bims-meract 2025-01-19 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–01–19
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

MTHFD2 Enhances cMYC O-GlcNAcylation to Promote Sunitinib Resistance in Renal Cell Carcinoma.
Co-targeting of metabolism using dietary and pharmacologic approaches reduces breast cancer metastatic burden.
RSL3 induces ferroptosis by activating the NF-κB signalling pathway to enhance the chemosensitivity of triple-negative breast cancer cells to paclitaxel.
Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.
Differential Mitochondrial Redox Responses to the Inhibition of NAD+ Salvage Pathway of Triple Negative Breast Cancer Cells.
Leptin increases chemosensitivity by inhibiting CPT1B in colorectal cancer cells.
PIN1 prolyl isomerase promotes initiation and progression of bladder cancer through the SREBP2-mediated cholesterol biosynthesis pathway.
Mitochondrial chaperonin DNAJC15 promotes vulnerability to ferroptosis of chemoresistant ovarian cancer cells.
DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma.
Glucosylceramide Synthase Inhibition in Combination with Aripiprazole Sensitizes Hepatocellular Cancer Cells to Sorafenib and Doxorubicin.
Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
Effective Targeting of Glutamine Synthetase with Amino Acid Analogs as a Novel Therapeutic Approach in Breast Cancer.
ZNFX1 functions as a master regulator of epigenetically induced pathogen mimicry and inflammasome signaling in cancer.
Targeting lipid metabolism: novel insights and therapeutic advances in pancreatic cancer treatment.
Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting.
SRC enhanced cisplatin resistance in bladder cancer by reprogramming glycolysis and pentose phosphate pathway.
AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer.
DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer.
Blockade of neutral sphingomyelinase 2 exerts antitumor effect on metastatic castration resistant prostate cancer cells and promotes tumor regression when combined with Enzalutamide.
Exploring the role of ELOVLs family in lung adenocarcinoma based on bioinformatic analysis and experimental validation.
Elucidating stearoyl metabolism and NCOA4-mediated ferroptosis in gastric cancer liver metastasis through multi-omics single-cell integrative mendelian analysis: advancing personalized immunotherapy strategies.
Targeting Asparagine Metabolism in Solid Tumors.
Elucidating the role of pyrimidine metabolism in prostate cancer and its therapeutic implications.
Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
A review of the pathogenesis of mitochondria in breast cancer and progress of targeting mitochondria for breast cancer treatment.

Cancer Res. 2025 Jan 13.

MTHFD2 Enhances cMYC O-GlcNAcylation to Promote Sunitinib Resistance in Renal Cell Carcinoma.

Jinwen Liu, Gaowei Huang, Hao Lin, Rui Yang, Wenhao Zhan, Cheng Luo, Yukun Wu, Lingwu Chen, Xiaopeng Mao, Junxing Chen, Bin Huang.

Sunitinib is a first-line targeted therapy for patients with renal cell carcinoma (RCC), but resistance represents a significant obstacle to the treatment of advanced and metastatic RCC. Metabolic reprogramming is a characteristic of RCC, and changes in metabolic processes might contribute to resistance to sunitinib. Here, we identified MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, as a critical mediator of sunitinib resistance in RCC. MTHFD2 was elevated in sunitinib resistant RCC cells, and loss of MTHDF2 conferred sensitivity to sunitinib. In patients, MTHFD2 was highly expressed in RCC and was associated with poor outcomes. Mechanistically, MTHFD2 stimulated UDP-GlcNAc biosynthesis and promoted cMYC O-GlcNAcylation by driving the folate cycle. O-GlcNAcylation enhanced cMYC stability and promoted MTHFD2 and CCND1 transcription. Targeting MTHFD2 or cyclin D1 sensitized tumor cells to sunitinib in vitro and in vivo. Consistently, development of a peptide drug capable of efficiently degrading MTHFD2 enabled reversal of sunitinib resistance in RCC. These findings identify a noncanonical metabolic function of MTHFD2 in cell signaling and response to therapy and reveal the interplay between one-carbon metabolism and sunitinib resistance in RCC. Targeting MTHFD2 could be an effective approach to overcome sunitinib resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0050
NPJ Breast Cancer. 2025 Jan 14. 11(1): 3

Co-targeting of metabolism using dietary and pharmacologic approaches reduces breast cancer metastatic burden.

Qianying Zuo, Jin Young Yoo, Erik R Nelson, Matthew J Sikora, Rebecca B Riggins, Zeynep Madak-Erdogan.

Patients with metastatic breast cancer face reduced quality of life and increased mortality rates, necessitating more effective anti-cancer strategies. Building on previous research that identified metastatic-niche-specific metabolic vulnerabilities, we investigated how a ketogenic diet enhances estrogen receptor (ER)-positive liver metastatic breast cancer's response to Fulvestrant (Fulv) treatment. Using in vitro cell lines and in vivo xenograft metastasis mouse models, we examined the molecular mechanisms of combining ER targeting with a ketogenic diet. We found that Fulv treatment downregulates the ketogenesis pathway enzyme OXCT1, leading to β-hydroxybutyrate accumulation and decreased tumor cell viability. We also explored interactions between glucose, palmitic acid, and β-hydroxybutyric acid. These findings establish the molecular basis and clinical potential of a ketogenic diet to enhance Fulv efficacy in patients with ER+ liver metastatic breast cancer, potentially improving survival outcomes and quality of life in this population.

DOI: https://doi.org/10.1038/s41523-024-00715-6
Sci Rep. 2025 Jan 11. 15(1): 1654

RSL3 induces ferroptosis by activating the NF-κB signalling pathway to enhance the chemosensitivity of triple-negative breast cancer cells to paclitaxel.

