bims-meract 2025-01-26 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–01–26
twenty-six papers selected by
Andrea Morandi, Università degli Studi di Firenze

Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells.
SCARB1 links cholesterol metabolism-mediated ferroptosis inhibition to radioresistance in tumor cells.
Targeting estrogen-regulated system xc- promotes ferroptosis and endocrine sensitivity of ER+ breast cancer.
Hyper-energy metabolism of Oxidative phosphorylation and enhanced glycolysis contributes to radioresistance in glioma cells.
Targeting FABP4/UCP2 axis to overcome cetuximab resistance in obesity-driven CRC with drug-tolerant persister cells.
Fuel for thought: targeting metabolism in lung cancer.
V-ATPase in glioma stem cells: a novel metabolic vulnerability.
ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer.
Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction.
CD36 enrichment in HER2-positive mesenchymal stem cells drives therapy refractoriness in breast cancer.
Prostate cancer-selective anticancer action of an oxindole derivative via HO-1-mediated disruption of metabolic reprogramming.
Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.
LCAT Deficiency Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance by Promoting Triglyceride Catabolism and Fatty Acid Oxidation.
Dysfunctional mitochondrial bioenergetics sustains drug resistance in cancer cells.
ADAR1 Promotes the Progression and Temozolomide Resistance of Glioma Through p62-Mediated Selective Autophagy.
Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis.
Fatty Acid Synthase (FASN) Inhibitors Suppress Metformin-Induced Fat Accumulation and Apoptosis in H4IIE Hepatocellular Carcinoma Cells.
Lipid Metabolism Related Gene ACSL3 as a Biomarker for Predicting Immunotherapy Outcomes in Lung Adenocarcinoma.
Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation.
Metabolic interplays between the tumour and the host shape the tumour macroenvironment.
CD44-Mediated Metabolic Rewiring is A Targetable Dependency of IDH-Mutant Leukemia.
Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A.
Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer.
CAMKIIδ Reinforces Lipid Metabolism and Promotes the Development of B Cell Lymphoma.
Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells.
Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.

Cell Death Dis. 2025 Jan 18. 16(1): 28

Inhibition of KLF5 promotes ferroptosis via the ZEB1/HMOX1 axis to enhance sensitivity to oxaliplatin in cancer cells.

Zheng Zhang, Huaxiang Xu, Junyi He, Qiangsheng Hu, Yuxin Liu, Zijin Xu, Wenhui Lou, Wenchuan Wu, Lei Zhang, Ning Pu, Chenye Shi, Yaolin Xu, Wenquan Wang, Liang Liu.

As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domain-containing 7 (FBW7) inhibited the migration and proliferation of pancreatic cancer cells through its substrate c-Myc. We further found that another key substrate of FBW7, KLF5, could inhibit ferroptosis. Inhibiting KLF5 significantly enhances the cytotoxicity of oxaliplatin rather than other chemotherapy drugs. Mechanistically, we found that KLF5 inhibited the expression of heme oxygenase 1 (HMOX1) via repressing zinc finger E-box-binding homeobox 1 (ZEB1). Inhibition of KLF5 facilitated the cytotoxic effect of oxaliplatin via promoting ferroptosis. Oxaliplatin combined with KLF5 inhibitor significantly potentiated cell death in vitro and inhibited tumor growth in vivo compared with either treatment alone. These results reveal a critical role of KLF5 in sensitized chemotherapy of pancreatic cancer, and suggest that ferroptosis combined with platinum-based chemotherapy rather than gemcitabine-based chemotherapy is expected to bring better therapeutic effects.

DOI: https://doi.org/10.1038/s41419-025-07330-8
J Adv Res. 2025 Jan 18. pii: S2090-1232(25)00045-1. [Epub ahead of print]

SCARB1 links cholesterol metabolism-mediated ferroptosis inhibition to radioresistance in tumor cells.

Xiaojuan Mao, Jingwen Xiong, Mengjiao Cai, Chao Wang, Qian He, Binxian Wang, Jing Chen, Zhengtao Xiao, Baofeng Wang, Suxia Han, Yilei Zhang.

   INTRODUCTION: Ferroptosis is an iron-dependent form of cell death triggered by the excessive accumulation of lipid peroxides. Understanding the regulatory mechanisms of ferroptosis and developing strategies to target this process hold significant clinical applications in tumor therapy.
OBJECTIVE: Our study aims to search for novel candidate genes involved in the regulation of ferroptosis and to investigate their mechanism of action in ferroptosis and tumor therapy.
METHODS: We employed a CRISPR-Cas9 library to perform a genome-wide screen under ferroptosis inducer treatment conditions, revealing Scavenger Receptor Class B Member 1(SCARB1) as a novel candidate gene involved in ferroptosis regulation. Subsequently, lipidomic analyses, metabolic interventions, and relevant cellular experimental analyses were performed to elucidate the role of SCARB1 in ferroptosis, lipid peroxidation, and tumor therapy.
RESULTS: Our study confirmed that SCARB1 significantly inhibits ferroptosis and lipid peroxidation induced by ferroptosis inducers. Mechanistically, SCARB1 inhibits ferroptosis through the regulation of cholesterol metabolism, and the upregulation of CoQ10 level is demonstrated to mediate the suppression of ferroptosis by SCARB1 after lipidomic analysis and metabolic intervention. Interestingly, SCARB1 exerts a tumor suppressive effect regarding tumor growth, migration and invasion, which is possibly independent of ferroptosis regulation. However, SCARB1 promotes radioresistance through the upregulation of cholesterol metabolism and inhibition of ferroptosis, while the combination of ferroptosis inducers can overcome radioresistance in tumor cells with high SCARB1 expression.
CONCLUSION: This study establishes a theoretical foundation for the regulation of ferroptosis by SCARB1 and highlights the potential of targeting lipid metabolism to overcome radioresistance in cancer therapy. The identification of SCARB1 as a key player in ferroptosis and its dual role in tumor suppression and radioresistance provides new avenues for therapeutic intervention in cancer treatment.

