bims-meract 2025-02-09 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–02–09
29 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.
Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells.
Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma.
Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism.
JMJD6 Rewires ATF4-Dependent Glutathione Metabolism to Confer Ferroptosis Resistance in SPOP-Mutated Prostate Cancer.
Integrative pan-cancer genomic analysis highlights mitochondrial protein p32 as a potential therapeutic target in Myc-driven tumorigenesis.
Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.
Modulating lipid metabolism improves tumor immunotherapy.
PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma.
Targeting the hERG1/β1 integrin complex in lipid rafts potentiates statins anti-cancer activity in pancreatic cancer.
Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN.
SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer.
Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins.
Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.
Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.
GUK1 activation is a metabolic liability in lung cancer.
AKR1B1 Inhibits Ferroptosis and Promotes Gastric Cancer Progression via Interacting With STAT3 to Activate SLC7A11.
Identification of mitochondrial carrier homolog 2 as an important therapeutic target of castration-resistant prostate cancer.
Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells.
Identification and validation of TSPAN13 as a novel temozolomide resistance-related gene prognostic biomarker in glioblastoma.
TGF-β secreted by cancer cells-platelets interaction activates cancer metastasis potential by inducing metabolic reprogramming and bioenergetic adaptation.
CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells.
RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic-nuclear shuttling in human triple-negative breast cancer.
Cellular senescence-associated gene IFI16 promotes HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma.
Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity.
Early tolerance and late persistence as alternative drug responses in cancer.
Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types.
LRP11 facilitates lipid metabolism and malignancy in hepatocellular carcinoma by stabilizing RACK1 through USP5 regulation.

J Pharmacol Exp Ther. 2025 Jan;pii: S0022-3565(24)00092-2. [Epub ahead of print]392(1): 100034

Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.

Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu.

  Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

Keywords:  Enzalutamide resistance; Metformin; Prostate cancer

DOI:  https://doi.org/10.1124/jpet.124.002424
Nat Commun. 2025 Feb 04. 16(1): 1358

Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.

Xiaofan Sun, Yue Li, Juan Du, Fangshu Liu, Caiping Wu, Weihao Xiao, Guopan Yu, Xiaowei Chen, Robert Peter Gale, Hui Zeng.

Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.

DOI: https://doi.org/10.1038/s41467-025-56520-7
Pharmacol Res. 2025 Feb 03. pii: S1043-6618(25)00068-4. [Epub ahead of print]213 107643

Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells.

Zhiwei Yuan, Taiyan Yu, Xu Wang, Kelin Meng, Tianlai Wang, Boyu Wang, Yu Xi, Congjian Wang, Chenxi Zeng, Shaojie Hu, Yitao Tian, Hui Xiong, Qi Wang, Wenbin Zou, Xue Wang, Yi Gao, Xiangning Fu, Lequn Li.

  Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.

Keywords:  Autophagy; Glutamine metabolism; IFN-γ signaling; Immunotherapy; Non-small cell lung cancer; V9302

DOI:  https://doi.org/10.1016/j.phrs.2025.107643
Sci Transl Med. 2025 Feb 05. 17(784): eadp8913

Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma.

Brittany Lipchick, Adam N Guterres, Hsin-Yi Chen, Delaine M Zundell, Segundo Del Aguila, Patricia I Reyes-Uribe, Yulissa Tirado, Subhasree Basu, Xiangfan Yin, Andrew V Kossenkov, Yiling Lu, Gordon B Mills, Qin Liu, Aaron R Goldman, Maureen E Murphy, David W Speicher, Jessie Villanueva.

Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant (NRASMUT) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in NRASMUT melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor-resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRASMUT melanomas that are resistant to global MAPK pathway inhibitors.

DOI: https://doi.org/10.1126/scitranslmed.adp8913
Nat Commun. 2025 Feb 01. 16(1): 1241

Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism.

Xiao-Qing Song, Tian-Jian Yu, Yang Ou-Yang, Jia-Han Ding, Yi-Zhou Jiang, Zhi-Ming Shao, Yi Xiao.

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.

DOI: https://doi.org/10.1038/s41467-025-56458-w
Cancer Res. 2025 Feb 04.

JMJD6 Rewires ATF4-Dependent Glutathione Metabolism to Confer Ferroptosis Resistance in SPOP-Mutated Prostate Cancer.

Chuanjie Zhang, Jiawei Ding, Kiat Shenq Lim, Wenjie Zhou, Wenyu Miao, Siqi Wu, Hanqing Liu, Da Huang, Chufeng Chen, Hongchao He, Jun Xiao, Dan-Feng Xu, Yan Shen, Hai Huang, Yi Gao.

Ferroptosis inducers have shown therapeutic potential in prostate cancer (PCa), but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic crosstalk between cancer cells could shed light on therapeutic strategies to more robustly activate ferroptosis. Here, we found that aberrant accumulation of jumonji domain containing 6 (JMJD6) proteins correlated with poorer prognosis of PCa patients. Mechanistically, PCa-associated speckle type BTB/POZ protein (SPOP) mutants impaired the proteasomal degradation of JMJD6 proteins. Elevated JMJD6 and ATF4 coordinated enhancer-promoter loop interactions to stimulate the glutathione biosynthesis pathway. Independent of androgen receptor, JMJD6 recruited mediator subunits (Med1/14) to assemble de novo enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus induced intrinsic resistance to ferroptosis, dependent on enhanced JMJD6-ATF4 activity. Consequently, targeting JMJD6 rendered SPOP-mutated PCa selectively sensitive to ferroptosis. The JMJD6 antagonist SKLB325 synergized with erastin in multiple pre-clinical PCa models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated PCa to increase sensitivity to ferroptosis inducers.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2796
Med Oncol. 2025 Feb 01. 42(3): 60

Integrative pan-cancer genomic analysis highlights mitochondrial protein p32 as a potential therapeutic target in Myc-driven tumorigenesis.

