bims-meract 2025-03-23 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–03–23
23 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
Targeting ncRNAs to overcome metabolic reprogramming‑mediated drug resistance in cancer (Review).
Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity.
YAP-mediated DDX3X confers resistance to ferroptosis in breast cancer cells by reducing lipid peroxidation.
Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs.
Mitochondrial fatty acid oxidation as the target for blocking therapy-resistance and inhibiting tumor recurrence: The proof-of-principle model demonstrated for ovarian cancer cells.
PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway.
Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis.
Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
Pentose phosphate recycling driven by Gli1 contributes to chemotherapy resistance in cancer cells.
Metabolic reprogramming and synergistic cytotoxicity of genistein and chemotherapy in human breast cancer cells.
Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting IDO-Mediated Tryptophan Metabolism.
The role of fructose-1,6-bisphosphatase 1 on regulating the cancer progression and drug resistance.
A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.
Integration of scRNA-seq and bulk RNA-seq to reveal the association and potential molecular mechanisms of metabolic reprogramming regulated by lactylation and chemotherapy resistance in ovarian cancer.
Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer.
Monounsaturated fatty acids promote cancer radioresistance by inhibiting ferroptosis through ACSL3.
Lactate accumulation induces H4K12la to activate super-enhancer-driven RAD23A expression and promote niraparib resistance in ovarian cancer.
Metformin sensitizes triple-negative breast cancer to histone deacetylase inhibitors by targeting FGFR4.
The tumor microenvironment is an ecosystem sustained by metabolic interactions.
Lnc-TPT1-AS1/CBP/ATIC Axis Mediated Purine Metabolism Activation Promotes Breast Cancer Progression.
CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer.
Pak1 dysregulates Pyruvate metabolism in PDAC cells by exerting a phosphorylation-mediated regulatory effect on PDHA1.

Nat Commun. 2025 Mar 16. 16(1): 2597

Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.

Haibin Deng, Liang Zhao, Huixiang Ge, Yanyun Gao, Yan Fu, Yantang Lin, Mojgan Masoodi, Tereza Losmanova, Michaela Medová, Julien Ott, Min Su, Wenxiang Wang, Ren-Wang Peng, Patrick Dorn, Thomas Michael Marti.

Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB's role in countering mitochondria-associated ferroptosis independently of lactate's function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.

DOI: https://doi.org/10.1038/s41467-025-57906-3
Int J Oncol. 2025 May;pii: 35. [Epub ahead of print]66(5):

Targeting ncRNAs to overcome metabolic reprogramming‑mediated drug resistance in cancer (Review).

Junxin Li, Yanyu Li, Lin Fu, Huiling Chen, Fei Du, Zhongshu Wang, Yan Zhang, Yu Huang, Jidong Miao, Yi Xiao.

  The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

Keywords:  drug‑resistant; ferroptosis; glutamine; glycolysis; lipid metabolism; mitochondrion; non‑coding RNA

DOI:  https://doi.org/10.3892/ijo.2025.5741
Nat Cancer. 2025 Mar 19.

Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity.

Liang Zhou, Guangyu Lian, Tao Zhou, Zhe Cai, Shuai Yang, Weining Li, Lilin Cheng, Ying Ye, Mingfeng He, Jianru Lu, Qifeng Deng, Bihui Huang, Xiaoqian Zhou, Desheng Lu, Feng Zhi, Jun Cui.

Ferroptosis is closely linked with various pathophysiological processes, including aging, neurodegeneration, ischemia-reperfusion injury, viral infection and, notably, cancer progression; however, its post-translational regulatory mechanisms remain incompletely understood. Here we revealed a crucial role of S-palmitoylation in regulating ferroptosis through glutathione peroxidase 4 (GPX4), a pivotal enzyme that mitigates lipid peroxidation. We identified that zinc finger DHHC-domain containing protein 8 (zDHHC8), an S-acyltransferase that is highly expressed in multiple tumors, palmitoylates GPX4 at Cys75. Through small-molecule drug screening, we identified PF-670462, a zDHHC8-specific inhibitor that promotes the degradation of zDHHC8, consequently attenuating GPX4 palmitoylation and enhancing ferroptosis sensitivity. PF-670462 inhibition of zDHHC8 facilitates the CD8+ cytotoxic T cell-induced ferroptosis of tumor cells, thereby improving the efficacy of cancer immunotherapy in a B16-F10 xenograft model. Our findings reveal the prominent role of the zDHHC8-GPX4 axis in regulating ferroptosis and highlight the potential application of zDHHC8 inhibitors in anticancer therapy.

DOI: https://doi.org/10.1038/s43018-025-00937-y
Free Radic Biol Med. 2025 Mar 13. pii: S0891-5849(25)00169-8. [Epub ahead of print]232 330-339

YAP-mediated DDX3X confers resistance to ferroptosis in breast cancer cells by reducing lipid peroxidation.

Jia-Zih Dai, Wen-Jing Hsu, Mei-Hsiang Lin, Pei-Wei Shueng, Chi-Ching Lee, Ching-Chieh Yang, Cheng-Wei Lin.