Keywords:  Ferroptosis; Lipid metabolism; Radioresistance; SCARB1; Tumor therapy

DOI:  https://doi.org/10.1016/j.jare.2025.01.026
Cell Death Dis. 2025 Jan 20. 16(1): 30

Targeting estrogen-regulated system xc- promotes ferroptosis and endocrine sensitivity of ER+ breast cancer.

Jiawei Cao, Tong Zhou, Tao Wu, Rixu Lin, Ju Huang, Dejin Shi, Jiawei Yu, Yinrui Ren, Changrui Qian, Licai He, Guang Wu, Zhixiong Dong, Shaofei Yuan, Haihua Gu.

Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of cases. Endocrine therapies targeting estrogen are the first line therapies for ER+ breast cancer. However, resistance to these therapies occurs in about half of patients, leading to decreased survival rates. Inducing ferroptosis is a promising therapeutic strategy for cancer treatment for refractory and malignant cancers including triple-negative breast cancer. Nevertheless, ER+ breast cancer is relatively resistant to ferroptosis inducers. Here, we uncovered that ERα suppressed ferroptosis in ER+ breast cancer. Silencing ERα triggered ferroptosis, which was attenuated by ferroptosis inhibitor Ferrostatin-1, and was enhanced by ferroptosis inducer Erastin. Mechanistically, ERα transcriptionally upregulated the expression of SLC7A11 and SLC3A2, two subunits of the system xc-, which is one key inhibitory regulator of ferroptosis. Overexpression of the exogenous SLC7A11 and SLC3A2 was able to mitigate ferroptosis induced by ERα inhibition. Moreover, SLC7A11 and SLC3A2 levels were elevated in endocrine-resistant breast cancer cells and tumors. Importantly, the system xc- inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance.

DOI: https://doi.org/10.1038/s41419-025-07354-0
Free Radic Res. 2025 Jan 20. 1-14

Hyper-energy metabolism of Oxidative phosphorylation and enhanced glycolysis contributes to radioresistance in glioma cells.

Yogesh Rai, Ankit Kumar Tiwari, Rakesh Pandey, B S Dwarakanath, Anant Narayan Bhatt.

  PurposeThe concept of dual-state hyper-energy metabolism characterized by elevated glycolysis and OxPhos has gained considerable attention during tumor growth and metastasis in different malignancies. However, it is largely unknown how such metabolic phenotypes influence the radiation response in aggressive cancers. Therefore, the present study aimed to investigate the impact of hyper-energy metabolism (increased glycolysis and OxPhos) on the radiation response of a human glioma cell line.MethodsModulation of the mitochondrial electron transport chain was carried out using a 2,4-dinitrophenol (DNP). Metabolic characterization was carried out by assessing glucose uptake, lactate production, mitochondrial mass, membrane potential, and ATP production. The radiation response was examined by cell growth, clonogenic survival, and cell death assays. Macromolecular oxidation was assessed by DNA damage, lipid peroxidation, and protein carbonylation assay.ResultsHypermetabolic OPM-BMG cells exhibited a significant increase in glycolysis and OxPhos following irradiation as compared to the parental BMG-1 cells. Enhanced radioresistance of OPM-BMG cells was evidenced by the increase in α/β ratio (9.58) and D1 dose (4.18 Gy) as compared to 4.36 and 2.19 Gy in BMG-1 cells respectively. Moreover, OPM-BMG cells were found to exhibit increased resistance against radiation-induced cell death, and macromolecular oxidation as compared to BMG-1 cells. Inhibition of glycolysis and mitochondrial complex-II significantly enhanced the radiosensitivity of OPM-BMG cells compared to BMG-1 cells.ConclusionOur results demonstrate that the hyper-energy metabolism of increased glycolysis and OxPhos confer radioresistance. Consequently targeting glycolysis and OxPhos in combination with radiation may overcome therapeutic resistance in aggressive cancers like glioma.

Keywords:  2-DG; Cancer bioenergetics; Glioma; Hyper-energy metabolism; Malonate; OXPHOS; Radioresistance Glycolysis

DOI:  https://doi.org/10.1080/10715762.2025.2456740
Transl Oncol. 2025 Jan 16. pii: S1936-5233(25)00005-1. [Epub ahead of print]53 102274

Targeting FABP4/UCP2 axis to overcome cetuximab resistance in obesity-driven CRC with drug-tolerant persister cells.

Yi-Chiao Cheng, Ming-Yao Chen, Vijesh Kumar Yadav, Narpati Wesa Pikatan, Iat-Hang Fong, Kuang-Tai Kuo, Chi-Tai Yeh, Jo-Ting Tsai.

  Colorectal cancer (CRC) is closely linked to obesity, a condition that significantly impacts tumor progression and therapeutic resistance. Although cetuximab, an EGFR-targeting monoclonal antibody, is a cornerstone in metastatic CRC treatment, resistance often emerges, leading to poor outcomes. This study investigated the role of drug-tolerant persister (DTP) cells and their metabolic interactions within the tumor microenvironment (TME) in cetuximab resistance. Using patient-derived organoids and in vivo models, we identified the FABP4/UCP2 axis as a critical mediator of resistance. Organoids derived from cetuximab non-responders revealed upregulated FABP4 and UCP2 expression post-treatment. Coculture experiments with adipocytes showed that FABP4 and UCP2 promote lipid metabolic reprogramming, facilitating cancer cell survival in a dormant state. CRISPR/Cas9 mediated inhibition of FABP4 disrupted this metabolic interaction, sensitising resistant cells to cetuximab. In vivo, the FABP4 inhibitor BMS309403, either alone or in combination with cetuximab, significantly reduced tumor growth in resistant CRC models, highlighting its therapeutic potential. These findings establish the FABP4/UCP2 axis as a pivotal driver of cetuximab resistance in obesity-associated CRC and suggest that targeting this metabolic pathway could improve outcomes in DTP-resistant CRC patients.