Qiufen Bi, Jun Nie, Qiang Wu, Liang Sun, Shuang Zhu, Jin Bai, Yong Liu, Fang Huang, Keli Chai.

  Tumor metabolic reprogramming, particularly involving mitochondrial metabolism, is a hallmark of malignancy. The mitochondrial protein p32 (C1QBP) has emerged as a critical regulator in various cancers, frequently associated with poor patient prognosis. However, the role of p32 across different cancer types remains largely unexplored. Our bioinformatics analysis demonstrates that p32 is significantly overexpressed in several malignancies and is closely involved in multiple oncogenic pathways related to tumor progression and metabolic reprogramming. Moreover, p32 expression positively correlates with genomic heterogeneity and drug sensitivity. We identified a strong association between p32 and c-Myc in both normal and cancerous tissues. We confirmed that p32 is a direct transcriptional target of c-Myc, which upregulates p32 by binding to its promoter. Functional experiments established that p32 is crucial for MYC-driven tumorigenesis, with its knockdown or knockout inhibiting tumor proliferation and extending survival. Targeting p32 may inhibit MYC-driven tumorigenesis, highlighting its potential as a therapeutic target in MYC-driven cancers.

Keywords:  Bioinformatics; Mitochondrial metabolism; Pan-cancer analysis; Tumorigenesis; c-Myc; p32

DOI:  https://doi.org/10.1007/s12032-025-02604-9
Clin Cancer Res. 2025 Feb 03.

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.

Anne P M Beerkens, Sandra Heskamp, Flavia V Reinema, Gosse J Adema, Paul N Span, Johan Bussink.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3296
J Immunother Cancer. 2025 Feb 04. pii: e010824. [Epub ahead of print]13(2):

Modulating lipid metabolism improves tumor immunotherapy.

Yu Ping, Qiuqing Fan, Yi Zhang.

  Immunotherapy has progressed significantly in cancer treatment; however, several factors influence its outcomes. Abnormal lipid metabolism, which is frequently observed in cancers, promotes tumor proliferation, invasion, and metastasis. Li et al from the Medical Oncology Department of Chongqing University Cancer Hospital constructed a lipid metabolism scoring system and reported that MK1775 inhibited fatty acid oxidation in tumor-associated macrophages and reduced T-cell infiltration, further enhancing the efficacy of immunotherapy. This study demonstrated the critical role of lipid metabolism scoring system and lipid metabolism in immunotherapy. Currently, the metabolism of lipids, such as fatty acids, phospholipids, and cholesterol, has been reported to affect the tumor microenvironment by regulating immune cells, including T cells, natural killer cells, and macrophages. These metabolic changes can impair the efficacy of immunotherapy, resulting in tumor progression. Consequently, lipid metabolism emerges as an important immune regulator for improving immunotherapeutic outcomes and provides a novel and powerful strategy for tumor combination therapy.

Keywords:  Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-010824
Nat Commun. 2025 Feb 01. 16(1): 1237

PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma.

Valentin Van den Bossche, Julie Vignau, Engy Vigneron, Isabella Rizzi, Hannah Zaryouh, An Wouters, Jérôme Ambroise, Steven Van Laere, Simon Beyaert, Raphaël Helaers, Cédric van Marcke, Lionel Mignion, Elise Y Lepicard, Bénédicte F Jordan, Céline Guilbaud, Olivier Lowyck, Hajar Dahou, Antonella Mendola, Manon Desgres, Léo Aubert, Isabelle Gerin, Guido T Bommer, Romain Boidot, Perrine Vermonden, Aurélien Warnant, Yvan Larondelle, Jean-Pascal Machiels, Olivier Feron, Sandra Schmitz, Cyril Corbet.

Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy.

DOI: https://doi.org/10.1038/s41467-025-56675-3
Cell Death Discov. 2025 Feb 03. 11(1): 39

Targeting the hERG1/β1 integrin complex in lipid rafts potentiates statins anti-cancer activity in pancreatic cancer.

Claudia Duranti, Jessica Iorio, Valeria Manganelli, Giacomo Bagni, Rossella Colasurdo, Tiziano Lottini, Michele Martinelli, Chiara Capitani, Giulia Boso, Franco Nicolas D'Alessandro, Maurizio Sorice, Andrea Becchetti, Roberta Misasi, Tina Garofalo, Annarosa Arcangeli.