Jialin Yuan, Cong Liu, Chengwei Jiang, Ning Liu, Zhaoying Yang, Hua Xing.

  Chemotherapy resistance in triple-negative breast cancer (TNBC) leads to poor therapeutic effects and a poor prognosis. Given that paclitaxel-based chemotherapy is the main treatment method for TNBC, enhancing its chemosensitivity has been a research focus. Induced ferroptosis of tumour cells has been proven to increase chemosensitivity, but its ability to sensitize TNBC cells to paclitaxel (PTX) is unknown. In our experiments, measurements of viability and proliferation validated the synergistic effect of PTX combined with RSL3 on TNBC cells. The accumulation of intracellular Fe2+ and lipid reactive oxygen species, as well as the expression of malondialdehyde, illustrated that RSL3 enhanced the chemosensitivity of TNBC to PTX by inducing ferroptosis. Through transcriptome sequencing, a series of differentially expressed genes were identified, in which the expression of cytokines, such as CXCLs, was significantly increased in the treatment group, and the effect of combination therapy on TNBC was enriched mainly in the NFκB signalling pathway. In subsequent validation experiments, the use of the NF-κB inhibitor BAY11-7082 reversed the inhibitory effects of PTX and RSL3 on TNBC cell activity. In a xenograft immunodeficient mouse model, the inhibitory effects of PTX and RSL3 on TNBC in vivo were further verified. Our research validated the synergistic effects of PTX and RSL3 both in vivo and in vitro, with RSL3 inducing ferroptosis by activating the NF-κB signalling pathway, thereby increasing the chemosensitivity of TNBC to PTX. This study provides new insights for improving the therapeutic efficacy of treatment strategies.

Keywords:  Chemosensitivity; Ferroptosis; Triple-negative breast cancer

DOI:  https://doi.org/10.1038/s41598-025-85774-w
Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01534-1. [Epub ahead of print]44(1): 115183

Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.

Gopalakrishnan Ramakrishnan, Alexander R Terry, Veronique Nogueira, Ahmed Magdy, Nissim Hay.

  AMPK's role in tumor initiation and progression is controversial. Here, we provide genetic evidence that AMPK is required for metastasis in mouse models of breast cancer. In a mouse model of spontaneous breast cancer metastasis, the deletion of AMPK before and after tumor onset decreased breast cancer metastasis, and similar results were obtained after AMPK deletion in breast cancer cell lines. The deletion of AMPK induces reactive oxygen species (ROS) levels in vitro and lipid oxidation in vivo, which likely impede metastasis. Indeed, antioxidants restore the ability of AMPK-deficient tumors to metastasize. By inhibiting acetyl-coenzyme A (CoA) carboxylases 1 and 2, AMPK maintains NADPH levels by reducing NADPH consumption in fatty acid synthesis and increasing NADPH generation via fatty acid oxidation, thus increasing the dependency on auxotrophic fatty acids. Consistently, AMPK is required for the expression of the fatty acid transporter CD36 in tumors, and ectopic expression of CD36 in AMPK-deficient cells restored their ability to metastasize.

Keywords:  AMPK; CD36; CP: Cancer; CP: Metabolism; ROS; breast cancer metastasis

DOI:  https://doi.org/10.1016/j.celrep.2024.115183
Cancers (Basel). 2024 Dec 24. pii: 7. [Epub ahead of print]17(1):

Differential Mitochondrial Redox Responses to the Inhibition of NAD+ Salvage Pathway of Triple Negative Breast Cancer Cells.

Jack Kollmar, Junmei Xu, Diego Gonzalves, Joseph A Baur, Lin Z Li, Julia Tchou, He N Xu.

  Background/Objectives: Cancer cells rely on metabolic reprogramming that is supported by altered mitochondrial redox status and an increased demand for NAD+. Over expression of Nampt, the rate-limiting enzyme of the NAD+ biosynthesis salvage pathway, is common in breast cancer cells, and more so in triple negative breast cancer (TNBC) cells. Targeting the salvage pathway has been pursued for cancer therapy. However, TNBC cells have heterogeneous responses to Nampt inhibition, which contributes to the diverse outcomes. There is a lack of imaging biomarkers to differentiate among TNBC cells under metabolic stress and identify which are responsive. We aimed to characterize and differentiate among a panel of TNBC cell lines under NAD-deficient stress and identify which subtypes are more dependent on the NAD salvage pathway. Methods: Optical redox imaging (ORI), a label-free live cell imaging microscopy technique was utilized to acquire intrinsic fluorescence intensities of NADH and FAD-containing flavoproteins (Fp) thus the mitochondrial redox ratio Fp/(NADH + Fp) in a panel of TNBC cell lines. Various fluorescence probes were then added to the cultures to image the mitochondrial ROS, mitochondrial membrane potential, mitochondrial mass, and cell number. Results: Various TNBC subtypes are sensitive to Nampt inhibition in a dose- and time-dependent manner, they have differential mitochondrial redox responses; furthermore, the mitochondrial redox indices linearly correlated with mitochondrial ROS induced by various doses of a Nampt inhibitor. Moreover, the changes in the redox indices correlated with growth inhibition. Additionally, the redox state was found fully recovered after removing the Nampt inhibitor. Conclusions: This study supports the utility of ORI in rapid metabolic phenotyping of TNBC cells under NAD-deficient stress to identify responsive cells and biomarkers of treatment response, facilitating combination therapy strategies.