Keywords:  Adipocytes; Cetuximab resistance; Colorectal cancer; Drug-tolerant persister cells; FABP4/UCP2 Axis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2025.102274
Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3692-3717

Fuel for thought: targeting metabolism in lung cancer.

Jaime L Schneider, SeongJun Han, Christopher S Nabel.

  For over a century, we have appreciated that the biochemical processes through which micro- and macronutrients are anabolized and catabolized-collectively referred to as "cellular metabolism"-are reprogrammed in malignancies. Cancer cells in lung tumors rewire pathways of nutrient acquisition and metabolism to meet the bioenergetic demands for unchecked proliferation. Advances in precision medicine have ushered in routine genotyping of patient lung tumors, enabling a deeper understanding of the contribution of altered metabolism to tumor biology and patient outcomes. This paradigm shift in thoracic oncology has spawned a new enthusiasm for dissecting oncogenotype-specific metabolic phenotypes and creates opportunity for selective targeting of essential tumor metabolic pathways. In this review, we discuss metabolic states across histologic and molecular subtypes of lung cancers and the additional changes in tumor metabolic pathways that occur during acquired therapeutic resistance. We summarize the clinical investigation of metabolism-specific therapies, addressing successes and limitations to guide the evaluation of these novel strategies in the clinic. Beyond changes in tumor metabolism, we also highlight how non-cellular autonomous processes merit particular consideration when manipulating metabolic processes systemically, such as efforts to disentangle how lung tumor cells influence immunometabolism. As the future of metabolic therapeutics hinges on use of models that faithfully recapitulate metabolic rewiring in lung cancer, we also discuss best practices for harmonizing workflows to capture patient specimens for translational metabolic analyses.

Keywords:  Lung cancer; immunometabolism; metabolism; resistance

DOI:  https://doi.org/10.21037/tlcr-24-662
J Exp Clin Cancer Res. 2025 Jan 17. 44(1): 17

V-ATPase in glioma stem cells: a novel metabolic vulnerability.

Alessandra Maria Storaci, Irene Bertolini, Cristina Martelli, Giorgia De Turris, Nadia Mansour, Mariacristina Crosti, Maria Rosaria De Filippo, Luisa Ottobrini, Luca Valenti, Elisa Polledri, Silvia Fustinoni, Manuela Caroli, Claudia Fanizzi, Silvano Bosari, Stefano Ferrero, Giorgia Zadra, Valentina Vaira.

   BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth.
METHODS: V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels.
RESULTS: Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes.
CONCLUSIONS: V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.

Keywords:  Bafilomycin A1; Glioma; Glioma stem cell; Metabolism; V-ATPase

DOI:  https://doi.org/10.1186/s13046-025-03280-3
Sci Rep. 2025 Jan 23. 15(1): 2992

ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer.

Bo Shi, Junjie Chen, Haoran Guo, Xinyu Shi, Qingliang Tai, Guoliang Chen, Huihui Yao, Xiuwei Mi, Runze Zhong, Yang Lu, Yiyuan Zhao, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He.

  Acyl-CoA oxidase 1 (ACOX1), a member of the acyl-coenzyme A oxidase family, is considered a crucial regulator whose dysregulation is implicated in the occurrence and progression of various cancers. This study aims to elucidate the impact of ACOX1 in CRC, shedding light on its potential as a therapeutic target. Through analysis of the GEO dataset, it was found that ACOX1 is significantly downregulated in colorectal cancer (CRC), and this lower expression level is associated with a worse prognosis. Additionally, in vitro as well as in vivo, ACOX1 overexpression dramatically reduced the proliferation and metastasis of CRC cells. Mass spectrometry revealed the crucial role of ACOX1 in fatty acid β-oxidation, as its overexpression led to a substantial increase in reactive oxygen species (ROS) derived from fatty acid β-oxidation. Further experiments demonstrated that ACOX1 overexpression, through modulation of fatty acid metabolism, increased ROS levels, reduced the phosphorylation activation of the key autophagy regulator mTOR, enhanced autophagy, and ultimately suppressed the growth and metastasis of CRC. In conclusions, ACOX1 expression is decreased in CRC. ACOX1 may regulate autophagy by reprogramming lipid metabolism to modulate the ROS/mTOR signaling pathway, consequently inhibiting the proliferation and migration of CRC.

Keywords:  ACOX1; Autophagy; Colorectal Cancer; ROS; mTOR

DOI:  https://doi.org/10.1038/s41598-025-87728-8
Mol Oncol. 2025 Jan 23.

Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction.

Connor S Murphy, Heather Fairfield, Victoria E DeMambro, Samaa Fadel, Carlos A Gartner, Michelle Karam, Christian Potts, Princess Rodriguez, Ya-Wei Qiang, Habib Hamidi, Xiangnan Guan, Calvin P H Vary, Michaela R Reagan.

  Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.

Keywords:  ACSL; Triacsin C; cell metabolism; fatty acid; hematological malignancies; multiple myeloma

DOI:  https://doi.org/10.1002/1878-0261.13794
J Exp Clin Cancer Res. 2025 Jan 20. 44(1): 19

CD36 enrichment in HER2-positive mesenchymal stem cells drives therapy refractoriness in breast cancer.

