bims-meract 2026-02-08 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–02–08
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer.
Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer.
Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.
FOLR1 Mediated by ITCH Promotes Paclitaxel Resistance by Suppressing Pyroptosis in Nasopharyngeal Carcinoma.
Lactylation enhances YTHDF3 stability to promote cisplatin resistance via m6A-dependent KDM6B decay in bladder cancer.
Delactylation of the tumor suppressor ARHGDIB drives metastasis and chemoresistance in bladder cancer.
Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy.
Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
Pemetrexed sensitizes cisplatin therapy by inducing ferroptosis in NSCLC cells.
ESM1 SUMOylation mediates bevacizumab resistance in ovarian cancer through ITGB1-FAK-driven angiogenesis.
Targeting glycerophospholipid biosynthesis overcomes chemoresistance driven by SLFN11 loss in Ewing sarcoma.
Targeting Lipid Metabolism in CAFs: A Therapeutic Opportunity in Solid Tumors.
A SLC7A5-Specific Near-Infrared Fluorescent Probe for Cancer-Targeted Imaging Applications.
VAMP7 governs ferroptosis suppression and cisplatin resistance in esophageal cancer: a dual-targeting therapeutic paradigm.
Neutrophil Extracellular Traps Enhance Platinum Resistance in Ovarian Cancer via SHP-1 Activation.
Targeting ENO1 reprograms macrophage polarization to trigger antitumor immunity and improves the therapeutic effect of radiotherapy.
Cuproptosis promotes inflammatory osteolysis via GYS1-mediated glycogen metabolism.
c-Myc/GRPEL1 maintains fatty acid synthesis via FASN to support PDAC cell proliferation.
Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
Co-disruption of GPX4 and DHODH Ferroptosis Defense Systems via Excipient-Free Self-Assembled Nanoassemblies for Enhanced Ferroptosis Therapy in Triple-Negative Breast Cancer.

Cell Death Discov. 2026 Feb 04.

Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer.

Xianchao Sun, Ying Zhang, Wei Zhang, Liang Jin, Shiyong Xin.

While androgen receptor (AR) pathway inhibitors such as enzalutamide have demonstrated significant therapeutic efficacy in prostate cancer (PCa) treatment, the inevitable development of acquired resistance continues to pose a major clinical challenge in managing advanced PCa. We characterized Neurexophilin 4 (NXPH4) as a contributor to enzalutamide resistance (EnzR). Gain- and loss-of-function studies were conducted in PCa cell lines and mouse subcutaneous xenograft models to elucidate the role of NXPH4 in castration-resistant prostate cancer (CRPC). Additionally, the regulatory mechanisms of gene expression were assessed using a series of molecular and biochemical experiments. Our study demonstrates that AR as a transcriptional activator of NXPH4. Elevated NXPH4 expression facilitated PCa proliferation under enzalutamide treatment through mitochondrial metabolic reprogramming. We identified that NXPH4 partially localizes to mitochondria and physically interacts with aldehyde dehydrogenase 1 family member L2 (ALDH1L2), a critical enzyme in one-carbon metabolism. Androgen deprivation stimulated NXPH4 mitochondrial translocation and enhanced its binding to ALDH1L2. NXPH4-mediated metabolic reprogramming promotes PCa progression. Notably, the combination of NXPH4 knockdown and enzalutamide treatment showed potent synergistic effects, significantly suppressing cell proliferation in vitro and substantially inhibiting tumor growth in vivo. These findings reveal a previously unrecognized mechanism of EnzR and identify the NXPH4-ALDH1L2 complex as a promising therapeutic target for CRPC treatment.

DOI: https://doi.org/10.1038/s41420-026-02944-z
Neoplasia. 2026 Feb 05. pii: S1476-5586(26)00012-6. [Epub ahead of print]73 101283

Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer.

