bims-meract 2025-12-07 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–12–07
twenty-one papers selected by
Andrea Morandi, Università degli Studi di Firenze

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.
STARD4 suppresses tumorigenesis and attenuates enzalutamide resistance via lipid metabolic reprogramming and AR stabilization in prostate cancer.
Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.
SLBP Promotes Lung Adenocarcinoma Progression by Inhibiting Ferroptosis and Reprogramming Glutamine Metabolism via FADS2 Interaction.
AGR2 suppresses ferroptosis via the p53/FPN1 regulatory axis and drives therapeutic vulnerabilities in pancreatic cancer.
IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer.
Aberrant sialic acid metabolism promotes metabolic reprogramming and metastasis in breast cancer.
Adaptability of lung and liver metastatic breast cancer cells to glucose.
Mitochondrial Metabolic Reprogramming along with NRF2/KEAP1-Mediated Antioxidant Mechanisms Drive Temozolomide Resistance in Glioblastoma Multiforme.
Tumor peripheral stiffness modulates lenvatinib resistance in HCC preclinical models by regulating FIS1-dependent mitophagy.
Sodium's role and therapeutic targeting in cancer.
LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment.
Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity.
Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.
Post-translational switch of DHCR24 acetylation sustains sterol synthesis and promotes HCC via the 7-ketocholesterol/p62 axis.
Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.
Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration.
NQO1 as a predictor of response to adjuvant GemCap treatment for pancreatic cancer.
A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.
Targeting emerging amino acid dependencies and transporters in cancer therapy.
Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.

bioRxiv. 2025 Nov 17. pii: 2025.11.17.688927. [Epub ahead of print]

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.

Kelley R McCutcheon, Josh Wu, Yasemin Ceyhan Ozdemir, Brock J McKinney, Sharan Srinivasan, Ayaha Itokawa, Oliver J Newsom, Anna Vigil, Douglas B Fox, Lucas B Sullivan, James V Alvarez.

Breast cancer recurrence remains a major clinical challenge, often associated with therapy resistance and altered metabolic states. To define metabolic vulnerabilities of recurrent disease, we performed a CRISPR knockout screen targeting 421 metabolic genes in paired primary and recurrent HER2-driven breast cancer cell lines. While both primary and recurrent tumors shared dependencies on core metabolic pathways, recurrent tumors exhibited selective essentiality for the de novo pyrimidine synthesis pathway, including Cad , Dhodh , and Ctps . Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant. BAY treatment robustly inhibited pyrimidine synthesis in all lines, but only recurrent cells underwent iron-dependent lipid peroxidation and ferroptotic cell death. Lipidomic profiling revealed enrichment of polyunsaturated ether phospholipids in recurrent cells, which may predispose them to ferroptosis. A sensitizer CRISPR screen in primary cells further identified nucleotide salvage and lipid metabolic pathways as modifiers of DHODH inhibitor sensitivity. Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28 / Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.

DOI: https://doi.org/10.1101/2025.11.17.688927
J Exp Clin Cancer Res. 2025 Dec 02.

STARD4 suppresses tumorigenesis and attenuates enzalutamide resistance via lipid metabolic reprogramming and AR stabilization in prostate cancer.

Yi Zhang, Xi Wang, Jiuyi Wang, Ke Ma, Lei Jia, Bo Liu, Xianglin Yuan, Qiang Li, Qinzhang Wang, Qinyu Li, Kai Zeng.

   BACKGROUND: Prostate cancer (PCa) is a globally prevalent malignancy in males and is imposing an increasing epidemiological burden. The androgen receptor (AR) signalling axis is fundamentally implicated in PCa tumorigenesis and disease progression. Although androgen deprivation therapy (ADT) elicits transient therapeutic responses in the majority of cases, progression to castration-resistant prostate cancer (CRPC) remains an almost universal clinical trajectory. Dysregulated lipid homeostasis, manifesting as intracellular lipid deposition, has been mechanistically linked to CRPC pathogenesis and therapeutic failure under enzalutamide regimens. However, effective strategies to mitigate lipid accumulation in PCa remain elusive.
METHODS: STARD4, a key gene involved in lipid metabolism, was identified as functionally significant in PCa through integrated bioinformatics analysis of public databases. RT‒qPCR, western blot analysis, and IHC staining were performed to evaluate STARD4 expression, while Kaplan-Meier survival analysis, Gleason score, and tumor stage were performed to assess its clinical significance in PCa. The biological functions of STARD4 and its contribution to enzalutamide resistance were elucidated through in vitro and in vivo experiments. The effect of STARD4 on abnormal lipid accumulation in PCa cells was evaluated by Oil Red O (ORO) staining, while its impact on endoplasmic reticulum (ER) stress was assessed through ER-tracking imaging and transmission electron microscopy (TEM). Mechanistic exploration involves a combination of techniques, including RNA-seq analysis, Gene ontology analysis, coimmunoprecipitation (Co-IP), and GST pull-down assay, to analyse the interactions and potential mechanisms involving STARD4, AR, and E3 ubiquitin ligase UBE4B.
RESULTS: In this study, we observed that STARD4 expression was markedly reduced in PCa tissues and was correlated with an adverse prognosis. STARD4 overexpression inhibited PCa cell proliferation, migration, and lipid accumulation while promoting apoptosis through ER stress. Mechanistically, STARD4 enhanced the interaction between UBE4B and AR, facilitating AR ubiquitination and degradation and thus suppressing AR signalling. Additionally, the upregulation of STARD4 expression enhanced sensitivity to enzalutamide in resistant cells by diminishing lipid accumulation and inhibiting the AR signalling pathway. In summary, STARD4 functions as a tumour suppressor in PCa by regulating cholesterol metabolism and modulating AR signalling.
CONCLUSIONS: Our findings identify STARD4 as a promising therapeutic target for reversing enzalutamide resistance in PCa while also providing novel insights for future research on lipid metabolism within the tumour microenvironment.