Plasma membrane macromolecular complexes function as signaling hubs that regulate cell behavior, which is particularly relevant in cancer. Our study provides evidence that the complex formed by the hERG1 potassium channel and the β1 subunit of integrin receptors preferentially localizes in Lipid Rafts (LRs) in Pancreatic Ductal Adenocarcinoma (PDAC) cell lines and primary samples. The complex recruits the p85 subunit of phosphatidyl-inositol-3-kinase (PI3K), activating phosphoinositide metabolism and triggering an intracellular signaling pathway centered on Akt. This pathway ultimately affects cancer cell proliferation through cyclins and p21, and cell migration through the small GTPase Rac-1 and f-actin organization. The hERG1/β1 integrin complex in LRs can be dissociated and the downstream signaling pathway can be inhibited by either disrupting LRs through methyl-beta-cyclodextrin (MβCD) or inhibiting cholesterol synthesis by statins. Treatment with a single chain bispecific antibody-scDb-hERG1-β1-specifically targeting the complex significantly potentiates the effects of both MβCD and statins on intracellular signaling. Consequently, these treatments decrease PDAC cell proliferation and motility in vitro. From a pharmacological perspective, different statins produce anti-neoplastic effects in synergy with scDb-hERG1-β1. Such combination also enhances tumor sensitivity to chemotherapeutic drugs, such as gemcitabine and oxaliplatin. The efficacy of these combination treatments depends on the amount of the hERG1/β1 integrin complex present on the plasma membrane of cancer cells. Finally, the combined treatment with statins and scDb-hERG1-β1 significantly reduces tumor growth and improves survival in vivo, in a preclinical mouse model. These results suggest that the combination of scDb-hERG1-β1 and statins represent a potential novel strategy for treating PDAC patients.

DOI: https://doi.org/10.1038/s41420-025-02321-2
Cell Death Dis. 2025 Jan 31. 16(1): 59

Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN.

Yuan Zeng, Haoran Jiang, Zhoufeng Chen, Jun Xu, Xiangting Zhang, Weimin Cai, Xianjie Zeng, Peipei Ma, Rong Lin, Huilin Yu, Yuanhang He, Huiya Ying, Ruoru Zhou, Xiao Wu, Fujun Yu.

FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellular carcinoma cell lines were established, and enhanced glycolytic activity was identified in resistant cells. Inhibiting glycolysis effectively suppressed the malignant behavior of both OXA- and 5-Fu-resistant cells. Mechanistically, active glycolysis induced elevated levels of lactylation, predominantly histone lactylation, with H3K14la playing a key role in regulating gene expression. The ubiquitin E3 ligase NEDD4 was identified as a downstream target of H3K14la. Furthermore, NEDD4, regulated by histone lactylation, interacted with PTEN to mediate its ubiquitination and subsequent degradation. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance.

DOI: https://doi.org/10.1038/s41419-025-07359-9
Neoplasia. 2025 Feb 03. pii: S1476-5586(25)00004-1. [Epub ahead of print]61 101125

SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer.

Xudong Li, Jingjing Ge, Mengdi Wan, Tongtong Feng, Xiaoqian Li, Haibo Zhang, Zhangyan Wang, Yongsheng Gao, Meiting Chen, Fei Pan.

  Over 60% of breast cancer cases are diagnosed with estrogen-receptor (ER) positive. Tamoxifen (TAM), a commonly employed medication for ER-positive breast cancer, often yields suboptimal therapeutic outcomes due to the emergence of TAM resistance, leading to the recurrence and a poor prognosis. The copper transporter, solute carrier family 31 member 1 (SLC31A1), has been associated with tumor aggressiveness and unfavorable outcomes in various types of tumors. In our current study, we found high expression of SLC31A1 that predicted poor survival in patients with breast cancer. Significantly, ER-positive breast cancer tissues in patients with recurrence post-TAM treatment exhibited considerably stronger SLC31A1 expression levels. In vitro experiments verified that TAM-resistant ER-positive breast cancer cell lines expressed notably higher SLC31A1 levels compared to the parental cell lines. Of great significance, SLC31A1 depletion notably rescued TAM sensitivity in chemoresistant ER-positive breast cancer cells, as demonstrated by the attenuated cell proliferative and invasive capabilities. Conversely, promoting SLC31A1 significantly facilitated the proliferation and invasion of wild-type breast cancer cells. Subsequently, we detected reduced copper levels in TAM-resistant breast cancer cells with SLC31A1 depletion. Mechanistically, we observed that in chemoresistant breast cancer cell lines, SLC31A1 knockdown resulted in a substantial decrease in the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of fatty acid oxidation (FAO). RNA-Seq analysis indicated that FAO might be implicated in SLC31A1-mediated breast cancer progression. CPT1A was also overexpressed in TAM-resistant breast cancer cells, accompanied by enhanced FAO rates and ATP levels. Suppressing CPT1A significantly enhanced the chemosensitivity of TAM-resistant breast cancer cells in response to TAM treatments. Intriguingly, copper exposure dose-dependently increased CPT1A expression in chemoresistant breast cancer cells, but this could be abolished upon SLC31A1 knockdown, along with enhanced apoptosis, which elucidated that copper uptake contributed to CPT1A expression. Furthermore, SLC31A1 overexpression significantly augmented CPT1A expression in parental breast cancer cells, accompanied by facilitated copper levels, FAO rates, and ATP levels, while being notably diminished upon CPT1A suppression. Finally, our in vivo studies confirmed that SLC31A1 deficiency re-sensitized TAM-resistant breast cancer cells to TAM treatment and abolished tumor growth. Collectively, all our studies demonstrated that SLC31A1/copper suppression could enhance TAM responses for chemoresistant ER-positive breast cancer cells through constraining the CPT1A-mediated FAO process.

Keywords:  CPT1A; ER-positive breast cancer; FAO; SLC31A1; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.neo.2025.101125
Mol Cancer. 2025 Feb 03. 24(1): 40

Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins.