  Metabolic shifts in cancer cells were found to participate in tumorigenesis, especially driving chemotherapeutic resistance. Ferroptosis is a newly discovered form of cell death induced by excessive accumulations of iron and lipid peroxidation. Susceptibility to ferroptosis can be intrinsically regulated by various cellular metabolic pathways. Therefore, inducing ferroptosis might be a promising anticancer therapeutic strategy. DEAD-box helicase 3 X-linked (DDX3X), a critical modulator of RNA metabolism, was identified as an oncogene in breast cancer and also participates in cancer metabolism and chemotherapeutic resistance. However, the molecular regulation of the association between DDX3X and ferroptosis is largely unknown. Herein, we investigated the correlation between resistance to ferroptosis and DDX3X expression in breast cancer cells. We found that elevation of DDX3X was associated with increased resistance to a ferroptosis inducer in breast cancer cells, and manipulating DDX3X expression regulated the sensitivity to the ferroptosis inducer. Importantly, DDX3X upregulated expression of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4) gene to confer ferroptosis resistance in breast cancer cells. Moreover, DDX3X was transcriptionally upregulated by the yes-associated protein (YAP). Knockdown of YAP downregulated DDX3X mRNA expression and facilitated lipid peroxidation, but that were restored in the presence of DDX3X. Clinically, coexpression of DDX3X and YAP was found in a variety of malignancy, and their elevation conferred poor survival prognosis in patients with breast cancer. Together, our findings reveal the crucial role of DDX3X in sensitivity to ferroptosis and underscore its potential as a diagnostic marker and therapeutic target. DDX3X renders resistance to ferroptosis and plays a role in mitigating lipid peroxidation, paving the way for therapeutic vulnerability via targeting cancer metabolism.

Keywords:  Breast cancer; DEAD-box helicase 3 X-linked; Ferroptosis; Glutathione peroxidase 4; Yes-associated protein

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.019
Signal Transduct Target Ther. 2025 Mar 21. 10(1): 92

Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs.

Niklas Gremke, Isabelle Besong, Alina Stroh, Luise von Wichert, Marie Witt, Sabrina Elmshäuser, Michael Wanzel, Martin F Fromm, R Verena Taudte, Sabine Schmatloch, Thomas Karn, Mattea Reinisch, Nader Hirmas, Sibylle Loibl, Thomas Wündisch, Anne-Sophie Litmeyer, Paul Jank, Carsten Denkert, Sebastian Griewing, Uwe Wagner, Thorsten Stiewe.

Activating PIK3CA mutations, present in up to 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (Her2-) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR+, Her2-, and PIK3CA-mutated metastatic BC patients. However, acquired resistance, often due to aberrant activation of the mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using in vitro and orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism. Mechanistically, mTORC1 suppresses the induction of autophagy during metabolic perturbation, leading to energy stress, a critical depletion of aspartate, and ultimately cell death. Supporting this mechanism, BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metabolically active drugs. In BC patients, high mTORC1 activity, indicated by 4E-BP1T37/46 phosphorylation, correlated with p62 accumulation, a sign of impaired autophagy. Together, these markers predicted poor overall survival in multiple BC subgroups. Our findings reveal that aberrant mTORC1 signaling, a common cause of PI3K inhibitor resistance in BC, creates a druggable metabolic vulnerability by suppressing autophagy. Additionally, the combination of 4E-BP1T37/46 phosphorylation and p62 accumulation serves as a biomarker for poor overall survival, suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.

DOI: https://doi.org/10.1038/s41392-025-02180-4
J Adv Res. 2025 Mar 17. pii: S2090-1232(25)00186-9. [Epub ahead of print]

Mitochondrial fatty acid oxidation as the target for blocking therapy-resistance and inhibiting tumor recurrence: The proof-of-principle model demonstrated for ovarian cancer cells.

Hui Lin, Lingfang Wang, Hanwen Chen, Yuqing Shen, Conghui Wang, Yite Xue, Zhi Zheng, Yanan Zhang, Dajing Xia, Yihua Wu, Fenfen Wang, Xiao Li, Xiaodong Cheng, Hui Wang, Junfen Xu, Weiguo Lu.

   INTRODUCTION: Cancer patients treated with current chemotherapeutic and targeted therapies frequently achieve partial remission, which ultimately relapse with more aggressive, drug-resistant tumor phenotypes. To a certain extent, drug-tolerant persister (DTP) cells are responsible for residual tumors after systemic anticancer therapy and the onset of acquired drug resistance. Therefore, novel therapies targeting DTP cells to prevent drug resistance and tumor recurrence are urgently needed.
OBJECTIVES: We aimed to investigate the traits and key vulnerabilities of drug-tolerant ovarian cancer persister cells and to seek out potential therapeutic strategies.
METHODS: We constructed paclitaxel-tolerant ovarian cancer persister cells by exposing ovarian cancer parental cells to a lethal dose of paclitaxel. Proteomics analysis, in vitro and in vivo assays were performed to identify biological processes that could serve as potential vulnerabilities in persister cells.
RESULTS: Paclitaxel-tolerant ovarian cancer persister cells were found to undergo a metabolic reprogramming through the upregulation of fatty acid oxidation (FAO). Treatment with the FAO inhibitor ST1326 suppressed FAO and increased sensitivity to paclitaxel in persister cells. Moreover, combination therapy with paclitaxel and ST1326 prevented ovarian tumor recurrence with satisfactory biosafety in a mouse model of ovarian cancer relapse, indicating that FAO disruption can improve the efficacy of paclitaxel-based therapy in ovarian cancer. Mechanistically, we found that paclitaxel treatment upregulated CEBPB, a transcription factor that induced the expression of the FAO-related enzyme HADHA and contributed to FAO elevation in persister cells.
CONCLUSIONS: This study revealed an upregulation of FAO in paclitaxel-tolerant ovarian cancer persister cells and provided a prospective paclitaxel-ST1326 combination therapy targeting persister cells that may prevent the development of acquired drug resistance and achieve superior long-term ovarian cancer control in the future. Our research established a conceptual framework for advancing personalized treatment approaches and enhancing patient outcomes in ovarian cancer therapy.