Mariah E Geisen, Josiane W Tessmann, Courtney O Kelson, Daheng He, Chi Wang, Abu Saleh Mosa Faisal, Ellen J Beswick, Yasmine Baca, Stephanie Rock, Jill M Kolesar, Yekaterina Y Zaytseva.

  The presence of BRAFV600E mutations is associated with poor prognosis in colorectal cancer (CRC). Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance. This study investigated the mechanisms of resistance to PLX8394, a second-generation BRAF inhibitor. Using primary and established BRAFV600E CRC cells, we show that the development of resistance to PLX8394 results in cross-resistance of cells to encorafenib. Moreover, the acquired resistance is associated with increased proliferation, invasion, and upregulation of lipid metabolism, including increased expression of fatty acid synthase (FASN), a key enzyme of lipid synthesis. Yet, the combination of PLX8394 and FASN inhibitor TVB3664 has a synergistic effect on cell viability and colony formation in parental CRC cells, but not in PLX-resistant cells. Importantly, we demonstrate that addition of TVB3664 to the PLX8394 or encorafenib regimen significantly postpones development of resistance to BRAF-targeted therapy by inhibiting the cell cycle progression via a decrease in pRb (Ser780) and downregulation of E2F transcription factor and Cyclin D1 expression. Consistently, clinical data show that patients with BRAFV600E CRC who have high FASN expression in tumor tissues have higher expression of cell cycle-associated genes, including CDKs, E2F, CCDN1 (Cyclin D1), survivin, and MKI67. Collectively, these findings identify FASN-driven lipid metabolism as a critical mediator of resistance to BRAF-targeted therapy and suggest that incorporation of FASN inhibitors may enhance therapeutic efficacy and delay acquired resistance in BRAFV600E CRC.

Keywords:  BRAF(V600E); Colorectal cancer; Fatty acid synthase; PLX8394; TVB3664

DOI:  https://doi.org/10.1016/j.neo.2026.101283
Mol Cancer. 2026 Feb 03.

Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.

Shi Dong, Taiyuan Li.



Keywords:  Cancer; Glucose; Glutamine; Lipid; Metabolic reprogramming; Polyamine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02582-0
Arch Pharm (Weinheim). 2026 Feb;359(2): e70194

FOLR1 Mediated by ITCH Promotes Paclitaxel Resistance by Suppressing Pyroptosis in Nasopharyngeal Carcinoma.

Gehou Zhang, Yexun Song, Honghui Liu, Jian Xiao, Shiyu Zeng, Wei Li, Guolin Tan, Xianyao Wang.

  Paclitaxel is a frequently employed chemotherapeutic agent for nasopharyngeal carcinoma (NPC) patients, and tumor cell resistance to paclitaxel poses a significant challenge to NPC treatment. This study investigated the impact and potential mechanisms of folate-receptor 1 (FOLR1) on paclitaxel resistance in NPC cells. Levels of FOLR1 in NPC tissues and cells were measured using RT-qPCR. Protein expression was analyzed by Western blot. IC50 of paclitaxel-treated NPC cells was assessed by CCK-8. EdU and Colony formation assay detected cell proliferation. Apoptosis and pyroptosis were evaluated utilizing flow cytometry. Expression and localization of ITCH and FOLR1 were detected by immunofluorescence staining. Interaction between ITCH and FOLR1 was tested by co-immunoprecipitation (Co-IP). The immunoprecipitation assay evaluated FOLR1 ubiquitination levels. An NPC xenograft model was constructed in nude mice. FOLR1 was overexpressed in NPC and correlates with a poor prognosis in NPC patients. Low levels of cell pyroptosis and elevated FOLR1 expression were strongly associated with paclitaxel resistance in NPC. Knockdown of FOLR1 reduced the chemoresistance of 5-8 F/paclitaxel cells to paclitaxel. ITCH was associated with FOLR1 and enhanced its degradation through ubiquitination. ITCH reduced paclitaxel resistance in NPC cells via downregulation of FOLR1. FOLR1 increased resistance to paclitaxel by suppressing pyroptosis in NPC through an NLRP3-dependent mechanism. FOLR1 inhibited pyroptosis by inhibiting the mTOR pathway and promoting autophagy. Lowering FOLR1 expression suppressed tumor growth and boosted paclitaxel sensitivity in mice. FOLR1 plays a significant role in promoting chemoresistance of NPC cells to paclitaxel through NLRP3 signaling.