Maria Angelica Freitas-Cortez, Fatemeh Masrorpour, Hong Jiang, Iqbal Mahmud, Yue Lu, Ailing Huang, Lisa K Duong, Qi Wang, Tiffany A Voss, Claudia S Kettlun Leyton, Bo Wei, Wai-Kin Chan, Kevin Lin, Jie Zhang, Efrosini Tsouko, Shonik Ganjoo, Hampartsoum B Barsoumian, Thomas S Riad, Yun Hu, Carola Leuschner, Nahum Puebla-Osorio, Jing Wang, Jian Hu, Michael A Davies, Vinay K Puduvalli, Cyrielle Billon, Thomas P Burris, Philip L Lorenzi, Boyi Gan, James W Welsh.

   BACKGROUND: Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7).
METHODS: To explore how cancer cells resist immune cell-mediated ferroptosis, we used a comprehensive range of techniques. We worked with cell lines including PD1-sensitive, PD1-resistant, B16F10, and QPP7 glioblastoma cells, and conducted in vivo studies in syngeneic 129 Sv/Ev, C57BL/6, and conditional knockout mice with Rora deletion specifically in CD8+ T cells, Cd8 cre;Rorafl mice. Methods included mass spectrometry-based lipidomics, targeted lipidomics, Oil Red O staining, Seahorse analysis, quantitative PCR, immunohistochemistry, PPARγ transcription factor assays, ChIP-seq, untargeted lipidomic analysis, ROS assay, ex vivo co-culture of CD8+ T cells with cancer cells, ATAC-seq, RNA-seq, Western blotting, co-immunoprecipitation assay, flow cytometry and Imaging Mass Cytometry.
RESULTS: PD1-resistant tumors upregulate Fabp7, driving protective metabolic changes that shield cells from ferroptosis and evade anti-tumor immunity. Fabp7 decreases the transcription of ferroptosis-inducing genes like Lpcat3 and increases the transcription of ferroptosis-protective genes such as Bmal1 through epigenetic reprogramming. Lipidomic profiling revealed that Fabp7 increases triglycerides and monounsaturated fatty acids (MUFAs), which impede lipid peroxidation and ROS generation. Fabp7 also improves mitochondrial function and fatty acid oxidation (FAO), enhancing cancer cell survival. Furthermore, cancer cells increase Fabp7 expression in CD8+ T cells, disrupting circadian clock gene expression and triggering apoptosis through p53 stabilization. Clinical trial data revealed that higher FABP7 expression correlates with poorer overall survival and progression-free survival in patients undergoing immunotherapy.
CONCLUSIONS: Our study uncovers a novel mechanism by which cancer cells evade immune-mediated ferroptosis through Fabp7 upregulation. This protein reprograms lipid metabolism and disrupts circadian regulation in immune cells, promoting tumor survival and resistance to immunotherapy. Targeting Fabp7 could enhance immunotherapy effectiveness by re-sensitizing resistant tumors to ferroptosis.

Keywords:  Bmal1; Cancer; Circadian clock; FABP7; Ferroptosis; Immunotherapy; Lpcat3

DOI:  https://doi.org/10.1186/s12943-024-02198-2
Nat Metab. 2025 Feb 06.

Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma.

Jiao Li, Kaimeng Huang, Meha Thakur, Fiona McBride, Ananthan Sadagopan, Daniel S Gallant, Prateek Khanna, Yasmin Nabil Laimon, Bingchen Li, Razan Mohanna, Maolin Ge, Cary N Weiss, Mingkee Achom, Qingru Xu, Sayed Matar, Gwo-Shu Mary Lee, Kun Huang, Miao Gui, Chin-Lee Wu, Kristine M Cornejo, Toni K Choueiri, Birgitta A Ryback, Sabina Signoretti, Liron Bar-Peled, Srinivas R Viswanathan.

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.

DOI: https://doi.org/10.1038/s42255-025-01218-9
Cancer Lett. 2025 Feb 01. pii: S0304-3835(25)00076-X. [Epub ahead of print] 217512

Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.

Elena Richiardone, Maria Virginia Giolito, Rim Al Roumi, Jérôme Ambroise, Romain Boidot, Bernhard Drotleff, Bart Ghesquière, Barbara Lupo, Livio Trusolino, Alberto Bardelli, Sabrina Arena, Olivier Feron, Cyril Corbet.

  Colorectal cancer (CRC) represents a prototypical example of a cancer type for which inter- and intra-tumor heterogeneities remain major challenges for the clinical management of patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity and phenotypic plasticity and sustain disease progression. In particular, acidosis is a common hallmark of solid tumors, including CRC, and it is known to induce aggressive cancer cell phenotypes. In this study, we report that long-term adaptation to acidic pH conditions is associated with common metabolic alterations, including a glycolysis-to-respiration switch and a higher reliance on the activity of phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition of PHGDH activity or mitochondrial respiration induces greater growth-inhibitory effects in acidosis-exposed CRC cells in 2D and 3D culture conditions, and in patient-derived CRC organoids. These data pave the way for drugs targeting the acidic tumor compartment as a "one-size-fits-all" therapeutic approach to delay CRC progression.

Keywords:  Colon cancer; PHGDH; acidosis; metabolism; microenvironment; mitochondrial respiration

DOI:  https://doi.org/10.1016/j.canlet.2025.217512
Cell. 2025 Jan 28. pii: S0092-8674(25)00093-5. [Epub ahead of print]

GUK1 activation is a metabolic liability in lung cancer.