Keywords:  Drug-tolerant persister; Fatty acid oxidation; Improved individual outcomes; Mitochondrial metabolism; Ovarian cancer; Paclitaxel

DOI:  https://doi.org/10.1016/j.jare.2025.03.026
J Exp Clin Cancer Res. 2025 Mar 19. 44(1): 99

PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway.

Xiaojin Liu, Bangxin Liu, Junwen Wang, Hongbin Liu, Jiasheng Wu, Yiwei Qi, Yuan Liu, Hongtao Zhu, Chaoxi Li, Liu Yang, Jian Song, Guojie Yao, Weidong Tian, Kai Zhao, Lin Han, Kai Shu, Suojun Zhang, Jianghong Man, Chao You, Haohao Huang, Ran Li.

   BACKGROUND: Glioma stem-like cells (GSCs) are key drivers of treatment resistance and recurrence in glioblastoma (GBM). Phosphoglycerate dehydrogenase (PHGDH), a crucial enzyme in the de novo serine synthesis pathway (SSP), is implicated in tumorigenesis and therapy resistance across various cancers. However, its specific role in GBM, particularly in radioresistance, remains poorly understood.
METHODS: In silico analysis of GBM patient data assessed SSP enrichment and PHGDH expression linked with tumor stemness. Comparative gene expression analysis focused on PHGDH in paired GBM specimens and GSCs. Genetic and pharmacological loss-of-function assays were performed in vitro and in vivo to evaluate PHGDH's impact on GSC self-renewal and malignant progression. Comprehensive transcriptomic and metabolomic analyses, along with chromatin immunoprecipitation, mass spectrometry, and various other biochemical assays, were used to elucidate PHGDH-mediated mechanisms in GBM progression and radioresistance.
RESULTS: PHGDH expression is significantly elevated in GSCs, associated with aggressive glioma progression and poor clinical outcomes. PHGDH activation enhances GSC self-renewal by regulating redox homeostasis, facilitating one-carbon metabolism, and promoting DNA damage response via SSP activation. Importantly, MYC was identified as a crucial transcriptional regulator of PHGDH expression. Furthermore, genetic ablation or pharmacological inhibition of PHGDH markedly reduced tumor growth and increased tumor sensitivity to radiotherapy, thereby improving survival outcomes in orthotopic GSC-derived and patient-derived GBM xenograft models.
CONCLUSIONS: This study underscores the pivotal role of MYC-mediated PHGDH activation in driving GSC malignant progression and radioresistance in GBM. Targeting PHGDH presents a promising approach to enhance radiotherapy efficacy in GBM patients.

Keywords:  Glioma stem cells; MYC; PHGDH; Radioresistance; Serine synthesis pathway

DOI:  https://doi.org/10.1186/s13046-025-03361-3
Cell Death Dis. 2025 Mar 20. 16(1): 193

Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis.

Jiao Deng, Yangkun Li, Lanlan Yin, Shuang Liu, Yanqi Li, Wancheng Liao, Lei Mu, Xuelai Luo, Jichao Qin.

Colorectal cancer stem cells (CCSCs) play a critical role in mediating chemoresistance. Lactylation is a post-translational modification induced by lactate that regulates gene expression. However, whether lactylation affects the chemoresistance of CCSCs remains unknown. Here, we demonstrate that histone lactylation enhances CCSC chemoresistance both in vitro and in vivo. Furthermore, our findings showed that p300 catalyzes the lactylation of histone H4 at K12, whereas HDAC1 facilitates its delactylation in CCSCs. Notably, lactylation at H4K12 (H4K12la) upregulates GCLC expression and inhibits ferroptosis in CCSCs, and the inhibition of p300 or LDHA decreases H4K12la levels, thereby increasing the chemosensitivity of CCSCs. Additionally, the GCLC inhibitor BSO promotes ferroptosis and sensitizes CCSCs to oxaliplatin. Taken together, these findings suggest that histone lactylation upregulates GCLC to inhibit ferroptosis signaling, thus enhancing CCSC chemoresistance. These findings provide new insights into the relationship between cellular metabolism and chemoresistance and suggest potential therapeutic strategies targeting p300, LDHA, and GCLC. We showed that histones H4K12 lactylation promoted chemoresistance in CSCs. p300 catalyzes the lactylation of histone H4 at K12, HDAC1 inhibits the histone lactylation at the same site. H4K12la in CSCs regulates the expression of the ferroptosis-related gene GCLC, thereby inhibiting ferroptosis and leading to chemoresistance. Targeting the p300, LDHA, or GCLC may be overcome tumor chemoresistance.