Keywords:  FOLR1; ITCH; nasopharyngeal carcinoma; paclitaxel resistance; pyroptosis

DOI:  https://doi.org/10.1002/ardp.70194
Cancer Lett. 2026 Jan 30. pii: S0304-3835(26)00045-5. [Epub ahead of print]642 218282

Lactylation enhances YTHDF3 stability to promote cisplatin resistance via m6A-dependent KDM6B decay in bladder cancer.

Kai Yu, Jiazhu Sun, Jiawei Zhang, Yuchen Shi, Junyan Wang, Yuqing Wu, Dingheng Lu, Xinyang Niu, Yuxiao Li, Suyuelin Huang, Jihuan Yuan, Zhixiang Qi, Fenghao Zhang, Jiangfeng Li, Hong Chen, Ben Liu.

  Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate-AARS2-YTHDF3-KDM6B-CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.

Keywords:  Bladder cancer; Cisplatin; H3K27me3; Lactylation; Ubiquitination; YTHDF3; m6A

DOI:  https://doi.org/10.1016/j.canlet.2026.218282
Cell Rep. 2026 Feb 03. pii: S2211-1247(26)00019-7. [Epub ahead of print]45(2): 116941

Delactylation of the tumor suppressor ARHGDIB drives metastasis and chemoresistance in bladder cancer.

Guanghui Xu, Yuqin Li, Shan Peng, Wei Zhao, Tianlei Xie, Minghao Zheng, Zhigang Wu, Yongming Deng, Yao Fu, Zhongqing Zhang, Xuyu Zhang, Yijing Chen, Jingyan Shi, Wei Chen, Meng Ding, Yihua Zhou, Wenli Diao, Hongqian Guo, Junlong Zhuang.

  Emerging evidence has highlighted lactylation as a critical link between metabolism and tumor progression. Through integrative lactylome and proteome profiling, we delineate the global landscape of protein lysine lactylation in bladder cancer, identifying lysine (K)47 and K50 of Rho guanosine diphosphate dissociation inhibitor β (ARHGDIB) as lactylation sites. Histone deacetylase (HDAC)2-mediated delactylation abrogates the tumor-suppressive function of ARHGDIB, promoting metastasis and cisplatin resistance of bladder cancer. Mechanistically, delactylation of ARHGDIB attenuates its binding affinity for Rac1, facilitating Rac1 membrane translocation and activation. This enhances DNA damage repair through the Rac1-MRN-ATM-CHK2 axis. Clinically, reduced ARHGDIB-K50 lactylation levels correlate with cisplatin resistance and poor prognosis. Entinostat, an inhibitor of class I HDAC, synergizes with cisplatin by preventing ARHGDIB delactylation. Collectively, our findings unveil a unique paradigm in which delactylation of tumor suppressors drives metastasis and chemoresistance. Targeting lactylation dynamics with HDAC inhibitors presents an avenue for intervention of bladder cancer.

Keywords:  ARHGDIB; CP: cancer; HDAC inhibitors; bladder cancer; cisplatin resistance; lactylation; metastasis

DOI:  https://doi.org/10.1016/j.celrep.2026.116941
EMBO Mol Med. 2026 Feb 02.

Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy.

Manon Baurès, Anne-Sophie Vieira Aleixo, Emeline Pacreau, Aysis Koshy, Vanessa Friedrich, Marc Diedisheim, Martin Raigel, Yichao Hua, Charles Dariane, Florence Boutillon, Lukas Kenner, Jean-Christophe Marine, Gilles Laverny, Daniel Metzger, Florian Rambow, Jacques-Emmanuel Guidotti, Vincent Goffin.