Keywords:  Androgen receptor; Enzalutamide resistance; Lipid metabolism; Prostate cancer; STARD4

DOI:  https://doi.org/10.1186/s13046-025-03600-7
Acta Neuropathol Commun. 2025 Nov 29.

Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.

Shigeo Ohba, Akiyoshi Hirayama, Takao Teranishi, Keisuke Hitachi, Hisateru Yamaguchi, Kazuhiro Murayama, Manabu Natsumeda, Kensuke Tateishi, Kunihiro Tsuchida, Hiroaki Wakimoto, Hideyuki Saya, Russell Pieper, Yuichi Hirose.

  Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.

Keywords:  Asparagine; Cancer metabolism; Glioma; Glutaminolysis; Isocitrate dehydrogenase

DOI:  https://doi.org/10.1186/s40478-025-02193-8
Exp Cell Res. 2025 Dec 02. pii: S0014-4827(25)00449-5. [Epub ahead of print] 114849

SLBP Promotes Lung Adenocarcinoma Progression by Inhibiting Ferroptosis and Reprogramming Glutamine Metabolism via FADS2 Interaction.

Wei Yan, Pengfei Xu, Dan Xiao, Dong Hong, Huiqun Liu, Yigang Liu, Yaqi Wang, Tanxiu Chen, Anwen Liu.

  SLBP is significantly overexpressed in lung adenocarcinoma (LUAD) and correlates strongly with poor patient prognosis. Functional studies demonstrated that SLBP potently enhances proliferation, invasion, and metastasis of LUAD cells both in vitro and in vivo. Mechanistically, SLBP suppresses ferroptosis-a form of regulated cell death-by modulating key biochemical markers, including GSH, MDA, and Fe2+ levels, and it restores cell viability upon treatment with ferroptosis inducers. RNA-seq and biochemical analyses revealed that SLBP transcriptionally upregulates and stabilizes SLC7A11, a critical ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death. Additionally, immunopurification and mass spectrometry (IP-MS) identified FADS2 as a novel SLBP-interacting partner. SLBP binds to FADS2, promotes its expression, and drives metabolic reprogramming toward glutamine dependency, significantly altering choline and metal ion metabolism. This metabolic shift enhances cellular proliferation under nutrient stress. Crucially, SLBP-mediated proliferation was shown to be functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth without affecting SLBP levels. Collectively, these results uncover SLBP as a multifunctional oncoprotein that promotes LUAD progression through dual mechanisms: inhibiting ferroptosis via SLC7A11 and rewiring glutamine metabolism through FADS2, offering new potential targets for therapeutic intervention.

Keywords:  FADS2; Ferroptosis; Glutamine metabolism; LUAD; SLBP; SLC7A11

DOI:  https://doi.org/10.1016/j.yexcr.2025.114849
Cell Death Dis. 2025 Dec 01. 16(1): 877

AGR2 suppresses ferroptosis via the p53/FPN1 regulatory axis and drives therapeutic vulnerabilities in pancreatic cancer.

Ziying Jian, Jialin Song, Liangqi Lu, Tao Pan, Hanzhe Zhang, Qi Zhang, Weiyu Zhang, Renjie Li, Jizhou Gong, Naipeng Shi, Shi Zuo, Tao Cheng, Yuhong Yang, Zhiheng Zhang.

Ferroptosis has emerged as a potential therapeutic target in cancer. This study shows the critical role of AGR2 in ferroptosis suppression across pancreatic cancer cell lines and in vivo models. Notably, human pancreatic cancer cells exhibit dose-dependent AGR2 upregulation upon exposure to ferroptosis inducers. Genetic ablation of AGR2 significantly sensitizes cells to ferroptosis through a p53-mediated mechanism, while p53 knockdown effectively rescues ferroptosis resistance. Mechanistic investigations demonstrate that AGR2 deficiency activates p53 signaling, downregulating the iron exporter SLC40A1 (encoding ferroportin/FPN1), inducing intracellular iron overload and consequent ferroptosis. Clinically, we find a positive correlation between AGR2 and FPN1 expression in PDAC specimens, with co-elevation of both markers predicting unfavorable patient prognosis. Therapeutically, administration of an AGR2-targeting peptide synergizes with ferroptosis inducers, significantly enhancing cell death in PDAC models. Our findings not only elucidate a novel AGR2/p53/FPN1 regulatory axis in ferroptosis control but also propose innovative combination strategies for pancreatic cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-08263-y
Mol Cancer Ther. 2025 Dec 05.

IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer.

Amy R Leslie, Shu Ning, Masuda Sharifi, Zachary A Schaaf, James P Maine, Wei Lou, Kristina D Leslie, Chengfei Liu, Hongyu Xu, Alan P Lombard, Hong-Wu Chen, Mamta Parikh, Marc Dall'Era, Allen C Gao.