Keywords:  FAD-containing flavoproteins; FK866; GMX1778; NAD+ biosynthesis; Nampt; TNBC; label-free optical redox/metabolic imaging; mitochondrial redox state; optical redox ratio

DOI:  https://doi.org/10.3390/cancers17010007
J Gastrointest Oncol. 2024 Dec 31. 15(6): 2507-2520

Leptin increases chemosensitivity by inhibiting CPT1B in colorectal cancer cells.

Xiuwei Mi, Huihui Yao, Yang Lu, Mei Yang, Yi Yang, Dong Fang, Songbing He.

   Background: Chemoresistance is a major cause of treatment failure in advanced colorectal cancer (CRC), severely impacting patient survival and quality of life. While conventional chemotherapy regimens can somewhat control tumor progression, their effectiveness is frequently compromised by the development of drug resistance in cancer cells. The aim of this study is to verify and elucidate the specific mechanisms by which leptin enhances chemosensitivity in CRC, providing valuable insights for the development of new combination chemotherapy options.
Methods: We examined the link between CRC chemoresistance and fatty-acid metabolism driven by the high expression of carnitine palmitoyltransferase-1b (CPT1B) through an integrated approach combining bioinformatics and clinical sample analysis. In vitro and in vivo experiments were conducted to evaluate the effect of leptin, an adipocyte-derived cytokine, on CRC cells' response to cisplatin.
Results: Leptin significantly enhanced CRC cells' chemosensitivity to cisplatin by downregulating CPT1B expression, thereby disrupting the fatty-acid oxidation pathways that support drug resistance. In mouse models, the coadministration of leptin and cisplatin resulted in notable reductions in tumor size and weight compared to cisplatin alone, underscoring leptin's potential to enhance chemotherapy efficacy.
Conclusions: These findings indicate that leptin, through modulation of CPT1B, may serve as a promising adjunct to chemotherapy for CRC, addressing the challenge of chemoresistance and improving therapeutic outcomes. The leptin-CPT1B axis may be potential therapeutic target, providing new avenues for CRC treatment strategies aimed at overcoming drug resistance.

Keywords:  Colorectal cancer (CRC); carnitine palmitoyltransferase-1b (CPT1B); chemosensitivity; leptin

DOI:  https://doi.org/10.21037/jgo-2024-950
Cancer Discov. 2025 Jan 14.

PIN1 prolyl isomerase promotes initiation and progression of bladder cancer through the SREBP2-mediated cholesterol biosynthesis pathway.

Xue Wang, Derrick Lee, Haibo Xu, Yuan Sui, Jill Meisenhelder, Tony Hunter.

Identities of functional pSer/Thr.Pro protein substrates of the PIN1 prolyl isomerase and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we found that PIN1 positively regulated bladder cancer cell proliferation, cell motility and urothelium clearance capacity in vitro and controlled tumor growth and potential metastasis in vivo. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways and a decrease in free/total cholesterol levels in PIN1-knockout bladder cancer cells. Moreover, we showed that PIN1 interacted with SREBP2 following its phosphorylation by the JNK MAP kinase at Ser455, which lies near the Site-2 cleavage site that generates the active, nuclear-form of SREBP2. Therapeutically, a combination of the sulfopin PIN1 covalent inhibitor and the simvastatin HMGCoA reductase inhibitor suppressed cell proliferation in vitro and tumor growth in vivo synergistically. Together, these findings emphasize that PIN1 can act as a driver and potential therapeutic target in bladder cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0866
Open Biol. 2025 Jan;15(1): 240151

Mitochondrial chaperonin DNAJC15 promotes vulnerability to ferroptosis of chemoresistant ovarian cancer cells.

Stefano Miglietta, Manuela Sollazzo, Iacopo Gherardi, Sara Milioni, Beatrice Cavina, Lorena Marchio, Monica De Luise, Camelia Alexandra Coada, Marco Fiorillo, Anna Myriam Perrone, Ivana Kurelac, Giuseppe Gasparre, Luisa Iommarini, Anna Maria Ghelli, Anna Maria Porcelli.

  DNAJC15 is a mitochondrial TIMM23-related co-chaperonin known for its role in regulating oxidative phosphorylation efficiency, oxidative stress response and lipid metabolism. Recently, it has been proposed that the loss of DNAJC15 correlates with cisplatin (CDDP)-resistance onset in ovarian cancer (OC), suggesting this protein as a potential prognostic factor during OC progression. However, the molecular mechanisms through which DNAJC15 contributes to CDDP response remains poorly investigated. Here, we show that high levels of DNAJC15 are associated with accumulation of lipid droplets, decreased tumorigenic features and increased sensitivity to CDDP in OC cells. When overexpressed, DNAJC15 induced a phenotype displaying increased lipid peroxidation and subsequent ferroptosis induction. To prove a role for DNAJC15-induced ferroptosis in promoting sensitivity to CDDP, we reduced lipid peroxidation upon Ferrostatin 1 treatment, which decreased cells' vulnerability to ferroptosis ultimately recovering their CDDP-resistant phenotype. In conclusion, our study uncovers the role of DNAJC15 in modulating ferroptosis activation and in the onset of CDDP resistance in OC cells.

Keywords:  DNAJC15; cisplatin resistance; ferroptosis; mitochondria; ovarian cancer

DOI:  https://doi.org/10.1098/rsob.240151
Dev Cell. 2025 Jan 07. pii: S1534-5807(24)00775-5. [Epub ahead of print]

DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma.

Ying Cao, Ruolan Qian, Ruilian Yao, Quan Zheng, Chen Yang, Xupeng Yang, Shuyi Ji, Linmen Zhang, Shujie Zhan, Yiping Wang, Tianshi Wang, Hui Wang, Chun-Ming Wong, Shengxian Yuan, Christopher Heeschen, Qiang Gao, René Bernards, Wenxin Qin, Cun Wang.

  Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. Employing kinome-based CRISPR screen, we find that knockout of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) synergizes with OXPHOS inhibitor IACS-010759 in liver cancer cells. Targeting DYRK1A combined with OXPHOS inhibitors activates TGF-β signaling, which is crucial for OXPHOS-inhibition-triggered cell death. Mechanistically, upregulation of glutamine transporter solute carrier family 1 member 5 (SLC1A5) transcription compensates for the increased glutamine requirement upon OXPHOS inhibition. DYRK1A directly phosphorylates SMAD3 Thr132, thereby suppressing the negative impact of TGF-β signaling on transcription of SLC1A5, leading to intrinsic resistance of liver cancer cells to OXPHOS inhibition. Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy.

Keywords:  DYRK1A; IACS-010759; TGF-β signaling; hepatocellular carcinoma; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.devcel.2024.12.035
Int J Mol Sci. 2024 Dec 31. pii: 304. [Epub ahead of print]26(1):

Glucosylceramide Synthase Inhibition in Combination with Aripiprazole Sensitizes Hepatocellular Cancer Cells to Sorafenib and Doxorubicin.

Richard Jennemann, Martina Volz, Roberto Carlos Frias-Soler, Almut Schulze, Karsten Richter, Sylvia Kaden, Roger Sandhoff.

  Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths due to its late diagnosis and restricted therapeutic options. Therefore, the search for appropriate alternatives to commonly applied therapies remains an area of high clinical need. Here we investigated the therapeutic potential of the glucosylceramide synthase (GCS) inhibitor Genz-123346 and the cationic amphiphilic drug aripiprazole on the inhibition of Huh7 and Hepa 1-6 hepatocellular cancer cell and tumor microsphere growth. Single and combinatorial treatments with both drugs at 5 µM concentration led to efficient cell cycle arrest, reduced expression of cyclins A and E, increased lipid storage in lysosomal compartments, accompanied by increased uptake of lysotracker, and elevated expression of the autophagy marker Lc3 II. Both drugs affected mitochondrial function, indicated by altered mitotracker uptake and impaired mitochondrial respiration. Aripiprazole in monotherapy, or even more pronounced in combination with Genz, also potentiated the effect of the cytostatic drugs sorafenib and doxorubicin on tumor cell- and tumor spheroid-growth inhibition. Targeting GCS with Genz with the parallel application of cationic amphiphilic drugs such as aripiprazole in combination with cytostatic drugs may thus represent a potent therapeutic approach in the treatment of HCC and potentially other cancer types.

Keywords:  Genz; anti-psychotic drugs; aripiprazole; cationic amphiphilic drugs (CAD); doxorubicin; glucosylceramide synthase; hepatocellular tumor spheroids; lysosomal function; mitochondrial function; sorafenib

DOI:  https://doi.org/10.3390/ijms26010304
Neuro Oncol. 2025 Jan 11. pii: noaf008. [Epub ahead of print]

Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.

Emma Martell, Helgi Kuzmychova, Harshal Senthil, Ujala Chawla, Esha Kaul, Akaljot Grewal, Versha Banerji, Christopher M Anderson, Chitra Venugopal, Donald Miller, Tamra E Werbowetski-Ogilvie, Sheila K Singh, Tanveer Sharif.

   BACKGROUND: The mitochondrial pyruvate carrier (MPC), a central metabolic conduit linking glycolysis and mitochondrial metabolism, is instrumental in energy production. However, the role of the MPC in cancer is controversial. In particular, the importance of the MPC in glioblastoma (GBM) disease progression following standard temozolomide (TMZ) and radiation therapy (RT) remains unexplored.
METHODS: Leveraging in vitro and in vivo patient-derived models of TMZ-RT treatment in GBM, we characterize the temporal dynamics of MPC abundance and downstream metabolic consequences using state-of-the-art molecular, metabolic, and functional assays.
RESULTS: Our findings unveil a disease stage-specific role for the MPC, where in post-treatment GBM, but not therapy-naïve tumors, the MPC acts as a central metabolic regulator that suppresses differentiation. Temporal profiling reveals a dynamic metabolic rewiring where a steady increase in MPC abundance favors a shift towards enhanced mitochondrial metabolic activity across patient GBM samples. Intriguingly, while overall mitochondrial metabolism is increased, acetyl-CoA production is reduced in post-treatment GBM cells, hindering histone acetylation and silencing neural differentiation genes in an MPC-dependent manner. Finally, the therapeutic translations of these findings are highlighted by the successful pre-clinical patient-derived orthotopic xenograft (PDOX) trials utilizing a blood-brain-barrier (BBB) permeable MPC inhibitor, MSDC-0160, which augments standard TMZ-RT therapy to mitigate disease relapse and prolong animal survival.
CONCLUSION: Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients.

Keywords:  Glioblastoma; differentiation; metabolism; mitochondrial pyruvate carrier; tumor recurrence

DOI:  https://doi.org/10.1093/neuonc/noaf008
Int J Mol Sci. 2024 Dec 25. pii: 78. [Epub ahead of print]26(1):

Effective Targeting of Glutamine Synthetase with Amino Acid Analogs as a Novel Therapeutic Approach in Breast Cancer.

Shimaa Abdelsattar, Hiba S Al-Amodi, Hala F Kamel, Ahood A Al-Eidan, Marwa M Mahfouz, Kareem El Khashab, Amany M Elshamy, Mohamed S Basiouny, Mohamed A Khalil, Khaled A Elawdan, Shorouk Elsaka, Salwa E Mohamed, Hany Khalil.