DOI: https://doi.org/10.1038/s41419-025-07498-z
Cell Rep. 2025 Mar 18. pii: S2211-1247(25)00212-8. [Epub ahead of print]44(4): 115441

Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.

Keqiang Rao, Xinchao Zhang, Yi Luo, Qiang Xia, Yuting Jin, Jing He.

  Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.

Keywords:  CP: Cancer; PIK3CB; PSMA4; ULK1; cGAS; innate immune system; lactylation; tumor growth; ubiquitin-independent degradation

DOI:  https://doi.org/10.1016/j.celrep.2025.115441
Cancer Lett. 2025 Mar 14. pii: S0304-3835(25)00197-1. [Epub ahead of print]618 217633

Pentose phosphate recycling driven by Gli1 contributes to chemotherapy resistance in cancer cells.

Qiangsheng Hu, Cong Jiang, Yi Qin, Borui Li, Jingyi Wang, Ting Wang, Shunrong Ji, Zeng Ye, Qing Dang, Mingyang Liu, Xianjun Yu, Xiaowu Xu.

  The Hedgehog Signaling Pathway plays an important role in cancer development and chemotherapy resistance. However, whether the pathway functions depend on the metabolic reprogramming of cancer cells has not been well studied. In this study, we found that the expression level of Gli1, a key transcription factor downstream of the Hedgehog Signaling Pathway, is significantly increased in patients with pancreatic cancer resistant to gemcitabine neoadjuvant chemotherapy. Through metabolomics analysis, we confirmed that Gli1 can promote the transformation of cancer cells from a glycolytic-dominated metabolic pattern to a unique metabolic pattern called "Pentose Phosphate Recycling". Transcriptome sequencing and in vitro experiments suggest that Gli1 promotes pentose phosphate recycling through transcriptional activation of key enzymes Phosphogluconate dehydrogenase (PGD) and Transketolase (TKT). The identified metabolic rerouting in oxidative and non-oxidative pentose phosphate pathway has important physiological roles in maximizing NADPH reduction and nucleotide synthesis. Therefore, the pentose phosphate cycle driven by Gli1 can resist gemcitabine-induced DNA damage by promoting pyrimidine synthesis and resist gemcitabine-induced ferroptosis by scavenging lipid Reactive Oxygen Species (Lipid ROS). Combining the Gli1 inhibitor GANT21 with gemcitabine exerts a maximal tumor suppressor effect by simultaneously promoting DNA damage and ferroptosis. Collectively, these results reveal that Gli1 drives chemotherapy resistance in cancer cells by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for reversing chemotherapy resistance.

Keywords:  Ferroptosis; Gemcitabine resistance; Hedgehog/GLI signaling pathway; Pancreatic ductal adenocarcinoma; Pentose phosphates recycling

DOI:  https://doi.org/10.1016/j.canlet.2025.217633
Life Sci. 2025 Mar 14. pii: S0024-3205(25)00196-1. [Epub ahead of print]370 123562

Metabolic reprogramming and synergistic cytotoxicity of genistein and chemotherapy in human breast cancer cells.

Sandra Tobón-Cornejo, Ariana Vargas-Castillo, Mandy Juarez, Joshua Ayork Acevedo-Carabantes, Lilia G Noriega, Omar Granados-Portillo, Alma Chávez-Blanco, Rocío Morales-Bárcenas, Nimbe Torres, Armando R Tovar, Alejandro Schcolnik-Cabrera.

  Breast cancer (BCa) is a heterogeneous disease, initially responsive to hormone therapy but often developing resistance to both hormonal and chemotherapy treatments. Novel therapeutic strategies are needed for drug-resistant BCa. Genistein, a phytoestrogen structurally similar to estrogen, competes with estrogen for receptor binding and exhibits anti-cancer effects. In this study, we investigated the cellular and metabolic impacts of genistein, alone or in combination with chemotherapy, in two human BCa cell lines-one estrogen receptor-positive (ER+) and one estrogen receptor-negative (ER-). We observed a strong synergistic effect on cell viability at low concentrations of genistein and chemotherapy, resulting in reduced clonogenic capacity and impaired cell migration. Genistein alone modulated cellular energy metabolism, notably reducing ATP production in MCF7 (ER+) cells. This metabolic shift was linked to a decreased dependence on fatty acids for energy, coupled with a decrease in the rate-limiting mitochondrial translocase CPT1 required for fatty acid oxidation, alongside with an increase in intracellular fatty acid levels. While the most significant changes occurred in ER+ cells, ER- cells also showed responses to genistein treatment. Collectively, our findings suggest that low genistein concentrations, in combination with conventional chemotherapy, induces synergistic anti-cancer effects, promoting cellular senescence.

Keywords:  Breast cancer; Cancer metabolism; Fatty acid metabolism; Genistein; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.lfs.2025.123562
Cancer Sci. 2025 Mar 18.