  A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc-/- LSCmed characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

Keywords:  Castration-Resistance; Club Cells; DNPC; FOSL1; LSCmed Cells

DOI:  https://doi.org/10.1038/s44321-026-00375-y
NPJ Precis Oncol. 2026 Jan 30.

Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.

Jiang Wu, Juan Li, Li Xu, Yuanyuan Liu, Li Jiang.

The current study explores the expression, functional significance, and underlying mechanisms of the mitochondrial protein NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4) in glioma cells. TCGA shows that elevated NDUFS4 expression is consistently observed in glioma tissues, correlating with advanced tumor grade and diminished patient survival. Single-cell RNA sequencing further localizes this elevated expression primarily to glioma cells, where NDUFS4 co-expressed genes are integral to cellular respiration and mitochondrial ATP synthesis. These findings were corroborated in patient tissues and various primary and established glioma cell types, confirming consistent NDUFS4 overexpression. Genetic silencing (via shRNA) or CRISPR/Cas9-mediated knockout of NDUFS4 impaired mitochondrial function, evidenced by reduced oxygen consumption rate, inhibited mitochondrial complex I activity and ATP production and increased oxidative stress. NDUFS4 depletion also suppressed glioma cell proliferation, migration, and invasion, while promoting apoptosis. This inhibitory effect is specific to malignant cells, sparing non-cancerous astrocytes. Conversely, NDUFS4 overexpression enhanced mitochondrial activity and promoted aggressive malignant phenotypes in primary and immortalized glioma cells. Further multi-omics integration and experimental investigation established COX5B (cytochrome c oxidase subunit 5B) as an important downstream effector of NDUFS4. shRNA-induced silencing of COX5B replicated the outcomes of NDUFS4 depletion in primary glioma cells, and crucially, restoring COX5B in NDUFS4-silenced glioma cells abrogated the anti-glioma effects. In vivo studies demonstrated that NDUFS4 silencing effectively impeded intracranial growth of patient-derived glioma xenografts by compromising mitochondrial function, downregulating COX5B, inhibiting proliferation and inducing apoptosis. Collectively, these comprehensive data underscore NDUFS4's essential role in glioma progression and position it as a promising therapeutic target for this aggressive malignancy.

DOI: https://doi.org/10.1038/s41698-026-01281-9
Front Pharmacol. 2025 ;16 1764937

Pemetrexed sensitizes cisplatin therapy by inducing ferroptosis in NSCLC cells.

Yumin Wang, Xin Zhang, Yuwei Cao, Ge Zhang, Yonglin Zhu, Yulin Li, Jichao Chen.

   Background: Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). Platinum-based chemotherapy combined with pemetrexed (PEM) is frequently recommended as the first-line therapeutic regimen for NSCLC. However, the mechanisms of how PEM boosts the antitumor activity of DDP are largely unknown. Emerging evidence indicated that DDP could induce ferroptosis, a new type of regulated cell death (RCD) characterized by iron-dependent toxic build-up of lipid peroxides on cellular membranes. It is tempting to speculate whether PEM increases the sensitivity of NSCLC to DDP through inducing ferroptosis.
Methods: In the present study, we first used RNA-seq and KEGG analysis to examine differentially expressed genes in PEM-challenged NSCLC cells. The effect of PEM on increased DDP-mediated anticancer activity was examined via a cytotoxicity assay and Western blot. PEM-triggered ferroptosis in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, and a Western blot in the presence or absence of ferroptosis inhibitors.
Results: In the present study, we found that the ferroptosis-related pathway was enriched by PEM. PEM significantly enhanced the ability of cisplatin to inhibit cell viability and proliferation in NSCLC cells. The combination of PEM and DDP synergistically induced ferroptosis, as evidenced by the increased reactive oxygen species (ROS), lipid peroxidation, and Fe2+ and decreased SOD. PEM facilitated DDP-mediated upregulated expression of pro-ferroptosis proteins (ACSL4, 12LOX, COX2, DMT1, TFR1, and TF) and downregulated the expression of anti-ferroptosis proteins (SLC7A11, GPX4, FPN1, FTH1, FTL, DHODH, FSP1, and GCH1). However, the effects were reversed by ferroptosis inhibitor ferrostatin-1 or deferoxamine in NSCLC cells.
Conclusion: In summary, these results provide in vitro experimental evidence that PEM boosts the antitumor activity and increases the sensitivity of NSCLC cells to DDP by inducing ferroptosis.