  Cancer cells undergo metabolic rewiring to support rapid proliferation and survival in challenging environments. Glutamine is a preferred resource for cancer metabolism, as it provides both carbon and nitrogen for cellular biogenesis. Recent studies suggest the potential anticancer activity of amino acid analogs. Some of these analogs disrupt cellular nucleotide synthesis, thereby inhibiting the formation of DNA and RNA in cancer cells. In the present study, we investigated the anticancer properties of Acivicin and Azaserine in the breast cancer MCF-7 cell line, comparing their effects to those on the non-tumorigenic MCF-10 epithelial cell line in vitro. Interestingly, at lower concentrations, both Acivicin and Azaserine showed potent inhibition of MCF-7 cell proliferation, as assessed by the MTT assay, without detectable toxicity to normal cells. In contrast, Sorafenib (Nexavar), a commonly used drug for solid tumors, showed harmful effects on normal cells, as indicated by increased lactate dehydrogenase (LDH) production in treated cells. Furthermore, unlike Sorafenib, treatment with Acivicin and Azaserine significantly affected apoptotic signaling in treated cells, indicating the role of both amino acid analogs in activating programmed cell death (PCD), as assessed by the Annexin-V assay, DAPI staining, and the relative expression of tumor suppressor genes PTEN and P53. ELISA analysis of MCF-7 cells revealed that both Acivicin and Azaserine treatments promoted the production of anti-inflammatory cytokines, including IL-4 and IL-10, while significantly reducing the production of tumor necrosis factor alpha (TNF-α). Mechanistically, both Acivicin and Azaserine treatment led to a significant reduction in the expression of glutamine synthetase (GS) at both the RNA and protein levels, resulting in a decrease in intracellular glutamine concentrations over time. Additionally, both treatments showed comparable effects on Raf-1 gene expression and protein phosphorylation when compared with Sorafenib, a Raf-1 inhibitor. Moreover, docking studies confirmed the strong binding affinity between Acivicin, Azaserine, and glutamine synthetase, as evidenced by their docking scores and binding interactions with the enzyme crystal. Collectively, these findings provide evidence for the anticancer activity of the two amino acid analogs Acivicin and Azaserine as antagonists of glutamine synthetase, offering novel insights into potential therapeutic strategies for breast cancer.

Keywords:  acivicin; amino acid analogs; azaserine; breast cancer; glutamine synthetase

DOI:  https://doi.org/10.3390/ijms26010078
Cancer Res. 2025 Jan 13.

ZNFX1 functions as a master regulator of epigenetically induced pathogen mimicry and inflammasome signaling in cancer.

Lora Stojanovic, Rachel Abbotts, Kaushelendra Tripathi, Collin M Coon, Saranya Rajendran, Elnaz Abbasi Farid, Galen Hostetter, Joseph W Guarnieri, Douglas C Wallace, Sheng Liu, Jun Wan, Gennaro Calendo, Rebecca Marker, Zahra Gohari, Mohammed M A Inayatullah, Vijay K Tiwari, Tanjina Kader, Sandro Santagata, Ronny Drapkin, Stefan Kommoss, Jacobus Pfisterer, Gottfried E Konecny, Ryan Coopergard, Jean-Pierre J Issa, Boris J N Winterhoff, Michael J Topper, George E Sandusky, Kathy D Miller, Stephen B Baylin, Kenneth P Nephew, Feyruz V Rassool.

DNA methyltransferase and poly (ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon genes (STING)-dependent pathogen mimicry response (PMR) in ovarian and other cancers. Here, we showed that combining DNMTis and PARPis upregulates expression of the nucleic-acid sensor NFX1-type zinc finger-containing 1 protein (ZNFX1). ZNFX1 mediated induction of PMR in mitochondria, serving as a gateway for STING-dependent interferon/inflammasome signaling. Loss of ZNFX1 in ovarian cancer cells promoted proliferation and spheroid formation in vitro and tumor growth in vivo. In patient ovarian cancer databases, expression of ZNFX1 was elevated in advanced stage disease, and ZNFX1 expression alone significantly correlated with an increase in overall survival in a phase 3 trial for therapy-resistant ovarian cancer patients receiving bevacizumab in combination with chemotherapy. RNA-sequencing revealed an association between inflammasome signaling through ZNFX1 and abnormal vasculogenesis. Together, this study identified that ZNFX1 as a tumor suppressor that controls PMR signaling through mitochondria and may serve as a biomarker to facilitate personalized therapy in ovarian cancer patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1286
Lipids Health Dis. 2025 Jan 13. 24(1): 12

Targeting lipid metabolism: novel insights and therapeutic advances in pancreatic cancer treatment.

Yanyan Zhang, Zhichao Yang, Yuchen Liu, Jinjin Pei, Ruojie Li, Yanhui Yang.

  Lipid metabolism in cancer is characterized by dysregulated lipid regulation and utilization, critical for promoting tumor growth, survival, and resistance to therapy. Pancreatic cancer (PC) is a highly aggressive malignancy of the gastrointestinal tract that has a dismal 5-year survival rate of less than 10%. Given the essential function of the pancreas in digestion, cancer progression severely disrupts its function. Standard treatments for PC such as surgical resection, chemotherapy, and radiotherapy. However, these therapies often face significant challenges, including biochemical recurrence and drug resistance.Given these limitations, new therapeutic approaches are being developed to target tumor metabolism. Dysregulation of cholesterol biosynthesis and alterations in fatty acids (FAs), such as palmitate, stearate, omega-3, and omega-6, have been observed in pancreatic cancer. These lipids serve as energy sources, signaling molecules, and essential components of cell membranes. Their accumulation fosters an immunosuppressive tumor microenvironment that supports cancer cell proliferation and metastasis.Moreover, lipid metabolism dysregulation within immune cells, particularly T cells, impairs immune surveillance and weakens the body's defenses against cancer. Abnormal lipid metabolism also contributes to drug resistance in PC. Despite these challenges, targeting lipid metabolism may offer a promising therapeutic strategy. By enhancing lipid peroxidation, the induction of ferroptosis-a form of regulated cell death-could impair the survival of PC cells and hinder disease progression.