Epacadostat Overcomes Cetuximab Resistance in Colorectal Cancer by Targeting IDO-Mediated Tryptophan Metabolism.

Yimin Zhou, Qiongyan Tao, Chubin Luo, Jinsong Chen, Genwen Chen, Jianyong Sun.

  Primary or acquired mutations in RAS/RAF genes resulting in cetuximab resistance have limited its clinical application in colorectal cancer (CRC) patients. The mechanism of this resistance remains unclear. RNA sequencing from cetuximab-sensitive and -resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab-resistant CRC patients. In vitro, in vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab-resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti-tumor effect. Furthermore, in vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN-γ pathway in cetuximab-resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN-γ then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8+ T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti-tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab-resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.

Keywords:  IDO; cetuximab; colorectal cancer; epacadostat; tryptophan metabolism; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.70057
Discov Oncol. 2025 Mar 18. 16(1): 346

The role of fructose-1,6-bisphosphatase 1 on regulating the cancer progression and drug resistance.

Mengmeng Wang, Xiaoju Huang, Dan Zhang, Yisan Liu, Pian Liu.

  Fructose-1,6-bisphosphatase 1 (FBP1) is the enzyme that limits the process of gluconeogenesis as it facilitates the hydrolysis of fructose-1,6-bisphosphate(F-1,6-BP) to produce fructose-6-phosphate(F6P) and inorganic phosphate. Gluconeogenesis is the production of glucose from small carbohydrate substrates. The gluconeogenic process is typically suppressed in cancer because it inhibits glycolysis. Apart from its involvement in cellular glucose metabolism, FBP1 also plays a role in gene transcription, mRNA translation and stability regulation, and the immune microenvironment of tumors. Because of its multifaceted functions, the mechanisms by which FBP1 is involved in tumor development are complex. Moreover, FBP1 deficiency is associated with radiation and chemotherapy resistance and poor prognosis in cancer patients. Restoration of FBP1 expression in cancer cells is expected to hold promise for cancer therapy. However, up to now few reviews have systematically summarized the important functional mechanisms of FBP1 in tumorigenesis and the small molecule compounds that restore FBP1 expression. Therefore, this article addresses the question "How does FBP1 contribute to cancer progression, and can targeting FBP1 be a potential therapeutic approach?" by summarizing the effects of FBP1 on cancer development and progression as well as its mediated drug resistance and the future clinical applications of potential small molecule modulators targeting FBP1.

Keywords:  Cancer; Drug resistance; FBP1; Small molecule drugs

DOI:  https://doi.org/10.1007/s12672-025-02112-2
Sci Adv. 2025 Mar 21. 11(12): eads9182

A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.

Mariana Bustamante Eduardo, Gannon Cottone, Curtis W McCloskey, Shiyu Liu, Flavio R Palma, Maria Paula Zappia, Abul B M M K Islam, Peng Gao, Joel Setya, Saya Dennis, Hongyu Gao, Qian Zhang, Xiaoling Xuei, Yuan Luo, Jason Locasale, Marcelo G Bonini, Rama Khokha, Maxim V Frolov, Elizaveta V Benevolenskaya, Navdeep S Chandel, Seema A Khan, Susan E Clare.

Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.

DOI: https://doi.org/10.1126/sciadv.ads9182
Front Immunol. 2025 ;16 1513806

Integration of scRNA-seq and bulk RNA-seq to reveal the association and potential molecular mechanisms of metabolic reprogramming regulated by lactylation and chemotherapy resistance in ovarian cancer.

Fang Ren, Xiaoao Pang, Feng Jin, Nannan Luan, Houhua Guo, Liancheng Zhu.

   Objective: Ovarian cancer (OC) ranks among the foremost causes of mortality in gynecological malignancies, with chemoresistance being the primary factor contributing to unfavorable prognosis. This work seeks to clarify the mechanisms of resistance-related lactylation in OC, intending to offer novel theoretical foundations and therapy strategies for addressing chemoresistance.
Methods: Through the combined analysis of bulk RNA-seq and single-cell RNA-seq data, we initially found lactylation genes linked to chemoresistance. Subsequently, we employed differential expression analysis, survival analysis, enrichment analysis, and other methodologies to further investigate the roles and molecular mechanisms of these genes in tumor resistance. Ultimately, we investigated the differential expression of these genes in resistant and non-resistant tissues and cells via experimentation.
Results: We found two candidate genes associated with lactylation chemoresistance, ALDH1A1 and S100A4. Analysis of single-cell data indicated that tumor cells represent the primary cell subpopulation relevant to resistance studies. Subpopulation analysis indicated that several tumor cell subtypes were markedly linked to resistance, with elevated expression levels of ALDH1A1 and S100A4 in the resistant subpopulation, notably correlating with various immunological and metabolic pathways. Analysis of metabolic pathways indicated that oxidative phosphorylation and glycolysis activity was elevated in the resistant subpopulation, and lactic acid buildup was associated with chemoresistance. The investigation of the marker gene protein-protein interaction network in the resistant subgroup elucidated the intricate interactions among these genes. The expression levels of ALDH1A1 and S100A4 in the OC tissues of the platinum-resistant cohort were markedly elevated compared to the sensitive cohort, with a considerable rise in S100A4 expression observed in resistant OC cells, demonstrating co-localization with lactylation.
Conclusion: This work elucidates the significant function of lactylation in OC chemoresistance and identifies ALDH1A1 and S100A4 as possible genes associated with drug resistance. These findings enhance our comprehension of the mechanisms behind chemoresistance in OC and offer critical insights for the formulation of novel therapeutic options.