Keywords:  cisplatin; drug resistance; ferroptosis; non-small-cell lung cancer; pemetrexed

DOI:  https://doi.org/10.3389/fphar.2025.1764937
Cell Rep. 2026 Feb 04. pii: S2211-1247(26)00005-7. [Epub ahead of print]45(2): 116927

ESM1 SUMOylation mediates bevacizumab resistance in ovarian cancer through ITGB1-FAK-driven angiogenesis.

Xiaomin Ran, Juan Zhang, Juan Yang, Hui Li, Dan Liu, Xing Tang, Wenchao Zhou, Xueru Liu, Yukun Li, Bikang Yang.

  Bevacizumab (Bev) resistance limits therapeutic efficacy in ovarian cancer (OC) patients. We identified ESM1 as a key gene in Bev-resistant OC. ESM1 secreted by OC-resistant cell lines activates the ITGB1/FAK axis to induce neovascularization and Bev resistance. Additionally, ESM1 overexpression promoted the growth and Bev resistance of OC, lung, intestinal, and hepatocellular carcinoma tumors. Then, we identified TRIM28 as an upstream regulator that stabilizes ESM1 by promoting SUMOylation, inhibiting its proteasomal degradation. In OC mice, TRIM28 overexpression promotes angiogenesis and Bev resistance via ESM1-mediated ITGB1/FAK activation. This work unveils a new molecular pathway underlying Bev resistance in OC and proposes TRIM28 and ESM1 as potential therapeutic targets.

Keywords:  CP: cancer; ESM1; angiogenesis; bevacizumab; ovarian cancer; resistant

DOI:  https://doi.org/10.1016/j.celrep.2026.116927
Cell Death Dis. 2026 Jan 31. 17(1): 190

Targeting glycerophospholipid biosynthesis overcomes chemoresistance driven by SLFN11 loss in Ewing sarcoma.

Kasturee Chakraborty, Ritambhar Burman, Saharsh Satheesh, Matthew Kieffer, Chandni Karuhatty, Zuo-Fei Yuan, Haiyan Tan, Ankhbayar Lkhagva, Anthony A High, Xusheng Wang, Alaa Refaat, Nathaniel R Twarog, Weixing Zhang, Yaxu Wang, Yiping Fan, Qian Li, M Madan Babu, Anang A Shelat, Elizabeth Stewart, Michael A Dyer, Puneet Bagga.

Ewing sarcoma (EWS) is a highly aggressive pediatric malignancy characterized by elevated expression of SLFN11, which impairs DNA repair by binding to and functionally inhibiting DNA repair complexes, thereby enhancing susceptibility to genotoxic therapies. However, relapse remains a major clinical challenge and is often accompanied by the emergence of therapeutic resistance linked to reduced SLFN11 expression. We hypothesized that SLFN11-deficient tumors undergo adaptive metabolic reprogramming to overcome chemosensitivity. Here, we leverage transcriptomic and metabolomic profiling in patient-derived EWS models to demonstrate that SLFN11 loss drives downregulated mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) expression, higher accumulation of glycerol-3-phosphate, fatty acid unsaturation, and enhanced glycerophospholipid (GPL) biosynthesis. Subsequently, targeting GPL biosynthesis (FSG67) restored DNA-damaging agent (SN-38) sensitivity in SLFN11-deficient EWS model, revealing a potential metabolic vulnerability to overcome chemoresistance. Furthermore, SLFN11 knockout tumors exhibited an elevated phosphocholine/glycerophosphocholine ratio, offering a potential non-invasive diagnostic biomarker.