Keywords:  Cancer therapy; Drug resistance; Ferroptosis; Lipid metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12944-024-02426-0
Autophagy. 2025 Jan 16.

Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting.

Guoshuai Xu, Qinghong Zhang, Renjia Cheng, Jun Qu, Wenqiang Li.

  Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients.

Keywords:  Anti-cancer therapies; MTORC1; MTORC2; macropinocytosis; metabolic reprogramming; methuosis

DOI:  https://doi.org/10.1080/15548627.2025.2452149
Commun Biol. 2025 Jan 10. 8(1): 36

SRC enhanced cisplatin resistance in bladder cancer by reprogramming glycolysis and pentose phosphate pathway.

Yuwen Gong, Dongyang Gao, Yibo Shi, Guangrui Fan, Xiaoquan Yu, Enguang Yang, Hui Cheng, Junqiang Tian, Hui Ding, Shanhui Liu, Shengjun Fu, Yan Tao, Yuan Shui, Liang Cheng, Lanlan Li, Zhiping Wang.

The development of cisplatin resistance often results in a grim prognosis in advanced or recurrent bladder cancer. However, effective treatment strategies for cisplatin resistance have not been well established. Herein, we found that overactivation of SRC is associated with cisplatin-resistance. SRC activates hexokinase2 which up-regulates glycolysis and especially the pentose phosphate pathway that leading to increased nucleotide synthesis and NADPH production which can neutralize reactive oxygen species (ROS) induced by cisplatin, thereby protecting bladder cancer cells from cisplatin-induced DNA damage. This phenomenon was effectively reversed by knockout of SRC and inhibition of SRC activity by the SRC inhibitor, eCF506. Moreover, we constructed Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) from cisplatin-resistant bladder cancer patient. eCF506 exhibited excellent anti-tumor effects and effectively enhanced cisplatin-sensitivity. Altogether, our findings demonstrate that targeting SRC is a promising approach to overcome cisplatin-resistance in bladder cancer, and providing new insights for combination therapy in bladder cancer.

DOI: https://doi.org/10.1038/s42003-024-07284-1
Acta Pharm Sin B. 2024 Dec;14(12): 5305-5320

AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer.

Zhiwen Fu, Tingting Wu, Chen Gao, Lulu Wang, Yu Zhang, Chen Shi.

  Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both in vitro and in vivo. Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.

Keywords:  AKR1C1; Alantolactone; Chemoresistance; Colorectal cancer; Combination therapy; Glutathione; Natural product; Oxaliplatin resistance

DOI:  https://doi.org/10.1016/j.apsb.2024.08.031
Cell Death Dis. 2025 Jan 14. 16(1): 16

DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer.

Xiao Hong Zhao, Man Man Han, Qian Qian Yan, Yi Meng Yue, Kaihong Ye, Yuan Yuan Zhang, Liu Teng, Liang Xu, Xiao-Jing Shi, Ting La, Yu Chen Feng, Ran Xu, Vinod K Narayana, David P De Souza, Lake-Ee Quek, Jeff Holst, Tao Liu, Mark A Baker, Rick F Thorne, Xu Dong Zhang, Lei Jin.

Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucleobases adenine and guanine along with the pyrimidine nucleoside uridine restored replication fork progression and cell proliferation, whereas the supplementation of exogenous aspartate recovered the nucleotide pool, demonstrating a causal role of the aspartate shortage in OXPHOS inhibition-induced nucleotide deficiencies and consequently replication stress and reductions in proliferation. Moreover, we demonstrate that glutamic-oxaloacetic transaminase 1 (GOT1) is critical for maintaining the minimum aspartate pool when OXPHOS is inhibited, as knockdown of GOT1 further reduced aspartate levels and rendered CRC cells more sensitive to OXPHOS inhibition both in vitro and in vivo. These results propose GOT1 targeting as a potential avenue to sensitize cancer cells to OXPHOS inhibitors, thus lowering the necessary doses to efficiently inhibit cancer growth while alleviating their adverse effects.

DOI: https://doi.org/10.1038/s41419-025-07334-4
Am J Cancer Res. 2024 ;14(12): 5697-5716

Blockade of neutral sphingomyelinase 2 exerts antitumor effect on metastatic castration resistant prostate cancer cells and promotes tumor regression when combined with Enzalutamide.

Shams Ge Shams, Dalal Dawud, Kasia Michalak, Maysoon M Makhlouf, Ahmed Moustafa, S Michal Jazwinski, Lin Kang, Mourad Zerfaoui, Khalid A El Sayed, Zakaria Y Abd Elmageed.