Keywords:  ALDH1A1; S100A4; chemoresistance; lactylation; metabolic pathways; ovarian cancer; single cell sequencing

DOI:  https://doi.org/10.3389/fimmu.2025.1513806
J Transl Med. 2025 Mar 18. 23(1): 347

Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer.

Yuqi Guo, Zhiyuan Zhang, Lintao Dong, Xinyi Shi, Xiaohan Li, Mingxiu Luo, Yajuan Fu, Yujing Gao.

   BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related mortality in men globally. While androgen deprivation therapy (ADT) can extend the asymptomatic phase and overall survival of patients with metastatic PCa, prolonged ADT often leads to the development of castration-resistant prostate cancer (CRPC) within 18-24 months. The mechanisms underlying CRPC remain incompletely understood, presenting a significant challenge in clinical prostate cancer treatment.
METHODS: In this study, we investigated the role of Wnt5a, a member of the Wnt family, in CRPC. Tumor tissues from CRPC patients were analyzed to assess the expression levels of Wnt5a. Prostate cancer cells were used to examine the impact of Wnt5a on androgen-dependent and -independent growth, as well as sensitivity to bicalutamide. RNA-seq analysis, qRT-PCR, intracellular cholesterol content and the activation of the androgen receptor (AR) signaling pathway were evaluated to elucidate the mechanistic role of Wnt5a in CRPC progression. Drug target Mendelian randomization analysis was performed to investigate the effect of PCSK9 inhibitor on prostate cancer.
RESULTS: Our study revealed a significant overexpression of Wnt5a in tissues from CRPC tumors. Wnt5a was found to enhance both androgen-dependent and -independent growth in prostate cancer cells while reducing their sensitivity to bicalutamide. Mechanistically, Wnt5a was shown to upregulate intracellular free cholesterol content and activate the AR signaling pathway, contributing to hormone therapy resistance in CRPC. PCSK9 inhibitor significantly reduced the risk of PCa.
CONCLUSIONS: The findings of this study highlight a novel molecular mechanism underlying endocrine therapy resistance in CRPC mediated by Wnt5a. Targeting Wnt5a or reducing cholesterol level would be a promising therapeutic strategy for the treatment of CRPC, providing new insights into potential avenues for combating this challenging form of prostate cancer.

Keywords:  Androgen receptor signaling; Castration resistance; Cholesterol; Prostate cancer

DOI:  https://doi.org/10.1186/s12967-025-06322-8
Cell Death Dis. 2025 Mar 18. 16(1): 184

Monounsaturated fatty acids promote cancer radioresistance by inhibiting ferroptosis through ACSL3.

Yulin Cao, Jiuming Li, Ying Chen, Yuanben Wang, Zhiang Liu, Liuying Huang, Bingxin Liu, Yuyang Feng, Surui Yao, Leyuan Zhou, Yuan Yin, Zhaohui Huang.

Radioresistance is a major challenge in tumor radiotherapy and involves in a mixture of cellular events, including ferroptosis, a new type of programmed cell death characterized by the excess accumulation of iron-dependent lipid peroxides. In the present study, we observed that surviving cancer tissues and cells after radiotherapy had significantly greater glutathione to oxidized glutathione (GSH/GSSG) ratios and lower lipid reactive oxygen species (ROS) and malondialdehyde (MDA) levels than nonirradiated tumors and cells. Untargeted lipidomic analyses revealed that oleic acid (OA) and palmitoleic acid (POA) were the most significantly upregulated unsaturated fatty acids in irradiated surviving cancer cells compared with those in control cancer cells irradiated with IR. Both OA and POA could protect cancer cells from the killing effects of the ferroptosis inducer erastin and RSL3, and OA had a stronger protective effect than POA, resulting in lower lipid ROS production than POA. Mechanistically, OA protected cells from ferroptosis caused by the accumulation of polyunsaturated fatty acid-containing phospholipids in an ACSL3-dependent manner. A mouse model demonstrated that ACSL3 knockdown combined with imidazole ketone erastin synergistically enhanced antitumor effects in radiation-resistant tumors in vivo. Our study reveals previously undiscovered associations between radiation and fatty acid metabolism and ferroptosis, providing a novel treatment strategy for overcoming cancer radioresistance.

DOI: https://doi.org/10.1038/s41419-025-07516-0
Mol Cancer. 2025 Mar 19. 24(1): 83

Lactate accumulation induces H4K12la to activate super-enhancer-driven RAD23A expression and promote niraparib resistance in ovarian cancer.

Bingfeng Lu, Shuo Chen, Xue Guan, Xi Chen, Yuping Du, Jing Yuan, Jielin Wang, Qinghua Wu, Lingfeng Zhou, Xiangchun Huang, Yang Zhao.