Lorenzo Castagnoli, Alma Franceschini, Valeria Cancila, Matteo Dugo, Martina Bigliardi, Claudia Chiodoni, Paolo Toneguzzo, Viola Regondi, Paola A Corsetto, Filippo Pietrantonio, Serena Mazzucchelli, Fabio Corsi, Antonio Belfiore, Antonio Vingiani, Giancarlo Pruneri, Francesca Ligorio, Mario P Colombo, Elda Tagliabue, Claudio Tripodo, Claudio Vernieri, Tiziana Triulzi, Serenella M Pupa.

   BACKGROUND: Growing evidence shows that the reprogramming of fatty acid (FA) metabolism plays a key role in HER2-positive (HER2 +) breast cancer (BC) aggressiveness, therapy resistance and cancer stemness. In particular, HER2 + BC has been defined as a "lipogenic disease" due to the functional and bi-directional crosstalk occurring between HER2-mediated oncogenic signaling and FA biosynthesis via FA synthase activity. In this context, the functional role exerted by the reprogramming of CD36-mediated FA uptake in HER2 + BC poor prognosis and therapy resistance remains unclear. In this study, we aimed to elucidate whether enhanced CD36 in mesenchymal HER2 + cancer stem cells (CSCs) is directly involved in anti-HER2 treatment refractoriness in HER2 + BC and to design future metabolism-based approaches targeting both FA reprogramming and the "root" of cancer.
METHODS: Molecular, biological and functional characterization of CD36-mediated FA uptake was investigated in HER2 + BC patients, cell lines, epithelial and mesenchymal CSCs. Cell proliferation was analyzed by SRB assay upon treatment with lapatinib, CD36 inhibitor, or Wnt antagonist/agonist. Engineered cell models were generated via lentivirus infection and transient silencing. CSC-like properties and tumorigenesis of HER2 + BC cells with or without CD36 depletion were examined by mammosphere forming efficiency assay, flow cytometry, cell sorting, ALDH activity assay and xenograft mouse model. FA uptake was examined by flow cytometry with FA BODIPY FL C16. Intratumor expression of CSC subsets was evaluated via multiplex immunostaining and immunolocalization analysis.
RESULTS: Molecular data demonstrated that CD36 is significantly upmodulated on treatment in therapy resistant HER2 + BC patients and its expression levels in BC cells is correlated with FA uptake. We provided evidence of a consistent enrichment of CD36 in HER2 + epithelial-mesenchymal transition (EMT)-like CSCs from all tested resistant cell models that mechanistically occurs via Wnt signaling pathway activation. Consistently, both in vitro and in vivo dual blockade of CD36 and HER2 increased the anti-CSC efficacy of anti-HER2 drugs favoring the transition of the therapy resistant mesenchymal CSCs into therapy-sensitive mesenchymal-epithelial transition (MET)-like epithelial state. In addition, expression of CD36 in intratumor HER2 + mesenchymal CSCs is significantly associated with resistance to trastuzumab in HER2 + BC patients.
CONCLUSIONS: These results support the metabolo-oncogenic nature of CD36-mediated FA uptake in HER2 + therapy-refractory BC. Our study provides evidence that targeting CD36 might be an effective metabolic therapeutic strategy in the treatment of this malignancy.

Keywords:  CD36; Cancer Stem Cells; Fatty Acid Uptake; HER2; Resistance to anti-HER2 therapy; Wnt pathway

DOI:  https://doi.org/10.1186/s13046-025-03276-z
Chem Biol Interact. 2025 Jan 20. pii: S0009-2797(25)00023-7. [Epub ahead of print] 111393

Prostate cancer-selective anticancer action of an oxindole derivative via HO-1-mediated disruption of metabolic reprogramming.

Kalpana Ghimire, Bhuwan Prasad Awasthi, Kiran Yadav, Jiwoo Lee, Hyunjin Kim, Byeong-Seon Jeong, Jung-Ae Kim.

  Prostate cancer, the second leading cause of cancer-related mortality in men, exhibits distinct metabolic reprogramming involving zinc and citrate metabolism. This study investigated whether targeting this unique metabolic profile could offer an effective therapeutic approach. A series of novel oxindole derivatives were synthesized and evaluated for their inhibitory effects on transcription factors (TFs) and antiproliferative activity across various cancer cell lines. Among these, compound 3D showed the strongest inhibition of master TFs (HIF-1α, c-Myc, and SP-1) and demonstrated selective antiproliferative activity in prostate cancer cells. In PC-3 and LNCaP cells, compound 3D suppressed aerobic glycolysis by downregulating lactate-modulating genes (LDHA, MCT1/4, and CAIX) and the zinc influx transporter (ZIP1), without affecting the zinc efflux transporter (ZnT4). Notably, 3D selectively increased heme oxygenase-1 (HO-1) levels in prostate cancer cells, as shown by the proteome profiler oncogene array assay and confirmed by Western blotting. This response was reversed by ZnCl2 treatment. The decreases in LDHA, mitochondrial mass (measured by FACS), and cell proliferation induced by compound 3D were blocked by HO-1-IN-1, an HO-1 inhibitor, and ZnCl2. Furthermore, 3D induced a more pronounced reduction in the oxygen consumption rate (OCR) than in the extracellular acidification rate (EACR), indicating a strong effect on oxidative metabolism. 3D exhibited dose-dependent antitumor efficacy in vivo comparable to that of docetaxel. These findings reveal that the oxindole derivative 3D substantially lowers intracellular zinc levels, yielding potent antitumor effects in prostate cancer through HO-1 upregulation, which impairs mitochondrial function more significantly than aerobic glycolysis.

Keywords:  Heme oxygenase-1; Metabolic reprogramming; Oxindole analogues; Prostate cancer; Zn(2+)-dependent ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.cbi.2025.111393
Mol Cancer Ther. 2025 Jan 21.

Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.

Shan Lu, Xiao Pan, Eva Volckova, Anjali Shinde, Schuyler R Fuller, Regina Egan, Jianli Ma, Jong Kung, Christopher J Ott, Aaron N Hata, Cyril H Benes, Jing X Kang, Henning Willers.

Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation (mut) driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRASmut-enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRASmut models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1, SCD1, displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRASmut cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids (MUFA) to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRASmut but not wild-type cells. The radiosensitizing effect was notably small, especially compared to several DNA repair inhibitors. As an alternative strategy to targeting MUFA metabolism, adding polyunsaturated FAs (PUFA) phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRASmut cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRASmut tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced inter-tumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0213
Cancer Lett. 2025 Jan 20. pii: S0304-3835(25)00033-3. [Epub ahead of print] 217469

LCAT Deficiency Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance by Promoting Triglyceride Catabolism and Fatty Acid Oxidation.

Min Xu, Peiyi Xie, Shaoqing Liu, Xukang Gao, Shiguang Yang, Zhiqiu Hu, Yue Zhao, Yong Yi, Qiongzhu Dong, Christiane Bruns, Xiaoni Kong, Mien-Chie Hung, Ning Ren, Chenhao Zhou.

  Lecithin cholesterol acyltransferase (LCAT), a crucial enzyme in lipid metabolism, plays important yet poorly understood roles in tumours, especially in hepatocellular carcinoma (HCC). In this study, our investigation revealed that LCAT is a key downregulated metabolic gene and an independent risk factor for poor prognosis in patients with HCC. Functional experiments showed that LCAT inhibited HCC cell proliferation, migration and invasion. Mechanistically, LCAT interacts with caveolin-1 (CAV1) to promote the binding of CAV1 to PRKACA and inhibit its phosphorylation, thereby inhibiting triglyceride (TAG) catabolism. On the other hand, LCAT inhibits fatty acid oxidation (FAO) by interacting with CPT1A to promote its ubiquitination and degradation. These events result in an inadequate supply of raw materials and energy and inhibit the malignant behaviours of HCC cells. In addition, LCAT is a reliable predictive biomarker for the efficacy of lenvatinib treatment in HCC patients, and the inhibition of FAO can increase lenvatinib sensitivity in patients with LCATlow HCC. This study revealed that LCAT plays a critical role in the regulation of lipid metabolic reprogramming and is a reliable predictive biomarker for the efficacy of lenvatinib treatment in HCC patients.

Keywords:  Fatty acid oxidation; Hepatocellular carcinoma; LCAT; Lenvatinib; Lipolysis

DOI:  https://doi.org/10.1016/j.canlet.2025.217469
Am J Physiol Cell Physiol. 2025 Jan 24.

Dysfunctional mitochondrial bioenergetics sustains drug resistance in cancer cells.

Davide Gnocchi, Dragana Nikolic, Silvia Russo, Maria Laura Matrella, Rosa R Paparella, Sujeet Kumar, Subhas S Karki, Carlo Sabbà, Tiziana Cocco, Simona Lobasso, Antonio Mazzocca.

  Resistance to drugs is one of the major issues affecting the response to pharmacological treatments for tumors. Different mechanisms have been proposed to explain the development of cancer drug resistance (CDR), and several approaches to overcome it have been suggested. However, the biological basis of CDR remains unclear. Here, we investigated whether mitochondrial damage and consequent mitochondrial dysfunction are major causes of drug resistance in different tumors. To this end, we used cell lines from three tumors: hepatocellular carcinoma, breast cancer, and colon cancer. We then applied a protocol that recapitulates chemotherapy regimens in patients, rendering each cell line resistant to the drug commonly used in their respective treatments. The combination of cellular respiration analysis, gene expression analysis of cytochrome c oxidase isoforms, and mass spectrometry assessment of cardiolipin reveals that mitochondrial dysfunction is the underlying cause of the resistant phenotype. Importantly, we disclosed for the first time the rapid inhibition of oxidative phosphorylation (OXPHOS) by L-lactate, the major product of fermentation. Finally, we demonstrated that inhibition of lactic acid fermentation and activation of OXPHOS can increase drug sensitivity in all tested drug-resistant cancer cells. Taken together, our results suggest that inhibiting fermentation and enhancing mitochondrial function in cancer cells may be a concrete option to control the worrisome phenomenon of CDR.

Keywords:  Cancer drug resistance; L-lactate; cardiolipin; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpcell.00538.2024
CNS Neurosci Ther. 2025 Jan;31(1): e70168

ADAR1 Promotes the Progression and Temozolomide Resistance of Glioma Through p62-Mediated Selective Autophagy.

Yuyan Zhang, Huiling Guo, Jiahao Bu, Weiwei Wang, Li Wang, Zhibo Liu, Yuning Qiu, Qimeng Wang, Lijuan Zhou, Xianzhi Liu, Liwei Ma, Jianwei Wei.

   BACKGROUND: Resistance to temozolomide (TMZ) remains is an important cause of treatment failure in patients with glioblastoma multiforme (GBM). ADAR1, as a member of the ADAR family, plays an important role in cancer progression and chemotherapy resistance. However, the mechanism by which ADAR1 regulates GBM progression and TMZ resistance is still unclear.
METHODS: We first constructed stable transfected strains in which ADAR1 was knocked down and overexpressed to investigate the effect of ADAR1 on the first-line glioma chemotherapy drug TMZ. Subsequently, we validated that ADAR1 induces autophagy activation and used autophagy inhibitors to suppress autophagy, demonstrating that ADAR1 enhances TMZ resistance through autophagy. We further knocked down p62 (SQSTM1) based on the overexpression of ADAR1, and the results showed that ADAR1 regulates selective autophagy through the p62 regulation. Finally, we demonstrated through mutations at both edited and nonedited sites that ADAR1 regulates selective autophagy in an edited dependent way.
RESULTS: Further analysis showed that in the presence of TMZ, elevated ADAR1 promoted TMZ induced autophagy activation. Further research revealed that ADAR1 enhances TMZ resistance through p62-mediated selective autophagy. Further, ADAR1 regulates selective autophagy in an edited dependent way. Our results indicate a relationship between ADAR1 levels and the response of glioma patients to TMZ treatment.
CONCLUSIONS: We found that the expression of ADAR1 is upregulated in GBM and is associated with tumor grade and TMZ resistance. Elevated expression of ADAR1 predicts poor prognosis in GBM patients and promotes tumor growth in vivo or in vitro.

