutase (SOD) levels were reduced, accompanied by decreased protein levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain1 (FTH1). VDAC1 knockdown induces ferroptosis in DLBCL, which provides new insights into the pathogenic mechanisms of DLBCL.

Keywords:  VDAC1; bioinformatics analysis; diffuse large B‐cell lymphoma; ferroptosis

DOI:  https://doi.org/10.1002/hon.70054
Front Immunol. 2025 ;16 1535554

IFNβ drives ferroptosis through elevating TRIM22 and promotes the cytotoxicity of RSL3.

Huiyue Dong, Ling Zhu, Jingjing Sun, Qiuyan Chen, Pengyang Liu, Wei Zhang, Huajing Zeng, Rong Lin, Zongyang Yu, Jun Lu.

   Background: Cyclic GMP-AMP synthase (cGAS)-stimulator-of-interferon genes (STING) pathway is a cytosolic DNA sensor system. The production of this pathway, interferon-β (IFNβ), could suppress the growth of tumor cells, yet it is unclear whether ferroptosis is involved in IFNβ-induced cell death.
Methods: The effects of IFNβ on ferroptosis were analyzed in HT1080, 4T1, HCT116 and 786-O cells. HT1080 and 4T1 cells treated with IFNβ were subjected to RNA-Seq analysis. STAT1, STAT3, TRIM21, and TRIM22 were silenced by siRNAs to examine their effects on IFNβ-induced ferroptosis. The cGAS-STING signaling pathway-activated mice were used to evaluate the effects of IFNβ on ferroptosis in vivo. HT1080 cells, three-dimensional (3D) spheroids, and the xenograft mouse models were treated with IFNβ, RSL3, or IFNβ combination with RSL3 to analyze whether IFNβ enhances RSL3-induced ferroptosis.
Results: Here, we found that IFNβ could promote intracellular Fe2+ and lipid peroxidation levels, and decrease GSH levels in tumor cells. RNA sequencing data revealed that IFNβ induced a transcriptomic disturbance in ferroptosis-related genes. Knockdown of tripartite motif-containing 22 (TRIM22) suppressed the levels of intracellular Fe2+ and lipid ROS. It also reduced heme oxygenase (HMOX1) protein levels and increased ferroptosis suppressor protein 1 (FSP1) levels in HT1080 cells treated with IFNβ. Furthermore, our results illustrated that IFNβ enhanced the RAS-selective lethal 3 (RSL3)-induced ferroptosis and the inhibitory effect of RSL3 on GPX4. Meanwhile, compared to the groups treated with either IFNβ or RSL3 alone, the combination treatment of IFNβ and RSL3 significantly inhibited the growth of HT1080 three-dimensional (3D) spheroids and tumor in a mouse xenograft model.
Conclusions: Our work reveals a role for IFNβ in promoting ferroptosis and provides evidence that IFNβ could be used with RSL3 to increase cytotoxic effects in tumor cells.

Keywords:  IFNβ; RSL3; TRIM22; cGAS-STING; ferroptosis

DOI:  https://doi.org/10.3389/fimmu.2025.1535554
J Exp Clin Cancer Res. 2025 Feb 19. 44(1): 61

GABA regulates metabolic reprogramming to mediate the development of brain metastasis in non-small cell lung cancer.

Mengqing Xie, Hao Qin, Li Liu, Jing Wu, Zhikai Zhao, Yaodong Zhao, Yujia Fang, Xin Yu, Chunxia Su.

   BACKGROUND: Brain metastasis (BrM) poses a significant challenge to the prognosis and quality of life for patients with non-small cell lung cancer (NSCLC). Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system (CNS), has been implicated in the progression of various tumors. However, its potential role in BrM of NSCLC and the underlying mechanisms remain largely unexplored.
METHODS: A multi-omics approach combined with in vivo and in vitro experiments identified GABA as a key target in BrM of NSCLC. Functional and mechanistic studies were conducted to investigate how GABA mediates brain metastasis through the activation of the NF-κB pathway.
RESULTS: GABA levels were significantly elevated in both cells and serum of patients with NSCLC who had BrM. GABA markedly enhanced the brain metastatic capabilities and malignancy of NSCLC cells. Mechanistically, tumor cells with a tendency for brain metastasis can inhibit 4-aminobutyrate aminotransferase (ABAT) by downregulating forkhead box A2 (FOXA2) expression, leading to increased GABA accumulation. GABA subsequently activates the NF-κB pathway and the astrocytes, thus facilitating the brain metastasis of NSCLC.
CONCLUSIONS: Our findings indicate that GABA plays a crucial role in the development of NSCLC brain metastasis by activating the NF-κB pathway through the FOXA2/ABAT/GABA axis. Additionally, the interaction between NSCLC and astrocytes creates an inhibitory microenvironment that promotes tumor colonization.