  Ovarian cancer is a gynecological malignancy with the highest recurrence and mortality rates. Although niraparib can effectively affect its progression, the challenge of drug resistance remains. Herein, niraparib-resistant ovarian cancer cell lines were constructed to identify the abnormally activated enhancers and associated target genes via RNA in situ conformation sequencing. Notably, the target gene RAD23A was markedly upregulated in niraparib-resistant cells, and inhibiting RAD23A restored their sensitivity. Additionally, abnormal activation of glycolysis in niraparib-resistant cells induced lactate accumulation, which promoted the lactylation of histone H4K12 lysine residues. Correlation analysis showed that key glycolysis enzymes such as pyruvate kinase M and lactate dehydrogenase A were significantly positively correlated with RAD23A expression in ovarian cancer. Additionally, H4K12la activated the super-enhancer (SE) of niraparib and RAD23A expression via MYC transcription factor, thereby enhancing the DNA damage repair ability and promoting the drug resistance of ovarian cancer cells. Overall, the findings of this study indicate that lactic acid accumulation leads to lactylation of histone H4K12la, thereby upregulating SE-mediated abnormal RAD23A expression and promoting niraparib resistance in ovarian cancer cells, suggesting RAD23A as a potential therapeutic target for niraparib-resistant ovarian cancer.

Keywords:  Glycolysis; H4K12la; Niraparib resistance; RAD23A; Super-enhancer

DOI:  https://doi.org/10.1186/s12943-025-02295-w
J Biomed Sci. 2025 Mar 17. 32(1): 36

Metformin sensitizes triple-negative breast cancer to histone deacetylase inhibitors by targeting FGFR4.

Zhangyuan Gu, Fugui Ye, Hong Luo, Xiaoguang Li, Yue Gong, Shiqi Mao, Xiaoqing Jia, Xiangchen Han, Boyue Han, Yun Fu, Xiaolin Cheng, Jiejing Li, Zhiming Shao, Peizhen Wen, Xin Hu, Zhigang Zhuang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by high malignancy, strong invasiveness, and a propensity for distant metastasis, leading to poor prognosis and relatively limited treatment options. Metformin, as a first-line oral hypoglycemic agent, has garnered widespread research interest in recent years due to its potential in cancer prevention and treatment. However, its efficacy varies significantly across different tumor types. Histone deacetylase inhibitors (HDACi), such as SAHA, have demonstrated antitumor activity, but TNBC responds poorly to HDACi monotherapy, possibly due to feedback activation of the JAK-STAT pathway. Exploring the synergistic potential and underlying mechanisms of combining metformin with HDACi in TNBC treatment is crucial.
METHODS: We predicted the synergistic effects of metformin and SAHA in TNBC using multiple computational methods (CMap, DTsyn, and DrugComb). We also developed a cancer-specific compound mimic library (CDTSL) and applied a three-step strategy to identify genes fitting the "metformin sensitization" model. Subsequently, we evaluated the synergistic effects of metformin and SAHA in TNBC cell lines through cell proliferation, colony formation, and apoptosis assays. Furthermore, we investigated the molecular mechanisms of the combined treatment using techniques such as transcriptome sequencing, chromatin immunoprecipitation (ChIP), Western blotting, and measurement of extracellular acidification rate (ECAR). Additionally, we assessed the in vivo antitumor effects of the combined therapy in a nude mouse subcutaneous xenograft model.
RESULTS: CMap, DTsyn, and DrugComb all predicted the synergistic effects of SAHA and metformin in TNBC. The screening results revealed that HDAC10 played a key role in metformin sensitization. We found that the combination of metformin and SAHA exhibited synergistic antitumor effects (combination index CI < 0.9) in TNBC cell lines. Mechanistically, metformin inhibited histone acetylation on FGFR4, thereby blocking the feedback activation of FGFR4 downstream pathways induced by SAHA. Furthermore, metformin interfered with the glycolysis process induced by SAHA, altering the metabolic reprogramming of tumor cells. In in vivo experiments, the combined treatment of metformin and SAHA significantly inhibited the growth of subcutaneous tumors in nude mice.
CONCLUSIONS: Metformin enhances the sensitivity of TNBC to HDAC inhibitors by blocking the FGFR4 pathway and interfering with metabolic reprogramming. When used in combination with SAHA, metformin exhibits synergistic antitumor effects. Our study provides a theoretical basis for the combined application of HDAC inhibitors and metformin, potentially offering a new strategy for the treatment of TNBC.

Keywords:  Drug synergism; Histone deacetylase inhibitors; Metformin; Triple-negative breast neoplasms

DOI:  https://doi.org/10.1186/s12929-025-01129-7
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00203-7. [Epub ahead of print]44(3): 115432

The tumor microenvironment is an ecosystem sustained by metabolic interactions.

Emily Jane Kay, Sara Zanivan.

  Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.

Keywords:  CAFs; CP: Cancer; CP: Metabolism; immune cells; metabolism; stroma immune; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115432
Cancer Sci. 2025 Mar 17.

Lnc-TPT1-AS1/CBP/ATIC Axis Mediated Purine Metabolism Activation Promotes Breast Cancer Progression.