DOI: https://doi.org/10.1038/s41419-026-08432-7
Transl Res. 2026 Feb 03. pii: S1931-5244(26)00031-9. [Epub ahead of print]

Targeting Lipid Metabolism in CAFs: A Therapeutic Opportunity in Solid Tumors.

Qi Ai, Bin Wang, Wei Zhang, Xin-Yun Xu.

  Cancer-associated fibroblasts (CAFs), representing the predominant stromal cell population within the solid tumor microenvironment (TME), are thought to play a significant role in facilitating tumorigenesis and progression. Nonetheless, recent experimental efforts to eradicate CAFs in solid tumors have inadvertently resulted in tumor progression, potentially due to the tumor-suppressive effects exhibited by specific CAF subtypes. Therefore, strategies that selectively target pro-tumorigenic CAFs may yield more favorable outcomes. Emerging evidence indicates that CAFs are instrumental in reprogramming lipid metabolism within TME, fostering a high-fat, immunosuppressive environment. To adapt to the hypoxic and nutrient-limited conditions of TME, cancer cells alter their metabolic processes, which subsequently influences the behavior of CAFs. The variability among CAF populations affects the metabolic pathways of cancer cells and neighboring immune cells. Despite the importance of these interactions, the discussion regarding lipid metabolism crosstalk between CAFs and the TME remains insufficiently explored in the literature. As a result, this study systematically reviews the various origins and heterogeneity of CAFs and closely investigates their roles in lipid metabolism reprogramming within the TME. Additionally, we analyze the metabolic interactions between CAFs and different components of the TME in solid tumors. Ultimately, we discuss potential therapeutic strategies and the challenges of targeting CAF lipid metabolism.

Keywords:  Cancer-associated fibroblasts; Combined therapy strategy; Immunosuppression; Lipid metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.trsl.2026.02.003
J Fluoresc. 2026 Feb 03.

A SLC7A5-Specific Near-Infrared Fluorescent Probe for Cancer-Targeted Imaging Applications.

Wei Zhang, Jialin Xu, Liping Dong, Yong Wang, Yang Wu.

  Extensive surgical resection improves survival in cancer patients. Fluorescence-guided imaging techniques have significantly enhanced the precision of cancer resections. Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), and no other targetable molecules have been identified. In this study, we verified that the L-type amino acid transporter 1 (LAT1, also known as SLC7A5) is overexpressed in triple-negative breast cancer (TNBC) cells and we constructed a novel near-infrared fluorescent dye Cys-PEG5-IR target to SLC7A5. We then report the SLC7A5 receptor specificity of Cys-PEG5-IR as a contrast agent for TNBC imaging in vitro and in vivo. The conjugation elevated cell fluorescence on SLC7A5-overexpressing TNBC cells and produced minimal cell fluorescence when treated with SLC7A5 knockdown. Tumor uptake of Cys-PEG5-IR was significantly higher than the unlabeled IR in the subcutaneous MDA-MB-231 TNBC xenograft. This work highlights the prospect of using methionine (Met) transport pathway as an alternative strategy for targeting cancer cells, especially TNBC cells.

Keywords:  Cancer imaging; Fluorescent imaging; Methionine (Met); SLC7A5

DOI:  https://doi.org/10.1007/s10895-025-04697-x
Cancer Cell Int. 2026 Feb 03.

VAMP7 governs ferroptosis suppression and cisplatin resistance in esophageal cancer: a dual-targeting therapeutic paradigm.