Enzalutamide resistance remains a significant challenge in the treatment of advanced prostate cancer. Identifying molecular drivers of enzalutamide resistance is crucial for developing effective therapeutic strategies. In this study, we identify insulin-like growth factor binding protein 3 (IGFBP3) as a key driver of enzalutamide resistance in castration-resistant prostate cancer (CRPC). We demonstrate that IGFBP3 expression is significantly upregulated in enzalutamide-resistant C4-2B MDVR cells compared to parental C4-2B cells. This upregulation was consistently observed across multiple enzalutamide-resistant CRPC models, including LNCaP-derived 42D and 42F cells, as well as long-term enzalutamide-resistant cell lines derived from LNCaP, VCaP, LAPC-4, and CWR-R1 cells. Additionally, Enzalutamide treatment directly induced IGFBP3 expression in sensitive cells. Elevated IGFBP3 expression was also observed in CRPC patient samples post-enzalutamide treatment and was associated with higher Gleason scores and reduced disease-free survival. Mechanistically, IGFBP3 activates the sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway, which promotes cell survival and resistance to enzalutamide. IGFBP3 knockdown decreased SphK1 expression, reduced S1P secretion, and enhanced enzalutamide sensitivity, whereas IGFBP3 overexpression induced SphK1 expression and S1P production, conferring enzalutamide resistance. Inhibition of IGFBP3 via siRNA reduced cell viability, induced apoptosis, and re-sensitized resistant models to enzalutamide. Similarly, targeting SphK1 with the inhibitor SKI-II suppressed SphK1 activity, reduced S1P production, enhanced enzalutamide sensitivity, and significantly inhibited resistant tumor growth while enhancing enzalutamide sensitivity. Collectively, these findings highlight IGFBP3-mediated SphK1 signaling as a critical mediator of enzalutamide resistance and suggest that targeting the IGFBP3/SphK1/S1P axis represents a promising therapeutic strategy to overcome resistance in advanced prostate cancer.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0644
Front Oncol. 2025 ;15 1698087

Aberrant sialic acid metabolism promotes metabolic reprogramming and metastasis in breast cancer.

Longyu Yang, Zhenhua Li, Meijin Wang, Xing Xiong, Shilin Zhang, Zhi Man, Chunyan Dong, Li Fu.

   Background: Dysregulated tumour metabolism is increasingly recognised as a central driver of malignant phenotypes. Against this background, the aberrant metabolism of N-acetylneuraminic acid (Neu5Ac), a core constituent of the sialic acid family, and its impact on breast cancer progression is now receiving significant research attention.
Methods: The purpose of this study is to employ metabolomic approaches to analyze and interpret differences in metabolite profiles connected to breast cancer. Following this, a comprehensive multi-omics analysis will be employed to reveal the differences at transcriptional and metabolic levels in cells after the addition of external sialic acid. Finally, modification proteomics will be applied to recognize and characterize proteins that have different sialylation patterns.
Results: Cells treated with sialic acid showed improved motility, underwent metabolic reprogramming, and experienced a significant rise in the sialylation levels of key proteins.
Conclusion: This study collectively elucidates the role of Neu5Ac metabolism in promoting breast cancer invasion and metastasis through the remodeling of lipid metabolic pathways and alterations in protein sialylation. The findings present novel evidence supporting the targeting of sialic acid metabolism and its modifications as potential therapeutic strategies for inhibiting tumor progression.

Keywords:  Neu5Ac; breast cancer; metabolic reprogramming; metastasis; sialylation

DOI:  https://doi.org/10.3389/fonc.2025.1698087
Cancer Cell Int. 2025 Oct 24. 25(1): 374

Adaptability of lung and liver metastatic breast cancer cells to glucose.

Marjorie Anne Layosa, Madeline P Sheeley, Alekya Raghavan, Chaylen Andolino, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.

   BACKGROUND: Breast cancer is the most common cancer among women, and metastasis is the leading cause of mortality. It is still unknown how breast cancer cells metabolically adapt to successfully metastasize to different organs to survive adverse conditions, including varying nutrient availability. The purpose of this study is to elucidate the metabolic characteristics and glucose adaptation mechanisms of breast cancer cells that preferentially metastasize to the lungs or the liver.
METHODS: Using a Wnt-driven breast cancer model with preferential metastasis to lung (metM-WntLung) or liver (metM-WntLiver), we measured 14C-glucose uptake, 13C6-glucose metabolic flux, metabolic enzyme levels, and cell viability under normal (5 mM), high (25 mM), and low (1 or 0 mM) glucose conditions.
RESULTS: Under normal glucose conditions, metM-WntLung cells were more glycolytic, exhibiting greater flux of 13C6-glucose-derived carbons into glycolytic intermediates, such as pyruvate and lactate. In contrast, metM-WntLiver cells favored oxidative phosphorylation, with higher levels of 13C6-glucose-derived carbons in tricarboxylic acid (TCA) cycle metabolites such as oxaloacetate indicative of higher pyruvate carboxylase (PC) activity. Exposure to high glucose reduced metM-WntLiver cell viability, with no effect on metM-WntLung cells, suggesting better adaptability of metM-WntLung cells to glucose excess. This was accompanied by increased PC activity and oxidative phosphorylation in metM-WntLung cells, whereas metM-WntLiver cells shifted to a more glycolytic phenotype. Under glucose deprivation, metM-WntLung cells were more viable than metM-WntLiver cells, suggesting that metM-WntLung cells have better adaptability to glucose deprivation. Inhibiting phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis, reduced metM-WntLung cell viability compared to metM-WntLiver cells. Similarly, inhibiting catabolism of glutamine, a gluconeogenic substrate, decreased metM-WntLung cell viability compared to metM-WntLiver cells, indicating that metM-WntLung cells rely on more on gluconeogenesis and glutamine metabolism under glucose deprivation.
CONCLUSION: Our findings reveal that metM-WntLung cells exhibit greater metabolic flexibility to glucose than metM-WntLiver cells by shifting from glycolysis to oxidative phosphorylation under high glucose conditions while utilizing gluconeogenesis and glutamine under glucose deprivation conditions.