Keywords:  Astrocyte; Brain metastasis; GABA; Metabolic reprogramming; NSCLC

DOI:  https://doi.org/10.1186/s13046-025-03315-9
Cancer Lett. 2025 Feb 18. pii: S0304-3835(25)00131-4. [Epub ahead of print] 217567

Lactate Drives Senescence-Resistant Lineages in Hepatocellular Carcinoma via Histone H2B Lactylation of NDRG1.

Lu Li, Jinyun Dong, Chunwei Xu, Shiqun Wang.

  Hepatocellular carcinoma (HCC) treatment options remain limited despite advances in targeted therapies for molecularly-defined cancers. To address tumor heterogeneity, we reconstructed HCC clonal evolution through single-cell RNA sequencing trajectory analysis, identifying 902 signature genes across seven cellular states. Weighted gene co-expression network analysis of public HCC datasets revealed tumor-grade-associated modules and established a 14-gene prognostic model linked to clonal evolution. Central to this model is the LDHA-NDRG1 axis - two hypoxia-responsive regulators showing coordinated spatiotemporal expression patterns during cancer progression. Dual-expressing cell lineages correlated with poor prognosis and senescence resistance through LDHA-mediated lactylation of histone H2B at K58 on NDRG1, an epigenetic mechanism connecting metabolic reprogramming to senescence evasion. Therapeutically, dual inhibition of this axis extended survival in metastatic HCC murine models. Our findings reveal that lactate-driven epigenetic modification via the LDHA-NDRG1 axis creates a molecularly distinct subpopulation enabling senescence resistance, providing mechanistic insights into HCC heterogeneity. This work proposes a precision medicine strategy targeting lactylation-mediated epigenetic regulation, with implications for developing combination therapies and patient stratification based on clonal evolution patterns.

Keywords:  Cellular Senescence; Hepatocellular Carcinoma; Lactate Metabolism; Lactylation; N-Myc Downstream Regulated 1

DOI:  https://doi.org/10.1016/j.canlet.2025.217567
Cell Death Dis. 2025 Feb 17. 16(1): 105

Small molecule-mediated inhibition of the oxidoreductase ERO1A restrains aggressive breast cancer by impairing VEGF and PD-L1 in the tumor microenvironment.

Ersilia Varone, Michele Retini, Alessandro Cherubini, Alexander Chernorudskiy, Alice Marrazza, Andrea Guidarelli, Alfredo Cagnotto, Marten Beeg, Marco Gobbi, Stefano Fumagalli, Marco Bolis, Luca Guarrera, Maria Chiara Barbera, Chiara Grasselli, Augusto Bleve, Daniele Generali, Manuela Milani, Michele Mari, Mario Salmona, Giovanni Piersanti, Giovanni Bottegoni, Massimo Broggini, Yvonne M W Janssen-Heininger, Jaehyung Cho, Orazio Cantoni, Ester Zito.

Cancer cells adapt to harsh environmental conditions by inducing the Unfolded Protein Response (UPR), of which ERO1A is a mediator. ERO1A aids protein folding by acting as a protein disulfide oxidase, and under cancer-related hypoxia conditions, it favors the folding of angiogenic VEGFA, leading tumor cells to thrive and spread. The upregulation of ERO1A in cancer cells, oppositely to the dispensability of ERO1A activity in healthy cells, renders ERO1A a perfect target for cancer therapy. Here, we report the upregulation of ERO1A in a cohort of aggressive triple-negative breast cancer (TNBC) patients in which ERO1A levels correlate with a higher risk of breast tumor recurrence and metastatic spread. For ERO1A target validation and therapy in TNBC, we designed new ERO1A inhibitors in a structure-activity campaign of the prototype EN460. Cell-based screenings showed that the presence of the Micheal acceptor in the compound is necessary to engage the cysteine 397 of ERO1A but not sufficient to set out the inhibitory effect on ERO1A. Indeed, the ERO1 inhibitor must adopt a non-coplanar rearrangement within the ERO1A binding site. I2 and I3, two new EN460 analogs with different phenyl-substituted moieties, efficiently inhibited ERO1A, blunting VEGFA secretion. Accordingly, in vitro assays to measure ERO1A engagement and inhibition confirmed that I2 and I3 bind ERO1A and restrain its activity with a IC50 in a low micromolar range. EN460, I2 and I3 triggered breast cancer cytotoxicity while specifically inhibiting ERO1A in a dose-dependent manner. I2 more efficiently impaired cancer-relevant features such as VEGFA secretion and related cell migration. I2 also acted on the tumor microenvironment and viability of xenografts and syngeneic TNBC. Thus, small molecule-mediated ERO1A pharmacological inhibition is feasible and promises to lead to effective therapy for the still incurable TNBC.