Jaime L Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M Gassaway, Christian W Johnson, Nicole Jones, Zongyu Li, Christian P Joschko, Toshio Fujino, Joao A Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V Sequist, Jessica J Lin, Nathalie Y R Agar, Steven P Gygi, Kevin M Haigis, Aaron N Hata, Marcia C Haigis.

  Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

Keywords:  ALK; GDP; GUK1; Ras signaling; anaplastic lymphoma kinase; cancer metabolism; guanylate kinase 1; lung cancer; non-small cell lung cancer; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.cell.2025.01.024
Cell Biol Int. 2025 Feb 06.

AKR1B1 Inhibits Ferroptosis and Promotes Gastric Cancer Progression via Interacting With STAT3 to Activate SLC7A11.

Kaiyan Yang, Xin Zhang, Fei Long, Jing Dai.

  Gastric cancer (GC) is a frequently diagnosed malignant tumor in clinical settings; however, the mechanisms underlying its tumorigenesis remain inadequately understood. In this study, we identified significantly elevated expression levels of AKR1B1 in GC tissues through quantitative polymerase chain reaction (qPCR) and western blotting assays. Furthermore, a negative correlation was established between patient survival probability and AKR1B1 expression levels. Functionally, our experiments, including colony formation, transwell migration, and xenograft assays, demonstrated that the depletion of AKR1B1 inhibited the proliferation and progression of GC cells both in vivo and in vitro. Additionally, the assessment of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and mitochondrial morphology confirmed that AKR1B1 depletion induces ferroptosis. Mechanistically, we found that AKR1B1 interacts with STAT3, which subsequently activates SLC7A11. Notably, the ferroptosis induced by AKR1B1 depletion could be reversed by the overexpression of SLC7A11, thereby substantiating these interactions. In conclusion, our findings identify AKR1B1 as a novel oncogene in GC and elucidate the mechanism involving the AKR1B1-STAT3-SLC7A11 pathway and ferroptosis, providing new insights for potential therapeutic strategies in the treatment of GC.

Keywords:  AKR1B1; SLC7A11; ferroptosis; gastric cancer

DOI:  https://doi.org/10.1002/cbin.12275
Cell Death Dis. 2025 Feb 05. 16(1): 70

Identification of mitochondrial carrier homolog 2 as an important therapeutic target of castration-resistant prostate cancer.

Yankui Liu, Anjie Chen, Yufan Wu, Jiang Ni, Rong Wang, Yong Mao, Ning Sun, Yuanyuan Mi.

We here investigate the expression of the mitochondrial carrier homolog 2 (MTCH2) and its potential function in castration-resistant prostate cancer (CRPC). Bioinformatic analyses reveal that MTCH2 overexpression is associated with critical clinical parameters of prostate cancer. Single-cell sequencing data indicate elevated MTCH2 expression in the prostate cancer epithelium. MTCH2 is also upregulated in locally treated CRPC tissue and various primary human CRPC cells. Using genetic silencing via shRNA and knockout (KO) through the CRISPR-sgRNA approach, we showed that the depletion of MTCH2 impaired mitochondrial function, resulting in a reduced oxygen consumption rate, diminished complex I activity, and decreased ATP levels, mitochondrial depolarization, and increased reactive oxygen species production in primary CRPC cells. The silencing or KO of MTCH2 significantly inhibited cell viability, proliferation, and migration, together with a marked increase in apoptosis in the primary CRPC cells. In contrast, ectopic expression of MTCH2 provided CRPC cells with pro-tumorigenic properties, enhancing ATP production and promoting cell proliferation and migration. MTCH2 silencing also markedly inhibited the growth of subcutaneous xenografts of the primary CRPC cells in nude mice. The MTCH2-silenced xenografts exhibited increased apoptosis, elevated lipid peroxidation, and decreased ATP levels. These results provide new insights into the role of MTCH2 in supporting mitochondrial function and CRPC progression.

DOI: https://doi.org/10.1038/s41419-025-07406-5
Oncoimmunology. 2025 Dec;14(1): 2460281

Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells.

Meng Li, Di Li, Hai-Yun Wang, Weixin Zhang, Zhenjian Zhuo, Huiqin Guo, Jiabin Liu, Yue Zhuo, Jue Tang, Jing He, Lei Miao.

  The exploration of therapeutic targets in neuroblastoma (NB), which needs more attempts, can benefit patients with high-risk NB. Based on metabolomic and transcriptomic data in mediastinal NB tissues, we found that the content of long-chain acylcarnitine (LCAC) was increased and positively associated with leptin expression in advanced NB. Leptin over-expression forced naïve CD4+ T cells to differentiate into Treg cells instead of Th17 cells, which benefited from NB cell proliferation, migration, and drug resistance. Mechanically, leptin in NB cells blunted the activity of carnitine palmitoyltransferase 2 (CPT2), the key enzyme for LCAC catabolism, by inhibiting sirtuin 3-mediated CPT2 deacetylation, which depresses oxidative phosphorylation (OXPHOS) for energy supply and increases lactic acid (LA) production from glycolysis to modulate CD4+ T cell differentiation. These findings highlight that excess leptin contributes to lipid metabolism dysfunction in NB cells and subsequently misdirects CD4+ T cell differentiation in tumor micro-environment (TME), indicating that targeting leptin could be a therapeutic strategy for retarding NB progression.