Keywords:  Breast cancer; Glucose; Metabolic adaptation; Metastasis

DOI:  https://doi.org/10.1186/s12935-025-04006-3
J Proteome Res. 2025 Dec 05.

Mitochondrial Metabolic Reprogramming along with NRF2/KEAP1-Mediated Antioxidant Mechanisms Drive Temozolomide Resistance in Glioblastoma Multiforme.

Manendra Singh Tomar, Chirag Kulkarni, Kaveri R Washimkar, Shobhit Verma, Amita Bhadkaria, Fabrizio Araniti, Madhav Nilakanth Mugale, Naibedya Chattopadhyay, Ashutosh Shrivastava.

  Temozolomide (TMZ) is a frontline chemotherapeutic agent for glioblastoma multiforme (GBM); however, approximately half of patients develop resistance to therapy. This study investigates the role of altered cellular bioenergetics and metabolism in the acquired TMZ resistance. Using untargeted metabolomics, we explored the metabolic rewiring in TMZ-resistant GBM cells and identified key alterations in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, and amino acid metabolism, all might be linked to cellular proliferation. Our findings suggest that while glycolysis remains important, increased TCA cycle activity contributes to the drug resistance, supported by increased levels of mitochondrial mass and mitochondrial membrane potential. We observed significantly elevated glutamine levels, which may enhance mitochondrial activity, thereby supporting increased energy production. Furthermore, resistant cells exhibited enhanced NRF2 level in parallel with higher levels of antioxidants, including glutathione and catalase enzyme, and a concomitant decrease in the level of its negative regulator, KEAP1. These factors collectively may contribute to drug resistance by mitigating oxidative stress. These findings indicate that mitochondrial metabolic reprogramming and NRF2/KEAP1-mediated antioxidant defense mechanisms play a crucial role in TMZ resistance, and targeting these pathways may offer a novel strategy to overcome resistance in GBM therapy.

Keywords:  drug resistance; glioblastoma multiforme; mitochondria metabolism; oxidative stress; temozolomide

DOI:  https://doi.org/10.1021/acs.jproteome.5c00734
JHEP Rep. 2025 Dec;7(12): 101588

Tumor peripheral stiffness modulates lenvatinib resistance in HCC preclinical models by regulating FIS1-dependent mitophagy.

Kunjin Wu, Jing Li, Yunong Fu, Kaibo Yang, Ting Lin, Yaohui Wang, Ming Wang, Yunxiang Long, Fengping Zhang, Bo Cheng, Yuan Li, Cong Wang, Feng Xu, Chang Liu, Kai Qu.

   Background & Aims: Hepatocellular carcinoma (HCC) displays heterogeneous responses to lenvatinib, with tumor microenvironment (TME) stiffness emerging as a key resistance modulator. This study investigates how tumor peripheral stiffness governs lenvatinib efficacy via mitochondrial fission/mitophagy and evaluates matrix-targeting combination therapies.
Methods: Clinical HCC tissues underwent stiffness measurement (atomic force microscopy [AFM]/rheometry) and survival correlation analyses. In vitro, cells grown on soft vs. stiff hydrogels (5 vs. 15 kPa) were assessed for their lenvatinib response, mitophagy, and mitochondrial fission 1 (FIS1)-trimethylation of histone H3 lysine 27 (H3K27me3) regulation. Subcutaneous xenografts received collagenase-lenvatinib combination therapy.
Results: Elevated tumor peripheral stiffness, quantified by AFM and rotational rheometry, was significantly associated with HCC recurrence. Patients with stiff peripheries exhibited reduced recurrence-free survival (p <0.05), correlating with upregulated mitophagy markers (Parkin and FIS1) and diminished H3K27me3 in high-stiffness human HCC tissues (p <0.0001). In vitro, HCC cells on stiff matrices (15 kPa) showed attenuated lenvatinib-induced apoptosis (TUNEL: p = 0.0003 vs. soft 5 kPa) and preserved mitochondrial membrane potential (JC-1: p = 0.0004), concomitant with fragmented mitochondria driven by FIS1 upregulation via H3K27me3 depletion at its promoter (chromatin immunoprecipitation: p <0.0001). FIS1 knockdown reversed mitochondrial fragmentation (p <0.001) and resensitized cells to lenvatinib. Stiffness amplified cytoprotective mitophagy under lenvatinib stress, evidenced by enhanced LC3/TOM20 colocalization (p = 0.0008) and mitochondrial Parkin accumulation. In vivo, collagenase-mediated matrix softening synergized with lenvatinib, suppressing tumor growth (volume: p <0.001; weight: p <0.001) while reducing FIS1/Parkin expression and augmenting apoptosis.
Conclusions: Tumor peripheral stiffness drives lenvatinib resistance in HCC via H3K27me3-mediated FIS1 upregulation, triggering mitochondrial fission and cytoprotective mitophagy to evade drug-induced apoptosis. Targeting matrix stiffness (via collagenase-mediated softening) synergizes with lenvatinib to overcome microenvironment-driven resistance, providing a novel mechanoadjuvant strategy for HCC therapy.
Impact and implications: This study shows that tumor peripheral matrix stiffness reduces lenvatinib sensitivity in HCC by enhancing FIS1-dependent mitophagy, explaining therapeutic response heterogeneity. These findings are clinically relevant, highlighting tumor stiffness as a potential biomarker for lenvatinib resistance and mitophagy as a targetable pathway. Clinically, stiffness assessments (e.g. imaging/biopsy) could be used to stratify patients for personalized treatment. Combining lenvatinib with matrix-softening agents or mitophagy inhibitors could improve efficacy. However, translational potential requires validation in larger cohorts and development of non-invasive stiffness measurement methods, given challenges associated with the clinical application of current invasive techniques or collagenase-based preclinical models.