Keywords:  ADAR1; TMZ resistance; autophagy; glioma; p62

DOI:  https://doi.org/10.1111/cns.70168
Nat Commun. 2025 Jan 20. 16(1): 867

Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis.

Bin Huang, Hui Wang, Shuo Liu, Meng Hao, Dan Luo, Yi Zhou, Ying Huang, Yong Nian, Lei Zhang, Bo Chu, Chengqian Yin.

S-palmitoylation is a reversible and widespread post-translational modification, but its role in the regulation of ferroptosis has been poorly understood. Here, we elucidate that GPX4, an essential regulator of ferroptosis, is reversibly palmitoylated on cysteine 66. The acyltransferase ZDHHC20 palmitoylates GPX4 and increases its protein stability. ZDHHC20 depletion or inhibition of protein palmitoylation by 2-BP sensitizes cancer cells to ferroptosis. Moreover, we identify APT2 as the depalmitoylase of GPX4. Genetic silencing or pharmacological inhibition of APT2 with ML349 increases GPX4 palmitoylation, thereby stabilizing the protein and conferring resistance to ferroptosis. Notably, disrupting GPX4 palmitoylation markedly potentiates ferroptosis in xenografted and orthotopically implanted tumor models, and inhibits tumor metastasis through blood vessels. In the chemically induced colorectal cancer model, knockout of APT2 significantly aggravates cancer progression. Furthermore, pharmacologically modulating GPX4 palmitoylation impacts liver ischemia-reperfusion injury. Overall, our findings uncover the intricate network regulating GPX4 palmitoylation, highlighting its pivotal role in modulating ferroptosis sensitivity.

DOI: https://doi.org/10.1038/s41467-025-56344-5
Dev Reprod. 2024 Dec;28(4): 163-174

Fatty Acid Synthase (FASN) Inhibitors Suppress Metformin-Induced Fat Accumulation and Apoptosis in H4IIE Hepatocellular Carcinoma Cells.

Deokbae Park, Hyejin Boo.

  We previously reported that metformin, a widely prescribed antidiabetic drug, induces the accumulation of triglyceride (TG) together with the apoptotic death of H4IIE via AMP-activated protein kinase (AMPK) in hepatocellular carcinoma (HCC) cells. However, the effect of cytoplasmic fat accumulation on the growth of HCCs remains controversial. Herein, we investigated the effect of fatty acid synthase (FASN) inhibitors on the basal- or metformin-induced changes including the content of cytoplasmic TG and the viability of HCC cells. Cerulenin and C75, inhibitors of FASN, did not significantly affect the basal TG content but dose-dependently suppressed the metformin-induced increase in the cytoplasmic TG content. Metformin-induced apoptosis of H4IIE cells was also significantly reduced by cerulenin and C75. Metformin enhanced the generation of reactive oxygen species which was suppressed by adding cerulenin or T75. Cerulenin also stimulated cell migration, which was suppressed by metformin. However, the degree of suppressive effect of metformin on TG synthesis, apoptosis, and cell migration was much more prominent by the inhibition of AMPK by compound C than cerulenin. In conclusion, our study found that excess fat accumulation is responsible for the apoptosis of H4IIE HCC cells and is informative for designing anti-tumor reagents, especially in HCC.

Keywords:  Apoptosis; Fatty acid synthase (FASN); Hepatocellular carcinoma (HCC); Metformin

DOI:  https://doi.org/10.12717/DR.2024.28.4.163
Cancer Res Treat. 2025 Jan 20.

Lipid Metabolism Related Gene ACSL3 as a Biomarker for Predicting Immunotherapy Outcomes in Lung Adenocarcinoma.

Taiping He, Jinhan Hu, Haoyue Guo, Meng Diao, Yuanyuan Wang, Yuhan Wu, Lei Cheng, Chao Zhao, Xuefei Li, Caicun Zhou.

   Purpose: Investigate the role of lipid metabolism in the tumor immune microenvironment (TIME) of lung adenocarcinoma (LUAD) and identify vital lipid metabolism-related genes (LMRGs) that contribute to immunotherapy outcomes.
Materials and Methods: 1130 LUAD patients were acquired utilizing public databases. Multiple algorithms were used to analyze the contribution of lipid metabolism in TIME. Importantly, cell lines, clinical samples (52 patients in surgery cohort and 36 in immunotherapy cohort), animal models, RNA-seq, experiments in protein and mRNA levels were conducted for identifying and validating key biomarker in LUAD immunotherapy.
Results: A prognostic signature comprising 33 LMRGs was developed and validated as an effective predictor of prognosis and TIME, with a C-index of 0.766 (95% CI: 0.729-0.804). Additionally, we identified Acyl-CoA Synthetase Long Chain Family Member 3 (ACSL3) as a potential biomarker for immunotherapy prognosis. The expression of ACSL3 was verified in 88 clinical tissues from LUAD patients, which indicated that elevated ACSL3 expression was correlated with worse progression-free survival (PFS) (p<0.001) and overall survival (OS) (p=0.008). Subsequent experiments revealed that knockdown of ACSL3 in vivo enhanced the efficacy of immunotherapy, potentially through increasing interferon α secretion, as indicated by Bulk RNA-seq and ELISA analysis, thereby promoting the infiltration of anti-tumor immune cells.
Conclusion: The study established a model that accurately predicts immunotherapy response, prognosis, and TIME dynamics in LUAD patients. Notably, the pivotal role of ACSL3 in driving tumor progression and immune evasion was uncovered, offering novel insights into the optimization of immunotherapy strategies for LUAD.