Jialiang Zhu, Minghua Xie, Lei Dai, Zhiming Yang, Wenbo Xue, Zhibin Jiang, Jingyue Zhou.

  Chemoresistance in esophageal cancer (EC) continues to impose formidable clinical challenges, driving disease recurrence and adverse outcomes. While vesicle-associated membrane protein 7 (VAMP7), a SNARE family regulator, has emerged as an oncogenic participant in tumor evolution, its mechanistic role in EC chemoresistance remains uncharted. Clinico-pathological analyses reveal pronounced VAMP7 overexpression in EC specimens, correlating with unfavorable prognosis, metastatic dissemination, advanced tumor staging, and cisplatin-refractory phenotypes. Functional interrogation demonstrates that VAMP7 silencing attenuates malignant hallmarks-proliferation, migratory capacity, and epithelial-mesenchymal transition (EMT)-while potentiating apoptotic cascades. Mechanistically, VAMP7 exhibits robust positive correlation with ferroptosis regulators GPX4 and NRF2, establishing its role as a ferroptosis checkpoint inhibitor that sustains cisplatin resistance. Combinatorial VAMP7 depletion and cisplatin treatment synergistically diminished neoplastic viability through dual mechanisms: amplification of ferroptosis biomarkers (lipid peroxidation, iron dysregulation) and induction of mitochondrial ultrastructural derangements. Conversely, ectopic VAMP7 expression in resistant clones upregulated GPX4/NRF2 axis activity and reinstated chemotolerance. Therapeutically, co-administration of ferroptosis agonists (RSL3/Erastin) with cisplatin abrogated VAMP7-mediated resistance, evidenced by suppressed xenograft growth and amplified mitochondrial pathology in preclinical models. This work identifies VAMP7 as a novel ferroptosis-chemoresistance nexus in EC, offering a translational framework for overcoming cisplatin refractoriness through coordinated inhibition of VAMP7 signaling and ferroptosis potentiation.

Keywords:  Chemoresistance; Cisplatin; Esophageal cancer; Ferroptosis; VAMP7

DOI:  https://doi.org/10.1186/s12935-025-04153-7
Cancer Lett. 2026 Jan 29. pii: S0304-3835(26)00051-0. [Epub ahead of print] 218288

Neutrophil Extracellular Traps Enhance Platinum Resistance in Ovarian Cancer via SHP-1 Activation.

Qian Zhao, Yao Yao, Ting Liang, Mengjie Chen, Minhui Zeng, Peixi Li, Shiyi Zhang, Tingting Yao.

  Platinum resistance continues to be a major therapeutic challenge in ovarian cancer, driving disease recurrence and limiting patient survival. In this study, we identify a significant enrichment of neutrophil extracellular traps (NETs) within the tumor microenvironment of platinum-resistant ovarian tumors. These NETs actively contribute to malignant progression by promoting epithelial-mesenchymal transition and fostering chemotherapy resistance. Mechanistically, we demonstrate that NETs drive chemoresistance through the unexpected activation of SHP-1. Although traditionally recognized as a tumor suppressor, SHP-1 assumes an oncogenic function in this context. Specifically, NETs trigger TGF-β signaling, resulting in Smad2 phosphorylation, which subsequently promotes both the enzymatic activation and nuclear translocation of SHP-1. Once in the nucleus, SHP-1 enhances RNA polymerase II-mediated transcription and nucleotide excision repair, ultimately enabling cancer cells to evade cisplatin-induced cytotoxicity. Our in vivo experiments corroborate these findings that elevated NETs levels exhibit poor response to cisplatin, while pharmacological inhibition of NETs effectively restores drug sensitivity. This study not only advances our understanding of microenvironment-driven drug resistance but also highlights the therapeutic potential of targeting the NETs/SHP-1 axis to overcome platinum resistance in ovarian cancer.