Yiyun Zhang, Hanyu Zhang, Mingcui Li, Yanling Li, Zhuo-Ran Wang, Weilun Cheng, Yansong Liu, Zhengbo Fang, Ang Zheng, Jingxuan Wang, Fei Ma.

  The purine biosynthetic pathway was recently identified to play a crucial role in breast cancer progression. However, little was known about the regulatory mechanisms of long non-coding RNA in breast cancer purine metabolism. In this study, we discovered that LncRNA TPT1-AS1 (TPT1-AS1) was downregulated in breast cancer tissues. Its introduction in breast cancer cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis suggested that the purine biosynthetic pathway was activated in TPT1-AS1-knockdown MCF-7 cells. Inosine monophosphate (IMP), the product of de novo purine biosynthesis, was significantly upregulated. Mechanistically, we found that TPT1-AS1 could physically interact with CBP (CREB-binding protein), which consequently led to the loss of H3K27Ac in the promoter area of ATIC, the key enzyme of IMP synthesis. This process could block breast cancer purine metabolism and inhibit breast cancer progression. In conclusion, our findings illustrate the role of non-coding RNAs in breast cancer purine metabolism reprogramming and present a potential candidate for breast cancer therapy.

Keywords:  ATIC; CBP; Lnc TPT1‐AS1; breast cancer; purine metabolism

DOI:  https://doi.org/10.1111/cas.70045
J Exp Clin Cancer Res. 2025 Mar 20. 44(1): 100

CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer.

Alina Catalina Palcau, Claudio Pulito, Valentina De Pascale, Luca Casadei, Mariacristina Valerio, Andrea Sacconi, Valeria Canu, Daniela Rutigliano, Sara Donzelli, Federica Lo Sardo, Francesca Romana Auciello, Fulvia Pimpinelli, Paola Muti, Claudio Botti, Sabrina Strano, Giovanni Blandino.

   BACKGROUND: Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is poorly studied. Specifically, the impact of circPVT1, a well-known oncogenic circRNA on triple negative breast cancer metabolism is mechanistically underexplored.
METHODS: The clinical significance of circPVT1 expression levels was assessed in human breast cancer samples using digital PCR and the cancer genome atlas (TCGA) dataset. The oncogenic activity of circPVT1 was assessed in TNBC cell lines and in MCF-10 A breast cell line by either ectopic expression or depletion of circPVT1 molecule. CircPVT1 mediated metabolic perturbation was assessed by 1 H-NMR spectroscopy metabolic profiling. The binding of circPVT1 to miR-33a-5p and c-Myc recruitment onto the Glutaminase gene promoter were assessed by RNA immunoprecipitation and chromatin immunoprecipitation assays, respectively. The circPVT1/miR-33a-5p/Myc/GLS1 axis was functionally validated in breast cancer patients derived organoids. The viability of 2D and PDO cell models was assessed by ATP light assay and Opera Phenix plus high content screening.
RESULTS: We initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10 A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1 H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10 A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity promoting transcriptionally glutaminase. This activity facilitates the conversion of glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids.
CONCLUSIONS: In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.

Keywords:  Breast cancer; MYC; Metabolism; Non-coding RNAs; Patients derived organoids

DOI:  https://doi.org/10.1186/s13046-025-03355-1
J Biol Chem. 2025 Mar 14. pii: S0021-9258(25)00258-3. [Epub ahead of print] 108409

Pak1 dysregulates Pyruvate metabolism in PDAC cells by exerting a phosphorylation-mediated regulatory effect on PDHA1.

Sowmiya Murugan, Srikanth Swamy Swaroop B, Prarthana Gopinath, Roshni Saravanan, Sandhya Sundaram, Gouthaman Shanmugasundaram, Ganesh Venkatraman, Suresh Kumar Rayala.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer with the worst prognosis. Treating PDAC poses significant challenges, as tumor cells adapt metabolic alterations to thrive in the hypoxic environment created by desmoplasia surrounding the tumor cells. p21-activated kinase (Pak1), a serine-threonine kinase is found to be upregulated in many solid tumors and promotes tumor progression via diverse signalling pathways. In this study, we focussed on exploring the role of Pak1 in mediating tumor cell metabolism. Deletion of the Pak1 gene reduced the tumorigenic potential of PDAC cells. Also, Pak1 regulated both glycolysis and mitochondrial respiration in PDAC cells, contributing to the Warburg phenomenon. Untargeted metabolomic analysis revealed that Pak1 was strongly associated with Pyruvate metabolism. Interestingly, we found that Pak1 interacted and phosphorylated Pyruvate dehydrogenase E1α (PDHA1) at Serine 152. This phosphorylation negatively regulates PDHA1 activity, implying the direct regulatory role of Pak1 in Pyruvate metabolism. Moreover, deleting the Pak1 gene altered the expression and activity of PDHA1 and LDHA, as both are involved in regulating the direction of pyruvate flux inside the cells. Our study demonstrated that Pak1 plays a significant role in PDAC metabolism and Warburg effect, partly by phosphorylating PDHA1.

Keywords:  PDAC; Pak1; Pyruvate dehydrogenase; Warburg effect

DOI:  https://doi.org/10.1016/j.jbc.2025.108409