Keywords:  Hepatocellular carcinoma; Lenvatinib sensitivity; Mechanical microenvironment; Mechanomedicine; Mitochondrial fission; Mitophagy

DOI:  https://doi.org/10.1016/j.jhepr.2025.101588
Trends Pharmacol Sci. 2025 Nov 28. pii: S0165-6147(25)00239-1. [Epub ahead of print]

Sodium's role and therapeutic targeting in cancer.

Junsha An, Limei Zhang, Yue Duan, Shuang Pu, Fu Peng.

  Cancer cells exhibit unique metabolic reprogramming characterized by a significant increase in intracellular sodium ion levels. Sodium influences cancer cell metabolism, immune function, and drug resistance, and can trigger a unique cell death pathway when overloaded. Sodium-related transporters regulate cellular sodium ion levels and cancer progression. Targeting these transporters with specific inhibitors might therefore be an effective way to treat cancer. However, the precise relationship between sodium and cancer cell behavior is insufficiently studied and our understanding of the relevant transporters remains inadequate. In this review we summarize current understanding of the role of sodium in cancer. We analyze the impact of sodium-related transporters on cancer and current therapeutic strategies that target these transporters. We also highlight key challenges and discuss potential strategies for future investigations.

Keywords:  cancer; immune response; metabolism; sodium; transporter

DOI:  https://doi.org/10.1016/j.tips.2025.10.015
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2505653122

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment.

Jeffrey Reina, Queralt Vallmajo-Martin, Jia Ning, Aubrey N Michi, Kay Yeung, Geoffrey M Wahl, Tony Hunter.

  Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify potential therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not significantly affect overall phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP's role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results support a tumor promoter role for LHPP phosphohistidine phosphatase in MDA-MB-231TNBC cells and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC.

Keywords:  LHPP; TNBC; phosphatase; phosphohistidine

DOI:  https://doi.org/10.1073/pnas.2505653122
Blood Adv. 2025 Dec 03. pii: bloodadvances.2024015408. [Epub ahead of print]

Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity.

Thomas Lefeivre, Theodora-Ioana Grosu, Cosmin Tudose, Luke Jones, Theresa Elizabeth Leon, Kieran Wynne, Giorgio Oliviero, Owen Smith, Amélie Trinquand, Marc R Mansour, Colm J Ryan, Jonathan Bond.

Loss-of-function mutations and deletions in core components of the epigenetic Polycomb Repressive Complex 2 (PRC2) are associated with poor initial treatment response in T-acute lymphoblastic leukemia (T-ALL), but the mechanisms that underpin resistance to individual therapies are unknown. We leveraged an isogenic T-ALL cellular model and primary patient data to investigate how PRC2 alterations affect signaling pathway activity in leukemia cells, and whether these changes may influence therapy response. Integration of transcriptomic, proteomic and phosphoproteomic results revealed markedly reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in leukemia cells lacking core PRC2 factor EZH2. Importantly, these results closely matched transcriptional readouts from T-ALL patient samples with PRC2 mutations and deletions. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels due to WNT/STOP suppression that bolstered leukemia cell asparagine reserves. These results also strongly correlated with transcriptional profiles of asparaginase resistance in an independent T-ALL patient cohort. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a potential avenue to tackle induction treatment failure in these cases.

DOI: https://doi.org/10.1182/bloodadvances.2024015408
Res Sq. 2025 Nov 19. pii: rs.3.rs-7682325. [Epub ahead of print]

Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.

Lee Graves, Sabrina Daglish, Owen Canterbury, Paul Graves, Sarah Carter, Sydney Beese, Maggie Hynek, Brandon Mouery, Andrei Mistreanu, Aadra Bhatt, Nestor Tellez, Mitchell Butler, Lucas Aponte-Collazo, Emily Fennell, Laura Herring, Scott Lyons, C Mills, Hani Ashamalla, Edwin Iwanowicz, John Morris Iv, James Bear, Yoshimi Greer, Stanley Lipkowitz.