Keywords:  Neuroblastoma; T cell differentiation; leptin; long-chain fatty acid; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2025.2460281
PLoS One. 2025 ;20(2): e0316552

Identification and validation of TSPAN13 as a novel temozolomide resistance-related gene prognostic biomarker in glioblastoma.

Haofei Wang, Zhen Liu, Zesheng Peng, Peng Lv, Peng Fu, Xiaobing Jiang.

Glioblastoma (GBM) is the most lethal primary tumor of the central nervous system, with its resistance to treatment posing significant challenges. This study aims to develop a comprehensive prognostic model to identify biomarkers associated with temozolomide (TMZ) resistance. We employed a multifaceted approach, combining differential expression and univariate Cox regression analyses to screen for TMZ resistance-related differentially expressed genes (TMZR-RDEGs) in GBM. Using LASSO Cox analysis, we selected 12 TMZR-RDEGs to construct a risk score model, which was evaluated for performance through survival analysis, time-dependent ROC, and stratified analyses. Functional enrichment and mutation analyses were conducted to explore the underlying mechanisms of the risk score and its relationship with immune cell infiltration levels in GBM. The prognostic risk score model, based on the 12 TMZR-RDEGs, demonstrated high efficacy in predicting GBM patient outcomes and emerged as an independent predictive factor. Additionally, we focused on the molecule TSPAN13, whose role in GBM is not well understood. We assessed cell proliferation, migration, and invasion capabilities through in vitro assays (including CCK-8, Edu, wound healing, and transwell assays) and quantitatively analyzed TSPAN13 expression levels in clinical glioma samples using tissue microarray immunohistochemistry. The impact of TSPAN13 on TMZ resistance in GBM cells was validated through in vitro experiments and a mouse orthotopic xenograft model. Notably, TSPAN13 was upregulated in GBM and correlated with poorer patient prognosis. Knockdown of TSPAN13 inhibited GBM cell proliferation, migration, and invasion, and enhanced sensitivity to TMZ treatment. This study provides a valuable prognostic tool for GBM and identifies TSPAN13 as a critical target for therapeutic intervention.

DOI: https://doi.org/10.1371/journal.pone.0316552
J Cancer. 2025 ;16(4): 1310-1323

TGF-β secreted by cancer cells-platelets interaction activates cancer metastasis potential by inducing metabolic reprogramming and bioenergetic adaptation.

Chunlian Zhong, Weiyu Wang, Yinyin Yao, Shu Lian, Xiaodong Xie, Judan Xu, Shanshan He, Lin Luo, ZhouZhou Ye, Jiajie Zhang, Mingqing Huang, Guihua Wang, Yanhong Wang, Yusheng Lu, Chengbin Fu.

  Metastasis is the leading cause of cancer-related deaths and poses a treatment challenge. Although studies have shown the importance of epithelial-mesenchymal transition (EMT) and metabolic reprogramming during cancer metastasis, the link between EMT and metabolic reprogramming, as well as the underlying molecular mechanisms by which both mediate cancer cell invasion and metastasis have not been elucidated. Here, we observed that interactions between platelets and cancer cells promote the secretion of TGF-β, thereby initiating EMT, promoting the invasion, and altering the metastatic and metabolic potential of colon cancer cells. TGF-β activates the AKT signaling pathway to enhance HK1 and HK2 expression in cancer cells, leading to increased glucose consumption, ATP production, and precise modulation of cell cycle distribution. In an energy-deficient model induced by oxidative phosphorylation (OXPHOS) inhibition with oligomycin A, TGF-β-induced highly metastatic HCT116 (H-HCT116) cells adapt by upregulating HK expression and glycolytic metabolism, while concurrently decreasing cell proliferation to conserve energy for survival. Mechanistically, H-HCT116 cells regulate cell division rates by downregulating CDK2, CDK4, and Cyclin D1 protein expression and upregulating p21 expression. Furthermore, H-HCT116 cells display enhanced motility, which is linked to increased mitochondrial metabolic activity. These findings indicated that cancer cells-platelets interaction secreted TGF-β activates cancer metastasis potential by inducing metabolic reprogramming and bioenergetic adaptation. The present study provides new insights into the adaptive strategies of highly metastatic cancer cells under adverse conditions and indicates that targeting glycolysis and metabolic reprogramming could serve as a viable approach to prevent cancer metastasis.

Keywords:  Cancer metastasis; bioenergetic adaptation; epithelial-to-mesenchymal transition (EMT); metabolic reprogramming; platelet-cancer cells interaction; transforming growth factor-β (TGF-β)

DOI:  https://doi.org/10.7150/jca.103757
Cancer Metab. 2025 Feb 07. 13(1): 6

CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells.

You-Yu Liu, Wei-Lun Huang, Sin-Tian Wang, Hui-Ping Hsu, Tzu-Ching Kao, Wei-Pang Chung, Kung-Chia Young.