DOI: https://doi.org/10.1038/s41419-025-07426-1
BMC Cancer. 2025 Feb 21. 25(1): 311

KAT7-acetylated YBX1 promotes hepatocellular carcinoma proliferation by reprogramming nucleotide metabolism.

He Huang, Longfei Ren, Yongqiang Zhou, Pengyu Chen, Haixia Zhao, Shang Li, Haiping Wang, Xun Li.

   BACKGROUND: Lysine acetylation is a critical post-translational modification regulating tumor initiation and progression. Lysine acetyltransferase 7 (KAT7)-mediated lysine acetylation is frequently dysregulated in cancer. However, the role of KAT7-mediated lysine acetylation in hepatocellular carcinoma (HCC) progression remains unclear.
METHODS: Bioinformatic analysis was used to investigate the expression, clinicopathological characteristics and diagnostic prognostic value of KAT7 in HCC. CCK-8 assays, colony-forming assays, apoptosis assays and nude mouse xenograft models were utilized to detect the oncogenic functions of KAT7 in HCC. Immunoprecipitation (IP) assay and mass spectrometry (MS) analysis were performed to identify the KAT7-binding protein Y-box binding protein 1 (YBX1). Transcriptome sequencing and functional enrichment analysis were employed to elucidate the downstream pathway regulated by KAT7 and YBX1. Chromatin immunoprecipitation (ChIP) assay was used to evaluate YBX1 binding to the promoter regions of ribonucleotide reductase regulatory subunit M2 (RRM2) and thymidine kinase 1 (TK1). Weighted gene co-expression network analysis and selection operator regression analysis were used to build risk prediction models.
RESULTS: This study demonstrated that elevated KAT7 expression is associated with poor prognosis in HCC patients. Knockdown of endogenous KAT7 in HCC cells attenuated tumorigenic phenotypes associated with cell proliferation, colony formation and orthotopic xenograft tumor growth, indicating a pro-tumorigenic role of KAT7 in HCC. YBX1 was identified as a novel non-histone substrate for KAT7, and the E508 residue of KAT7 is essential for binding. Following the functional enrichment analysis, KAT7 and YBX1 were correlated with nucleotide metabolism. Furthermore, KAT7 binds to YBX1 and modulates its post-translational expression, which enhances the transcriptional activity of the central nucleotide metabolism enzymes RRM2 and TK1. Additionally, we constructed a novel prognostic prediction model based on KAT7, YBX1, RRM2 and TK1, which validated the predictive accuracy and prognostic value of KAT7-mediated acetylation is consistent with clinical outcomes in HCC.
CONCLUSIONS: Our findings highlight that KAT7 acetylates YBX1 and promotes HCC progression by reprogramming nucleotide metabolism, offering therapeutic implications.

Keywords:  Acetylation; HCC; KAT7; Nucleotide metabolism; YBX1

DOI:  https://doi.org/10.1186/s12885-025-13708-w
Biotechnol Appl Biochem. 2025 Feb 17.

Etomidate Induces Mitochondrial Dysfunction in Glioma Cancer Cells by Inhibiting Mitochondrial Biogenesis Mediated by CREB/PGC-1α.

Hailiang Shi, Zhongcheng Cao, Kai Wei.

  Gliomas are one of the most prevalent types of solid tumors in the brain. Imbalances in mitochondrial metabolism have been implicated in the pathological progression of gliomas. Etomidate, an agonist of the γ-aminobutyric acid type A (GABAA) receptor, is widely used in clinical settings. In this study, we report a novel pharmacological function of etomidate in regulating mitochondrial metabolism in glioma cancer cells. U87 glioma tumor cells were treated with etomidate (0.5, 1.0, and 2.0 µg/mL) for 24 h. Quantitative real-time PCR, western blot analysis, mtDNA/nDNA ratio, MitoTracker Red staining, Complex I and IV activity, intracellular ATP levels, and mitochondrial respiration were assessed. First, etomidate exposure inhibited the expression of PGC-1α in U87 glioma tumor cells. Further investigation revealed that etomidate suppressed the expression of Nrf1 and TFAM, the two key executors of mitochondrial biogenesis. Etomidate treatment led to damage in mitochondrial biogenesis by decreasing the mtDNA/nDNA ratio, reducing the protein expression of cytochrome B, and lowering mitochondrial mass. These changes suggest impaired mitochondrial replication and function. Correspondingly, etomidate exposure induced a "loss of mitochondrial function" by diminishing the activities of Complex I and Complex IV, the mitochondrial respiratory rate (MRR), and ATP generation. These effects highlight the detrimental impact of etomidate on the energy metabolism of glioma cells. Mechanistically, etomidate inactivated the transcription factor CREB by reducing its phosphorylation at Ser133. Activation of CREB with the second messenger cAMP restored the expression of PGC-1α, the mtDNA/nDNA ratio, Complex IV activity, summarized mitochondrial respiratory rate (MRR), and ATP production. This suggests that CREB activation may serve as a potential therapeutic strategy to counteract etomidate's inhibitory effects on mitochondrial function in glioma cells. Our results suggest that damage to mitochondrial biogenesis is a key step in the anticancer properties of etomidate in gliomas, and the decrease in PGC-1α and its downstream molecules may be the critical mechanism behind this effect.