  Prostate cancer (PCa) is the second leading cause of cancer-related deaths among American men. The development of metastatic castration resistant PCa (mCRPC) is the current clinical challenge. Antiandrogens such as Enzalutamide (ENZ) are commonly used for CRPC treatment. However, patients with androgen receptor (AR)-negative tumors do not respond to ENZ, while AR-positive tumors frequently develop resistance, limiting the long-term efficacy of this therapy. This study investigates the efficacy of neutral sphingomyelinase 2 (n-SMase2) inhibition by DPTIP, both alone and in combination with ENZ, as a therapeutic strategy for mCRPC. In vitro assays were conducted to determine the half-maximal inhibitory concentration (IC50) of DPTIP and ENZ in mCRPC cells. The effect of these treatments on cell proliferation, migration, and colony formation was assessed. The antitumor effect of DPTIP was also evaluated in a preclinical PCa mouse model. Elevated n-SMase2 expression was observed in PCa patients compared to normal subjects at both mRNA and protein levels. In CWR-R1ca and PC-3 cells, DPTIP had IC50 values of 10.31 and 14.57 µM, while ENZ had IC50 values of 33.7 and 81 µM, respectively. Combined treatment significantly suppressed cell proliferation, colony formation, and migration of mCRPC cells. Mechanistically, the ERK1/2 activity and the expression of nSMase2 and NF-kB p65 were inhibited by DPTIP. The in vivo combination of DPTIP and ENZ reduced tumor size and weight more effectively than either drug alone, without significant changes in body weight. This study highlights the therapeutic potential of targeting n-SMase2 for mCRPC. Inhibition of n-SMase2 using DPTIP, both as a standalone treatment and in combination with ENZ, effectively suppressed the growth and migration of mCRPC cells. These findings suggest a promising novel approach to treating mCRPC and warrant further investigation in clinical settings.

Keywords:  DPTIP; Enzalutamide; Prostate cancer; mCRPC; mouse model; n-SMase2

DOI:  https://doi.org/10.62347/XXXA3182
BMC Cancer. 2025 Jan 10. 25(1): 62

Exploring the role of ELOVLs family in lung adenocarcinoma based on bioinformatic analysis and experimental validation.

Zihan Wang, Wenjing Cui, Long Liang, Jingge Qu, Yuqiang Pei, Danyang Li, Ying Luo, Yue Zhang, Yifan Qiu, Yongchang Sun.

   BACKGROUND: The role of lipid metabolic reprogramming in the development of various types of cancer has already been established. However, the exact biological function and significance of the elongation of very-long-chain fatty acids (ELOVLs) gene family, which can affect fatty acid metabolism, is still not well understood in lung adenocarcinoma (LUAD). The aim of our study is to explore whether there are genes related to the pathogenesis of LUAD in the ELOVLs family, and even to guide clinical medication and potential prognostic indicators.
METHODS: Gene expression profiling interactive analysis (GEPIA), human protein atlas (HPA), cBioPortal, Kaplan-Meier (KM) plotter, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm and SubMap algorithms were utilized to analyze the role of ELOVLs in the LUAD. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, cell counting kit-8 (CCK8), colony formation, wound healing, transwell migration assays and fatty acid metabolism detection were employed to confirm the significant role of ELOVL6 in vitro experiment.
RESULTS: Our results revealed that mRNA expression levels of ELOVL2, ELOVL4 and ELOVL6 and protein expression levels of ELOVL5 and ELOVL6 were elevated in LUAD tissues compared to normal subjects. The low-expressing ELOVL6 group showed superior overall survival (OS) and disease-specific survival (DSS) versus the high-expressing group. Meanwhile, patients with low-ELOVL6 expression were more sensitive to the 4 representative chemotherapeutic agents. In vitro, we revealed that interfering with ELOVL6 could influence the viability, proliferation, migration capacity and fatty acid metabolism of LUAD cells (A549 and H1299).
CONCLUSIONS: Our study indicated that ELOVL6 could be used as an indicator to evaluate the prognosis and therapeutic effect, and even potential therapeutic target for patients with LUAD.

Keywords:  ELOVLs; Fatty acid metabolism; Lung adenocarcinoma; Personalized treatment; Prognosis

DOI:  https://doi.org/10.1186/s12885-024-13415-y
Discov Oncol. 2025 Jan 15. 16(1): 46

Elucidating stearoyl metabolism and NCOA4-mediated ferroptosis in gastric cancer liver metastasis through multi-omics single-cell integrative mendelian analysis: advancing personalized immunotherapy strategies.

Zhongqiu Yang, Yuquan Chen, Yaping Miao, Haisheng Yan, Kexin Chen, Yaoqin Xu, Lanqian Su, Lanyue Zhang, Yalan Yan, Hao Chi, Jin Fu, Lexin Wang.

   BACKGROUND: The metabolism of stearoyl-GPE plays a key role in the liver metastasis of gastric cancer. This investigation delves into the mechanisms underlying the intricate tumor microenvironment (TME) heterogeneity triggered by stearoyl metabolism in gastric cancer with liver metastasis (LMGC), offering novel perspectives for LMGC.
OBJECTIVE: Utilizing Mendelian randomization, we determined that stearoyl metabolism significantly contributes to the progression of gastric cancer (GC). Following this, bulk transcriptome analyses and single-cell multiomics techniques to investigate the roles of stearoyl-GPE metabolism-related genes, particularly NCOA4, in regulating LMGC TME.
RESULTS: Our analysis highlights the crucial role of stearoyl metabolism in modulating the complex microenvironment of LMGC, particularly impacting monocyte cells. Through single-cell sequencing and spatial transcriptomics, we have identified key metabolic genes specific to stearoyl metabolism within the monocyte cell population, including NCOA4. Regarding the relationship between ferroptosis, stearoyl metabolism, and LMGC findings, it is plausible that stearoyl metabolism and LMGC pathways intersect with mechanisms involved in ferroptosis. Ferroptosis, characterized by iron-dependent lipid peroxidation, represents a regulated form of cell death. The activity of Stearoyl-CoA desaturase (SCD), a critical enzyme in stearoyl metabolism, has been associated with the modulation of lipid composition and susceptibility to ferroptosis. Furthermore, the LMGC is integral to cellular processes related to oxidative stress and lipid metabolism, both of which are significant factors in the context of ferroptosis.
CONCLUSION: This study enhances the understanding of the relationship between stearoyl metabolism and ferroptosis in promoting liver metastasis of gastric cancer and its role in the regulation of tumor heterogeneity. In addition, this study contributes to a deeper understanding of the dynamics of gastric cancer tumor microenvironment (TME) and provides a basis for the development of better interventions to combat cancer metastasis.