   BACKGROUND: HER2-positive patients comprise approximately 20% of breast cancer cases, with HER2-targeted therapy significantly improving progression-free and overall survival. However, subsequent reprogramed tumor progression due to PI3K signaling pathway activation by PIK3CA mutations and/or PTEN-loss cause anti-HER2 resistance. Previously, alpha isoform-specific PI3K inhibitors were shown to potentiate HER2-targeted therapy in breast cancer cells carrying PI3K pathway alterations with less potent effects on PTEN-loss than PIK3CA-mutant cells. Therefore, seeking for alternative combination therapy needs urgent attentions in PTEN-loss anti-HER2 resistant breast cancer.
METHODS: Since remodeling of fatty acid (FA) metabolism might contribute to HER-positive breast cancer and is triggered by the PI3K signal pathway, herein, we examined the effects of the inhibition of endogenous FA conversion, SCD-1 or exogenous FA transport, CD36, in combination with PI3K inhibitors (alpelisib and inavolisib) in anti-HER2 resistant PTEN-loss breast cancer cells.
RESULTS: The activated HER2/PI3K/AKT/mTOR signaling pathway positively correlated with SCD-1 and CD36 expression in PTEN-loss breast cancer cells. PI3K inhibition downregulated SCD-1, and accordingly, the addition of the SCD-1 inhibitor did not augment the antiproliferative effects of the PI3K inhibitors. CD36 was upregulated by blocking the PI3K signal pathway or limited serum supplementation, indicating that suppressing CD36 may decrease the excess transport of exogenous FA. The addition of the CD36 inhibitor synergistically enhanced the anti-proliferative effects of the PI3K inhibitors.
CONCLUSION: Simultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast cancer.

Keywords:  CD36 fatty acids transporter; Fatty acids metabolism; PI3K inhibitors; PTEN-loss; anti-HER2 resistant breast cancer

DOI:  https://doi.org/10.1186/s40170-025-00375-5
Clin Transl Med. 2025 Feb;15(2): e70203

RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic-nuclear shuttling in human triple-negative breast cancer.

Shumei Huang, Dongni Shi, Shuqin Dai, Xingyu Jiang, Rui Wang, Muwen Yang, Boyu Chen, Xuwei Chen, Lingzhi Kong, Lixin He, Pinwei Deng, Xiangfu Chen, Chuyong Lin, Yue Li, Jun Li, Libing Song, Yawei Shi, Weidong Wei.

   BACKGROUND: Resistance to paclitaxel-based chemotherapy is the major obstacle in triple-negative breast cancer (TNBC) treatment. However, overcoming paclitaxel resistance remains an unsolved problem. The present study aimed to determine whether paclitaxel treatment impairs Aly/REF export factor (ALYREF) cytoplasmic-nuclear shuttling, its mechanism, and the role of ubiquitinated ALYREF in paclitaxel resistance.
METHODS: The subcellular proportion of ALYREF was detected in samples from patients with TNBC using immunohistochemistry to analyze the relationship between ALYREF distribution and paclitaxel response. Cell viability assays, immunofluorescence assays, quantitative real-time reverse transcription PCR assays, western blotting, and terminal deoxynucleotidyl transferase nick-end-labelling assays were conducted to measure the biological function of the subcellular proportion of ALYREF and E3 ligase ring finger protein 31 (RNF31) on paclitaxel sensitivity in TNBC. The synergistic effects of an RNF31 inhibitor plus paclitaxel on TNBC were evaluated. Cox regression models were adopted to assess the prognostic role of RNF31 in TNBC.
RESULTS: Herein, we showed that regulation of ALYREF cytoplasmic-nuclear shuttling is associated with the paclitaxel response in TNBC. In paclitaxel-sensitive TNBC, ALYREF was trapped in the cytoplasm by paclitaxel, while in paclitaxel-resistant TNBC, ALYREF was efficiently transported into the nucleus to exert its function, allowing the export of the mRNAs encoding paclitaxel-resistance-related factors, including tubulin beta 3 class III (TUBB3), stathmin 1 (STMN1), and microtubule-associated protein Tau (TAU), ultimately inducing paclitaxel resistance in TNBC. Mechanistically, we found that RNF31 interacts with and ubiquitinates ALYREF, which facilitates ALYREF nuclear transportation via importin 13 (IPO13) under paclitaxel treatment. Notably, the RNF31 inhibitor and paclitaxel synergistically repressed tumour growth in vivo and in TNBC patient-derived organoids. In addition, analysis of patients with TNBC showed that elevated RNF31 levels correlated with poor prognosis.
CONCLUSION: These data indicated that RNF31-mediated ALYREF ubiquitylation could represent a potent target to reverse paclitaxel resistance in TNBC.
KEY POINTS: RNF31 facilitated ALYREF-mediated PTX resistance in TNBC. RNF31 promoted ALYREF nuclear transport via IPO13 in response to PTX treatment, subsequently enhancing the export of mRNAs encoding PTX resistance-related factors, including TUBB3, STMN1, and TAU. Blocking RNF31 trapped ALYREF in the cytoplasm and induced TNBC cell death upon PTX treatment. Inhibiting RNF31 activity re-sensitized PTX-resistant TNBC to PTX treatment.

Keywords:  ALYREF; cytoplasmic–nuclear shuttling; paclitaxel resistance; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/ctm2.70203
Nat Commun. 2025 Jan 31. 16(1): 1212

Cellular senescence-associated gene IFI16 promotes HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma.

Yuchuan Zhou, Liang Zeng, Linbo Cai, Wang Zheng, Xinglong Liu, Yuqi Xiao, Xiaoya Jin, Yang Bai, Mingyao Lai, Hainan Li, Hua Jiang, Songling Hu, Yan Pan, Jianghong Zhang, Chunlin Shao.