Keywords:  CREB; PGC‐1α; etomidate; gliomas; mitochondrial biogenesis

DOI:  https://doi.org/10.1002/bab.2722
Mol Metab. 2025 Feb 15. pii: S2212-8778(25)00020-1. [Epub ahead of print] 102113

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics.

Se Seul Im, Jihyeon Seo, Ji Eun You, Hye Won Bang, YongHwan Kim, Jiyeon Kweon, Yongsub Kim, Dong-Myung Shin, Jaekyoung Son.

   OBJECTIVES: Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.
METHODS: The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.
RESULTS: BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP+/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.
CONCLUSIONS: Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

Keywords:  BIX01294; Glutaminase; Glutathione; KDM6B; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102113
JHEP Rep. 2025 Mar;7(3): 101296

CPEB4 modulates liver cancer progression by translationally regulating hepcidin expression and sensitivity to ferroptosis.

M Eugenia Delgado, Salvador Naranjo-Suarez, Marta Ramírez-Pedraza, Beatriz I Cárdenas, Carmen Gallardo-Martínez, Alexandra Balvey, Eulalia Belloc, Judit Martín, Mark Boyle, Raúl Méndez, Mercedes Fernandez.

   Background & Aims: Liver cancer is a significant global health issue, with its incidence rising in parallel with the obesity epidemic. The limited therapeutic options available emphasize the need for a better understanding of the molecular pathways involved in its pathogenesis. While much of the previous research has focused on transcriptional changes, this study examines translational alterations, specifically the role of cytoplasmic polyadenylation element binding protein 4 (CPEB4), a key regulator of translation.
Methods: We analyzed publicly available patient databases and conducted studies using human and mouse liver cancer cells, xenograft and allograft models, mouse models of high-fat diet-related liver cancer, and CPEB4 knockout and knockdown mice and cell lines.
Results: Patient data analysis (n = 87) showed a strong correlation between low CPEB4 levels and reduced survival rates (p <0.001). In mouse models of diet-induced liver cancer (n = 10-15 per group), both systemic and hepatocyte-specific CPEB4 knockout mice exhibited significantly increased tumor burden compared with wild-type controls (p <0.05). In vitro studies using human and murine liver cancer cells (n = 3 biological replicates) demonstrated reduced sensitivity to ferroptosis upon CPEB4 depletion when induced by erastin or RSL3 (p <0.01). Mechanistically, CPEB4 deficiency suppressed hepcidin expression, leading to elevated ferroportin levels, decreased intracellular iron accumulation, and reduced lipid peroxidation (p <0.05).
Conclusions: This study uncovers a novel CPEB4-dependent mechanism linking translational control to liver cancer progression and ferroptosis regulation. Therapeutic strategies targeting CPEB4-mediated pathways hold promise for advancing treatment options in liver cancer.
Impact and implications: This study addresses the pressing need for improved therapies in liver cancer, particularly given its increasing prevalence linked to obesity and metabolic-associated fatty liver disease. By uncovering the role of the RNA-binding protein cytoplasmic polyadenylation element binding protein 4 (CPEB4) in modulating iron regulation and cancer cell sensitivity to ferroptosis, our research highlights a new translational mechanism with potential therapeutic relevance. These findings are particularly significant for clinicians, researchers, and policymakers focused on advancing targeted treatments for hepatocellular carcinoma. If further validated in human clinical studies, targeting CPEB4-mediated pathways could help develop treatments that enhance cancer cell susceptibility to ferroptosis, offering a promising strategy for improving outcomes in patients with advanced liver cancer. Limitations of the study include the need for further clinical validation to confirm these preclinical findings in human disease contexts.

Keywords:  Cytoplasmic polyadenylation element binding protein; Ferroptotic cell death; Hepatocellular carcinoma; Translation

DOI:  https://doi.org/10.1016/j.jhepr.2024.101296