Keywords:  ACSL3; Immunotherapy; Lipid metabolism; Lung adenocarcinoma; Tumor microenvironment

DOI:  https://doi.org/10.4143/crt.2024.1119
Nat Metab. 2025 Jan 20.

Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation.

Marteinn T Snaebjornsson, Philipp Poeller, Daria Komkova, Florian Röhrig, Lisa Schlicker, Alina M Winkelkotte, Adriano B Chaves-Filho, Kamal M Al-Shami, Carolina Dehesa Caballero, Ioanna Koltsaki, Felix C E Vogel, Roberto Carlos Frias-Soler, Ramona Rudalska, Jessica D Schwarz, Elmar Wolf, Daniel Dauch, Ralf Steuer, Almut Schulze.

Increased glycolytic flux is a hallmark of cancer; however, an increasing body of evidence indicates that glycolytic ATP production may be dispensable in cancer, as metabolic plasticity allows cancer cells to readily adapt to disruption of glycolysis by increasing ATP production via oxidative phosphorylation. Using functional genomic screening, we show here that liver cancer cells show a unique sensitivity toward aldolase A (ALDOA) depletion. Targeting glycolysis by disrupting the catalytic activity of ALDOA led to severe energy stress and cell cycle arrest in murine and human hepatocellular carcinoma cell lines. With a combination of metabolic flux analysis, metabolomics, stable-isotope tracing and mathematical modelling, we demonstrate that inhibiting ALDOA induced a state of imbalanced glycolysis in which the investment phase outpaced the payoff phase. Targeting ALDOA effectively converted glycolysis from an energy producing into an energy-consuming process. Moreover, we found that depletion of ALDOA extended survival and reduced cancer cell proliferation in an animal model of hepatocellular carcinoma. Thus, our findings indicate that induction of imbalanced glycolysis by targeting ALDOA presents a unique opportunity to overcome the inherent metabolic plasticity of cancer cells.

DOI: https://doi.org/10.1038/s42255-024-01201-w
Nat Rev Cancer. 2025 Jan 20.

Metabolic interplays between the tumour and the host shape the tumour macroenvironment.

Patricia Altea-Manzano, Amanda Decker-Farrell, Tobias Janowitz, Ayelet Erez.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

DOI: https://doi.org/10.1038/s41568-024-00786-4
Blood. 2025 Jan 22. pii: blood.2024027207. [Epub ahead of print]

CD44-Mediated Metabolic Rewiring is A Targetable Dependency of IDH-Mutant Leukemia.

Junhua Lyu, Yuxuan Liu, Ningning Liu, Hieu Vu, Feng Cai, Hui Cao, Pranita Kaphle, Zheng Wu, Giovanni A Botten, Yuannyu Zhang, Jin Wang, Sarada Achyutuni, Xiaofei Gao, Ilaria Iacobucci, Charles G Mullighan, Stephen S Chung, Min Ni, Ralph J DeBerardinis, Jian Xu.

Recurrent IDH mutations catalyze NADPH-dependent production of oncometabolite R-2HG for tumorigenesis. IDH inhibition provides clinical response in a subset of acute myeloid leukemia (AML) cases; however, most patients develop resistance, highlighting the need for more effective IDH-targeting therapies. By comparing transcriptomic alterations in isogenic leukemia cells harboring CRISPR base-edited IDH mutations, we identify the activation of adhesion molecules including CD44, a transmembrane glycoprotein, as a shared feature of IDH-mutant leukemia, consistent with elevated CD44 expression in IDH-mutant AML patients. CD44 is indispensable for IDH-mutant leukemia cells through activating pentose phosphate pathway and inhibiting glycolysis by phosphorylating G6PD and PKM2, respectively. This metabolic rewiring ensures efficient NADPH generation for mutant IDH-catalyzed R-2HG production. Combining IDH inhibition with CD44 blockade enhances the elimination of IDH-mutant leukemia cells. Hence, we describe an oncogenic feedforward pathway involving CD44-mediated metabolic rewiring for oncometabolite production, representing a targetable dependency of IDH-mutant malignancies.

DOI: https://doi.org/10.1182/blood.2024027207
Mol Carcinog. 2025 Jan 21.

Glutamine, Serine and Glycine at Increasing Concentrations Regulate Cisplatin Sensitivity in Gastric Cancer by Posttranslational Modifications of KDM4A.

Junhao Fu, Yuqi Ni, Yuqing Hu, Wanfen Tang, Jianfei Fu, Yue Wang, Shian Yu, Wenxia Xu.

  Gastric cancer is a common digestive system tumor with a high resistance rate that reduces the sensitivity to chemotherapy. Nutrition therapy is an important adjuvant approach to favor the prognosis of gastric cancer. Dietary amino acids contribute greatly to gastric cancer progression by mediating tumor gene expressions, epigenetics, signal transduction, and metabolic remodeling. In the present study, 20 types of amino acids were screened and glutamine, glycine and serine were identified as the critical regulators of cisplatin (DDP) sensitivity in gastric cancer cells. Moreover, KDM4A acetylation drove the reduced chemotherapy sensitivity in gastric cancer cells by maintaining protein stability and activating DNA repair ability when the concentrations of glutamine (Gln), serine (Ser), and glycine (Gly) decreased. Conversely, Gln/Ser/Gly at increasing concentrations stimulated ubiquitination degradation of KDM4A, which in turn elevated the sensitivity of gastric cancer cells to chemotherapy. Our findings unveiled the role of amino acid nutrition in regulating chemotherapy sensitivity of gastric cancer and the underlying mechanism, thus providing a scientific basis for expanding the clinical significance of nutrition therapy for gastric cancer patients.