ONC201 is a first-in-class, FDA approved small molecule activator of the mitochondrial ATP-dependent caseinolytic peptidase P (ClpP). This and other related small molecules referred to as ClpP agonists, exert antiproliferative effects in several cancer cell types. We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines. Senescence was determined by increased β-galactosidase activity, downregulation of phosphorylated Rb, c-Myc (Myc), and lamin B1, upregulation of senescent-associated secretory phenotype (SASP), and extended cell proliferation assays. These responses were not observed in ClpP knockout cell lines, demonstrating ClpP-dependence. Proteomics analyses identified multiple events related to the development of senescence including cell cycle arrest and mitochondrial dysfunction. Flow cytometry confirmed an S-phase arrest; DNA damage was detected by Comet assay, 53BP1, phospho-S*Q, and γH2A.X immunostaining. In parallel with this, activation of the ATM pathway and phosphorylation of Chk2 was observed. We determined that ClpP agonist-induced senescence was irreversible in both in vitro and in vivo studies. Following TR-57 treatment and drug washout, cells remained growth arrested which coincided with the loss of Myc protein. By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout. This response was reproduced in vivo wherein senescent 4T1-Luc cells did not develop tumors following injection into mice. Finally, the combination of a ClpP agonist with a known senolytic (venetoclax), synergistically increased the amount of cell death observed. Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.

DOI: https://doi.org/10.21203/rs.3.rs-7682325/v1
Cell Rep. 2025 Dec 04. pii: S2211-1247(25)01412-3. [Epub ahead of print]44(12): 116640

Post-translational switch of DHCR24 acetylation sustains sterol synthesis and promotes HCC via the 7-ketocholesterol/p62 axis.

Yunfei Zhou, Xinxin Yang, Jianwen Xu, Yidi Wu, Yin Fu, Yihong Dong, Xun Yang, Qiang Fu, Chenxu Guo, Yunjing Hou, Shuyuan Chang, Jun Yan, Ju Ran, Yumeng Wang, Qingxin Zhang, Tomii Ayaka, Lei Yu, Feng Geng, Liuyang Zhao, Xiaoyang Hu, Shuijie Li, Hongxue Meng, Dabin Liu.

  Dysregulated cholesterol synthesis fuels cancer progression, but its precise role in hepatocellular carcinoma (HCC) remains unclear. Here, we identify elevated acetylation of 24-dehydrocholesterol reductase (DHCR24) at Lys254 as a hallmark of HCC. Both total DHCR24 and its K254 acetylation independently predict poor patient survival. Acetylation stabilizes DHCR24, sustaining hepatic cholesterol synthesis and promoting tumorigenesis. Mechanistically, DHCR24 acetylation enhances 7-ketocholesterol accumulation, which upregulates p62 and drives HCC growth in vitro and in vivo. Pharmacologic inhibition of DHCR24 expression and acetylation with the US Food and Drug Administration (FDA)-approved drug irbesartan suppresses cell proliferation and reduces tumor burden in xenograft and carcinogen-induced mouse models. Reduced p62 expression parallels the antitumor effects. These findings define DHCR24 acetylation as a metabolic switch linking sterol synthesis to oncogenesis and highlight the DHCR24-7-ketocholesterol-p62 axis as a therapeutic target for HCC.

Keywords:  7-ketocholesterol; CP: cancer; DHCR24 acetylation; cholesterol metabolism; hepatocellular carcinoma; irbesartan; p62-autophagy axis; targeted therapy

DOI:  https://doi.org/10.1016/j.celrep.2025.116640
Res Sq. 2025 Nov 19. pii: rs.3.rs-7983397. [Epub ahead of print]

Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.

Juan Cubillos-Ruiz, Deepika Awasthi, Erin McMinn, Camilla Salvagno, Sung-Min Hwang, Tito Sandoval, Chang-Suk Chae, Wiam Madani, Jacqueline Crater, Kaushik Sen, Daniel Min, Alexander Emmanuelli, Chen Tan, Andrew Dannenberg, Diana Morales, Evelyn Cantillo, Eloise Chapman-Davis, William Zhang, Suzanne Cloonan.

Dendritic cells (DCs) orchestrate adaptive immune responses to pathogens and tumors, yet how dietary lipids influence DC metabolism and function remains largely unexplored. Here we show that dietary polyunsaturated fatty acids (PUFAs) govern DC activity via Nuclear factor erythroid 2-like 2 (Nrf2)-dependent control of ferroptosis. In mice, an n-6 PUFA-enriched diet suppressed DC Nrf2 signaling, depleted glutathione, and induced lipid peroxidation and ferroptosis, thereby compromising antigen presentation. By contrast, dietary n-3 PUFAs enhanced Nrf2 signaling and redox homeostasis, preserving DC integrity and T cell priming. Pharmacologic Nrf2 activation or ferroptosis inhibition restored the function of DCs from n-6 PUFA-fed mice. Notably, adoptive immunotherapy with DCs conditioned by a diet rich in n-3 PUFAs-but not n-6 PUFAs-elicited durable, T cell-dependent control of metastatic ovarian cancer. These findings identify dietary PUFAs as key modulators of the Nrf2-glutathione-ferroptosis axis in DCs and reveal a redox-sensitive metabolic checkpoint that can be leveraged to improve cancer immunotherapy.