Keywords:  Ferroptosis; LMGC; Multi-omics data; NCOA4; Single-cell RNA sequencing; Spatial transcriptomics; Stearoyl metabolism; Tumor heterogeneity; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/s12672-025-01769-z
Nutrients. 2025 Jan 03. pii: 179. [Epub ahead of print]17(1):

Targeting Asparagine Metabolism in Solid Tumors.

Keita Hanada, Kenji Kawada, Kazutaka Obama.

  Reprogramming of energy metabolism to support cellular growth is a "hallmark" of cancer, allowing cancer cells to balance the catabolic demands with the anabolic needs of producing the nucleotides, amino acids, and lipids necessary for tumor growth. Metabolic alterations, or "addiction", are promising therapeutic targets and the focus of many drug discovery programs. Asparagine metabolism has gained much attention in recent years as a novel target for cancer therapy. Asparagine is widely used in the production of other nutrients and plays an important role in cancer development. Nutritional inhibition therapy targeting asparagine has been used as an anticancer strategy and has shown success in the treatment of leukemia. However, in solid tumors, asparagine restriction alone does not provide ideal therapeutic efficacy. Tumor cells initiate reprogramming processes in response to asparagine deprivation. This review provides a comprehensive overview of asparagine metabolism in cancers. We highlight the physiological role of asparagine and current advances in improving survival and overcoming therapeutic resistance.

Keywords:  asparagine metabolism; cancer; glutamine metabolism; metabolic adaptation

DOI:  https://doi.org/10.3390/nu17010179
Sci Rep. 2025 Jan 15. 15(1): 2003

Elucidating the role of pyrimidine metabolism in prostate cancer and its therapeutic implications.

Liang Huang, Yu Xie, Shusuan Jiang, Kan Liu, Zhihao Ming, Hong Shan.

  Our study aims to investigate the role of pyrimidine metabolism in prostate cancer and its associations with the immune microenvironment, drug sensitivity, and tumor mutation burden. Through transcriptomic and single-cell RNA sequencing analyses, we explored metabolic pathway enrichment, immune infiltration patterns, and differential gene expression in prostate cancer samples. The results showed that pyrimidine metabolism-related genes were significantly upregulated in the P2 subgroup compared to the P1 subgroup, with enhanced metabolic activity observed in basal and luminal epithelial cells. In addition, immune infiltration analysis revealed a strong correlation between pyrimidine metabolism and immune cell regulation, particularly involving T cell activity. Tumors in the P2 subgroup, characterized by higher pyrimidine metabolism, exhibited greater infiltration of activated CD4 + T cells and M2 macrophages, indicating a potential link between metabolic reprogramming and the immune response in prostate cancer. Drug sensitivity analysis further demonstrated that tumors with elevated pyrimidine metabolism displayed increased responsiveness to several chemotherapeutic agents, including BI-2536, JW-7-24-1, and PAC-1, suggesting that targeting pyrimidine metabolism may enhance treatment efficacy. Moreover, key genes involved in pyrimidine de novo synthesis, such as RRM2, were identified as potential drivers of tumor progression, providing new insights into the molecular mechanisms underlying aggressive prostate cancer phenotypes. In conclusion, pyrimidine metabolism plays a critical role in prostate cancer progression, influencing immune infiltration and drug sensitivity. Targeting this metabolic pathway offers a promising strategy for the development of new therapeutic approaches, particularly for overcoming drug resistance and improving outcomes in patients with advanced prostate cancer.

Keywords:  Androgen; Metabolic reprogramming; Prostate Cancer; Pyrimidine metabolism; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s41598-025-86052-5
Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01557-2. [Epub ahead of print]44(1): 115206

Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.

Jean-Ehrland Ricci.

  Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.

Keywords:  CP: Cancer; CP: Metabolism; antitumor activity of immune cells; cancer; metabolism; therapeutic strategies; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.115206
J Transl Med. 2025 Jan 15. 23(1): 70

A review of the pathogenesis of mitochondria in breast cancer and progress of targeting mitochondria for breast cancer treatment.

Aoling Huang, Haochen Xue, Ting Xie, Lingyan Xiang, Zhengzhuo Chen, Aolong Ma, Honglin Yan, Jingping Yuan.

  With breast cancer being the most common tumor among women in the world today, it is also the leading cause of cancer-related deaths. Standard treatments include chemotherapy, surgery, endocrine therapy, and targeted therapy. However, the heterogeneity, drug resistance, and poor prognosis of breast cancer highlight an urgent need for further exploration of its underlying mechanisms. Mitochondria, highly dynamic intracellular organelles, play a pivotal role in maintaining cellular energy metabolism. Altered mitochondrial function plays a critical role in various diseases, and recent studies have elucidated its pathophysiological mechanisms in breast carcinogenesis. This review explores the role of mitochondrial dysfunction in breast cancer pathogenesis and assesses potential mitochondria-targeted therapies.

Keywords:  Apoptosis; Breast cancer; Mitochondria; Mitochondrial dynamics; Mitochondrial metabolism

DOI:  https://doi.org/10.1186/s12967-025-06077-2