Keywords:  KDM4A; gastric cancer; glutamine; glycine; serine

DOI:  https://doi.org/10.1002/mc.23881
Adv Sci (Weinh). 2025 Jan 21. e2413280

Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer.

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

  Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to a lack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis. Moreover, SCRN2 impedes the proteasomal degradation of histone-lysine N-methyltransferase 2C (KMT2C) by recruiting Bcl2-associated athanogene 2 to block the interaction of KMT2C with E3 ubiquitin-protein ligase CHIP. Consistently, SCRN2 transcriptionally activates Bcl2-modifying factor by amplifying histone H3 monomethylation at lysine 4 at its enhancer, thereby inducing intrinsic apoptosis. Notably, KMT2C knockdown restores the impaired TNBC progression caused by SCRN2 overexpression both in vitro and in vivo. Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition. Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.

Keywords:  DNA damage response; PARP inhibition; lysine methyltransferase; triple‐negative breast cancer; tumor suppressor

DOI:  https://doi.org/10.1002/advs.202413280
Adv Sci (Weinh). 2025 Jan 22. e2409513

CAMKIIδ Reinforces Lipid Metabolism and Promotes the Development of B Cell Lymphoma.

Jiawei Zhang, Senlin Xu, Hui Fang, Dehao Wu, Ching Ouyang, Yunfei Shi, Zhenkang Hu, Mingfeng Zhang, Yaoyao Zhong, Junwei Zhao, Yichao Gan, Shize Zhang, Xiaoqian Liu, Jie Yin, Yuan Li, Mengyue Tang, Yingda Wang, Ling Li, Wing C Chan, David Horne, Mingye Feng, Wendong Huang, Ying Gu.

  The most prevalent types of lymphomas are B cell lymphomas (BCL). Newer therapies for BCL have improved the prognosis for many patients. However, approximately 30% with aggressive BCL either remain refractory or ultimately relapse. These patients urgently need other options. This study shows how calcium/calmodulin-dependent protein kinase II delta (CAMKIIδ) is pivotal for BCL development. In BCL cells, ablation of CAMKIIδ inhibits both lipolysis from lipid droplets and oxidative phosphorylation (OXPHOS). With lipolysis blocked, BCL progression is markedly suppressed in two distinct BCL mouse models: MYC-driven EµMyc mice and Myc/Bcl2 double-expressed mice. When CAMKIIδ is present, it destabilizes transcription factor Forkhead Box O3A (FOXO3A) by phosphorylating it at Ser7 and Ser12. This then permits transcription of downstream gene IRF4 - a master transcription factor of lipid metabolism. The CAMKIIδ/FOXO3A axis bolsters lipid metabolism, mitochondrial respiration, and tumor fitness in BCL under metabolic stress. This study also evaluates Tetrandrine (TET), a small molecule compound, as a potent CAMKIIδ inhibitor. TET attenuates metabolic fitness and elicits therapeutic responses both in vitro and in vivo. Collectively, this study highlights how CAMKIIδ is critical in BCL progression. The results also pave the way for innovative therapeutic strategies for treating aggressive BCL.

Keywords:  B cell lymphoma; CAMKIIδ; FOXO3A; lipid metabolism

DOI:  https://doi.org/10.1002/advs.202409513
Sci Rep. 2025 Jan 18. 15(1): 2422

Second-generation BRAF inhibitor Encorafenib resistance is regulated by NCOA4-mediated iron trafficking in the drug-resistant malignant melanoma cells.

Ceyda Colakoglu Bergel, Isil Ezgi Eryilmaz, Gulsah Cecener, Unal Egeli.

  The current study established the first in vitro Encorafenib resistance protocol in BRAF-mutated malignant melanoma (MM) cells and investigated the resistance-related mechanisms. After establishing Encorafenib-resistant A375-MM cells, resistant-related mechanisms were investigated using WST-1, Annexin V, cell cycle, morphological analysis, live-cell, Western blot, RNA-Seq, transmission electron microscopy-(TEM), oxidative stress and iron colorimetric assay. The most resistant group, called A375-R, was determined in the cells treated with a constant dose of 10 nM over 3 months. The viability, apoptosis, and G0/G1 arrest reflected the acquired chemoresistance. Autophagic Beclin and LC3 proteins, and AKT signaling increased in the A375-R. RNA-Seq results also exhibited altered epigenetic regulation of resistance; particularly ferritin family members, ion transport pathways. Then, increased NCOA4, FTH1, and iron levels detected in A375-R suggest that the iron metabolism-related mechanism, such as ferritinophagy, might be triggered, which was supported by TEM and oxidative stress analysis. Iron storage, transport, and ferritinophagy have the promising potential to be targeted for combining with BRAF-targeted therapy to reverse Encorafenib resistance in MM. Moreover, this is the first study evaluating in vitro Encorafenib resistance mechanisms, and we suggest that our findings contribute to improving new drug combinations targeting BRAF and iron metabolism in different MM cells.

Keywords:  BRAF; Drug resistance; Encorafenib; Ferritinophagy; Iron metabolism; Malignant melanoma

DOI:  https://doi.org/10.1038/s41598-025-86874-3
Nat Cancer. 2025 Jan 17.

Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

DOI: https://doi.org/10.1038/s43018-024-00895-x