DOI: https://doi.org/10.21203/rs.3.rs-7983397/v1
Nat Commun. 2025 Dec 04.

Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration.

Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Ekaterina Eremenko, Miguel Portillo, Monica Einav, Alena Bruce Krejci, Uri Abdu, Ekaterina Khrameeva, Daniel Gitler, Sarah-Maria Fendt, Debra Toiber.

In the brain, tryptophan byproducts are involved in the biosynthesis of proteins, energy-rich molecules (e.g., NAD+), and neurotransmitters (serotonin and melatonin). Impaired tryptophan catabolism, seen in aging, neurodegeneration and psychiatric diseases, affects mood, learning, and sleep; however, the reasons for those impairments in the elderly and in those suffering from these ailments remain unknown. Our results from cellular, Drosophila melanogaster, and mouse models indicate that Sirtuin 6 (SIRT6) regulates tryptophan catabolism by balancing its usage. Mechanistically, SIRT6 regulates tryptophan and sleep quality through changes in gene expression of key genes (e.g., TDO2, AANAT), which results in elevated concentration of neurotoxic metabolites from the kynurenic pathway at the expense of serotonin and melatonin production. Such neurotoxic metabolites can affect various processes in the brain. However, by redirecting tryptophan through TDO2 inhibition in a SIRT6 knockout D. melanogaster model, the impairments in neuromotor behavior and vacuolar formation - parameters of neurodegeneration - can be significantly reversed.

DOI: https://doi.org/10.1038/s41467-025-67021-y
J Natl Cancer Inst. 2025 Dec 01. pii: djaf345. [Epub ahead of print]

NQO1 as a predictor of response to adjuvant GemCap treatment for pancreatic cancer.

Dylan Williams, Chandni Patel, Kate Murray, Lucy Oldfield, Benjamin Small, Lawrence N Barrera, Rachel O'Sullivan, James Birch-Ford, Anthony Evans, Fiona Campbell, Pedro A Perez-Mancera, Christopher M Halloran, Daniel Palmer, William Greenhalf, Ian M Copple, Chris Goldring, Thilo Hackert, Richard Jackson, John P Neoptolemos, Christoph Springfeld, Markus W Büchler, Christoph W Michalski, Paula Ghaneh, Eithne Costello.

   BACKGROUND: NAD(P)H Quinone Dehydrogenase 1 (NQO1), a detoxification enzyme regulated by the Nrf2 cytoprotective pathway, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). NQO1 levels are also influenced by the C609T single nucleotide polymorphism (SNP). We hypothesised that elevated NQO1 would confer chemoresistance in PDAC and predict poor patient outcome.
METHODS: NQO1 tumor levels and germline C609T SNP status were assessed in archival samples from the European Study Group for Pancreatic Cancer (ESPAC) trials. NQO1 expression (H-score) was treated as continuous for survival regression analyses and dichotomised for visual summaries. Nrf2 or downstream gene induction was assessed in Nrf2 reporter mice or in PDAC cells following exposure to gemcitabine (Gem), 5-fluorouracil (5-FU) or the capecitabine (Cap) metabolite 5-Fluoro-5'-deoxyuridine (5'-DFUR). Colony formation following NQO1 depletion was assessed.
RESULTS: NQO1 tumor levels correlated with germline C609T SNP status (p < .001). Contrary to our hypothesis, high NQO1 expression was associated with improved survival in ESPAC-4 patients randomised to GemCap (HR 0.87 (0.751, 0.999); P = .049), and had no association to outcome in the Gem-only treated arm [HR: 0.98 (0.78, 1.23) P = .867]. Including genotype data did not improve predictive model performance. Neither Gem nor 5-FU induced Nrf2 in vivo. At high concentrations they suppressed Nrf2/NQO1 in PDAC cells, an effect not mitigated by co-treatment with 5'-DFUR. NQO1 depletion experiments revealed that NQO1 inhibits colony formation. The strongest inhibition was observed when NQO1-positive cells were co-treated with Gem and 5'-DFUR, supporting our clinical data from ESPAC.
CONCLUSION: High tumor NQO1 predicts better outcome following GemCap therapy.

Keywords:  Gem; GemCap; NQO1; Nrf2; biomarker; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1093/jnci/djaf345
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2523039122

A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.

Vasiliki Liaki, Sara Barrambana, Myrto Kostopoulou, Carmen G Lechuga, Elena Zamorano-Dominguez, Domingo Acosta, Lucia Morales-Cacho, Ruth Álvarez, Pian Sun, Blanca Rosas-Perez, Rebeca Barrero, Silvia Jiménez-Parrado, Alejandra López-García, Marta San Roman, Juan Carlos López-Gil, Matthias Drosten, Bruno Sainz, Monica Musteanu, Eduardo Caleiras, Nelson Dusetti, Valeria Poli, Francisco Sánchez-Bueno, Carmen Guerra, Mariano Barbacid.

  Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Recent studies using RAS inhibitors have opened the door to more efficacious therapies, although their beneficial effect is still limited mainly due to the rapid appearance of tumor resistance. Here, we demonstrate that genetic ablation of three independent nodes involved in downstream (RAF1), upstream (EGFR), and orthogonal (STAT3) KRAS signaling pathways leads to complete and permanent regression of orthotopic PDACs induced by KRAS/TP53 mutations. Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment. This combination therapy also led to significant regression of genetically engineered mouse tumors as well as patient-derived tumor xenografts (PDX) in the absence of tumor relapses. Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

Keywords:  KRAS, RAF1, EGFR, STAT3; MRTX1133, RMC-6236/daraxonrasib, afatinib, SD36; Pancreatic Ductal Adenocarcinoma (PDAC); targeted therapy; tumor regression and resistance

DOI:  https://doi.org/10.1073/pnas.2523039122
Front Pharmacol. 2025 ;16 1717414

Targeting emerging amino acid dependencies and transporters in cancer therapy.

Alfred Akinlalu, Emmanuel Ogberefor, Tommy Gao, Dali Sun.

  Amino acid metabolism is an important vulnerability in cancer. Established strategies such as arginine depletion, glutaminase inhibition, tryptophan-kynurenine modulation, and methionine restriction have shown that these pathways can be targeted in patients. At the same time, clinical trials reveal two consistent challenges: tumors can adapt by redirecting their metabolism, and reliable biomarkers are needed to identify patients who are most likely to benefit. Recent studies point to additional amino acids with translational potential. In pancreatic cancer, histidine and isoleucine supplementation has been shown in preclinical models to be selectively cytotoxic to tumor cells while sparing normal counterparts. In glioblastoma, threonine codon-biased protein synthesis programs that support growth; in other contexts, lysine breakdown suppresses interferon signaling through changes in chromatin structure; and alanine released from stromal cells sustains mitochondrial metabolism and therapy resistance. These dependencies are closely tied to amino acid transporters, which act as both nutrient entry points and measurable biomarkers. In this review, we summarize current evidence on histidine, isoleucine, threonine, lysine, and alanine as emerging metabolic targets, and discuss opportunities and challenges for clinical translation, with emphasis on transporter biology, biomarker development, and therapeutic combinations.

Keywords:  SLC transporters; amino acid metabolism; amino acid transporters; cancer therapy; dietary modulation; glutaminase inhibition; metabolic targeting; nutritional intervention

DOI:  https://doi.org/10.3389/fphar.2025.1717414
Cell Commun Signal. 2025 Dec 02.

Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.

Piotr Chroscicki, Nikodem Kasak, Dorota Dymkowska, Laura Turos-Korgul, Dominik Cysewski, Vira Chumak, Dawid Stepnik, Monika Kusio-Kobialka, Agata Kominek, Magdalena Lebiedzinska-Arciszewska, Alicja Krop, Joanna Szczepanowska, Mariusz Wieckowski, Tomasz Stoklosa, Krzysztof Zablocki, Katarzyna Piwocka.

   BACKGROUND: Alterations in cancer cell metabolism have recently gained considerable attention as a possible cause of adaptation and resistance to therapy. However, the underlying molecular mechanisms, particularly in leukemia resistance occurring in the bone marrow microenvironment, remain unclear. Here, we explore the role of direct stroma-leukemia interactions and transfer of membrane vesicles along with proteins as a mechanism of stroma-driven protection.
METHODS: K562 CML leukemia cells and primary CD34 + CML blasts were cultured alone or co-cultured with HS-5 stromal cells to mimic the bone marrow microenvironment conditions. Imatinib treatment was used experimentally as it is a standard first-line treatment in CML. Assessment of vesicles transfer, metabolic parameters, mitochondrial function phenotyping, Trans-SILAC proteomics and metabolomics, together with apoptosis assessment, verified the influence of stroma on metabolic plasticity, protein transfer and adaptation to imatinib in leukemic cells. Trans-system evaluated necessity of direct cell-cell contact. Data from single-cell atlas of diagnostic CML bone marrow were used to correlate gene expression profiles with clinical outcome. Telaglenastat was used to validate the clinical potential of our findings.
RESULTS: Stromal cells enhanced metabolic plasticity and oxidative capacity in leukemia, thereby protecting against metabolic decline and oxidative stress caused by imatinib. Direct stroma-leukemia contact was necessary for vesicles transfer, metabolic rearrangement and protection from imatinib-induced apoptosis. This was accompanied with shift towards OXPHOS activity, associated with increased utilization of non-glucose substrates. We found the presence of stromal TCA-related proteins in leukemic cells, associated with higher TCA cycle dynamics and activity, increased glutamine and reduced oxidative stress. The gene expression profiles correlated with clinical resistance to TKIs. Targeting the glutamine-TCA axis by telaglenastat in combination with imatinib reversed the stroma-driven protection, leading to increased apoptosis.
CONCLUSION: This study describes a novel mechanism of direct bone marrow-mediated protection of leukemic cells from imatinib/TKI, related to transfer of metabolic proteins leading to higher activity of TCA cycle, metabolic plasticity and adaptation. Targeting the stroma-driven TCA cycle-related metabolism combined with imatinib presents a promising strategy to achieve therapeutic efficacy to overcome bone marrow microenvironment-mediated protection in CML.

Keywords:  Bone marrow stroma; Glutamine; Imatinib; Leukemia microenvironment; Metabolic plasticity; Mitochondria; Proteome; Resistance; TCA; TNTs

DOI:  https://doi.org/10.1186/s12964-025-02564-7