Glioblastoma multiforme (GBM) remains a therapeutic challenge due to its aggressive nature and recurrence. This study establishes a radioresistant GBM cell model through repeated irradiation and observes a cellular senescence-like phenotype in these cells. Comprehensive genomic and transcriptomic analyses identify IFI16 as a central regulator of this phenotype and contributes to radioresistance. IFI16 activates HMOX1 transcription thereby attenuating ferroptosis by reducing lipid peroxidation, ROS production, and intracellular Fe2+ content following irradiation. Furthermore, IFI16 interacts with the transcription factors JUND and SP1 through its pyrin domain, robustly facilitating HMOX1 expression, further inhibiting ferroptosis and enhancing radioresistance in GBM. Notably, glyburide, a sulfonylurea compound, effectively disrupts IFI16 function and enhances ferroptosis and radiosensitivity. By targeting the pyrin domain of IFI16, glyburide emerges as a potential therapeutic agent against GBM radioresistance. These findings underscore the central role of IFI16 in GBM radioresistance and offer promising avenues to improve GBM treatment.

DOI: https://doi.org/10.1038/s41467-025-56456-y
Clin Immunol. 2025 Jan 29. pii: S1521-6616(25)00015-4. [Epub ahead of print]272 110440

Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity.

Ana Vizcaino-Castro, Shipeng Chen, Baukje Nynke Hoogeboom, Annemarie Boerma, Toos Daemen, Cesar Oyarce.

   AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.
RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.
CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.

Keywords:  Anti-inflammatory macrophages; Cancer; Glutaminolysis; Macrophage metabolism; Macrophage polarization; Repurposed drugs

DOI:  https://doi.org/10.1016/j.clim.2025.110440
Nat Commun. 2025 Feb 03. 16(1): 1291

Early tolerance and late persistence as alternative drug responses in cancer.

Simona Punzi, Davide Cittaro, Guido Gatti, Gemma Crupi, Oronza A Botrugno, Antonino Alex Cartalemi, Alon Gutfreund, Caterina Oneto, Valentina Giansanti, Chiara Battistini, Giovanni Santacatterina, Lucrezia Patruno, Ilaria Villanti, Martina Palumbo, Daniel J Laverty, Francesca Giannese, Alex Graudenzi, Giulio Caravagna, Marco Antoniotti, Zachary Nagel, Ugo Cavallaro, Luisa Lanfrancone, Timothy A Yap, Giulio Draetta, Nathalie Balaban, Giovanni Tonon.

Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers.

DOI: https://doi.org/10.1038/s41467-024-54728-7
Sci Rep. 2025 Feb 03. 15(1): 4074

Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types.

Leif R Neitzel, Daniela T Fuller, Jessica Cornell, Samantha Rea, Carolina de Aguiar Ferreira, Charles H Williams, Charles C Hong.

Radioresistance is thought to be a major consequence of tumor milieu acidification resulting from the Warburg effect. Previously, using ogremorphin (OGM), a small molecule inhibitor of GPR68, an extracellular proton sensing receptor, we demonstrated that GPR68 is a key pro-survival pathway in glioblastoma cells. Here, we demonstrate that GPR68 inhibition also induces ferroptosis in lung cell carcinoma (A549) and pancreatic ductal adenocarcinoma (Panc02) cells. Moreover, OGM synergized with ionizing radiation to induce lipid peroxidation, a hallmark of ferroptosis, as well as reduce colony size in 2D and 3D cell culture. GPR68 inhibition is not acutely detrimental but increases intracellular free ferrous iron, which is known to trigger reactive oxygen species (ROS) generation. In summary, GPR68 inhibition induces lipid peroxidation in cancer cells and sensitizes them to ionizing radiation in part through the mobilization of intracellular free ferrous iron. Our results suggest that GPR68 is a key mediator of cancer cell radioresistance activated by acidic tumor microenvironment.

DOI: https://doi.org/10.1038/s41598-025-88357-x
Mol Med. 2025 Jan 31. 31(1): 35

LRP11 facilitates lipid metabolism and malignancy in hepatocellular carcinoma by stabilizing RACK1 through USP5 regulation.

Litao Liang, Wenbo Jia, Jinyi Wang, Yanzhi Feng, Deming Zhu, Wenhu Zhao, Chao Xu, Xiangyu Ling, Qingpeng Lv, Xiaoming Ai, Lianbao Kong, Wenzhou Ding.

  Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and a major public health challenge. Lipid metabolism plays a crucial role in the metabolic reprogramming observed in HCC, although the underlying mechanisms are still being elucidated. Nile red staining and lipid assays showed that LRP11 knockdown significantly reduces lipid accumulation in HCC cells, with a concurrent decrease in key lipid metabolism markers such as FSAN, ACLY and ACSL4, as demonstrated by Western blotting. Mass spectrometry (MS) and co-immunoprecipitation (Co-IP) revealed that LRP11 recruits USP5, enhancing USP5-mediated deubiquitination of RACK1. Truncation analysis identified LRP11 residues 309-500 as critical for interaction with the RACK1 residues 91-231. These findings suggest that LRP11 may influence lipid metabolism and progression in HCC through USP5-mediated stabilization of RACK1. Based on these results, LRP11 emerges as a potential target for further exploration in HCC therapy. Targeting LRP11 or disrupting its interactions with USP5 or RACK1 could offer new avenues for treatment, though additional research is required to validate these therapeutic possibilities.

Keywords:  Deubiquitination; Hepatocellular carcinoma; LRP11; Lipid metabolism

DOI:  https://doi.org/10.1186/s10020-025-01097-6