Keywords:  DNA repair; Neutrophil extracellular traps; Nuclear translocation; Ovarian cancer; Platinum resistance; SHP-1

DOI:  https://doi.org/10.1016/j.canlet.2026.218288
Cell Death Dis. 2026 Feb 02. 17(1): 194

Targeting ENO1 reprograms macrophage polarization to trigger antitumor immunity and improves the therapeutic effect of radiotherapy.

Yu-Sen Lin, Hsin-Yu Chang, Wei-Ze Hong, Jhen-Yu Chen, Wei-Ching Huang, Ta-Tung Yuan, Tao-Wei Ke, Yuan-Yao Tsai, Te-Hong Chen, Ji-An Liang, Jui-I Chao, K S Clifford Chao, Kevin Chih-Yang Huang.

Enolase 1 (ENO1) is a glycolytic enzyme involved in tumor progression that performs a variety of classical and nonclassical functions. However, the mechanism by which it promotes tumor progression is still not fully understood. Here, we revealed that TGFβ1/Smad3 signaling triggered the symmetric dimethylation of arginine (SDMA) on ENO1 by protein arginine methyltransferase 5 (PRMT5), leading to membranous ENO1 translocation. Surface ENO1 interacts with monocarboxylate transporter 4 (MCT4) for lactate secretion, which recruits M2 macrophages and promotes an immunosuppressive tumor microenvironment (TME). Targeting surface ENO1 with HuL001, a first-in-class humanized antibody, significantly reduced glycolysis, decreased extracellular lactate accumulation, reprogrammed macrophage polarization and inhibited tumor growth and distant metastasis. Moreover, targeting surface ENO1 significantly increased the therapeutic response to radiotherapy and delayed tumor regrowth by increasing antitumoral M1 macrophages and cytotoxic CD8+ T cells infiltration within TME. These results indicated that targeting surface ENO1 remodeled the tumor microenvironment and provided better therapeutic effects to radiotherapy in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC).

DOI: https://doi.org/10.1038/s41419-026-08416-7
Int J Oral Sci. 2026 Feb 03. 18(1): 13

Cuproptosis promotes inflammatory osteolysis via GYS1-mediated glycogen metabolism.

Lu Zhou, Hanqing Mao, Yuanhao Wen, Zhi Chen, Lu Zhang.

Copper, predominantly present in bones, plays a crucial role in bone formation. However, when copper homeostasis is disrupted, excessive copper can trigger harmful inflammation and a novel form of cell death known as cuproptosis. The impact of cuproptosis on bone metabolism remains unclear. In this study, we demonstrated that excessive copper acts as an aggravator in osteoclastogenesis and bone resorption. We observed that the expression levels of the copper importer SLC31A1 and dihydrolipoamide S-acetyltransferase (DLAT) were positively correlated with bone loss in both human chronic apical periodontitis (CAP) tissues and mouse CAP models. Untargeted metabolomics analysis and screening of glucose metabolism enzymes revealed that glycogen synthesis was inhibited during cuproptosis. Mechanistically, excessive copper hindered glycogen synthesis via glycogen synthase 1 (GYS1), which limited the availability of glycogenolysis-derived glucose-6-phosphate (G6P) flux into pentose phosphate pathway (PPP), and was unable to yield abundant NADPH to ensure high demand of glutathione (GSH) for macrophage survival. The inhibition of glycogen synthesis intensified cuproptosis and bone-resorption activity. Moreover, excessive copper bound to H3K27me3, which further epigenetically inhibited the gene transcription of GYS1, thereby affecting glycogen synthesis and exacerbating cuproptosis and bone resorption. Furthermore, the disruption of glycogen metabolism intensified cuproptosis and promoted inflammatory bone loss in vivo. Our finding highlighted the complex interplay among copper homeostasis, glycogen metabolism, and the osteo-immune system, suggesting new therapeutic strategies for managing inflammatory bone diseases and other copper accumulation-related conditions through the metabolic reprogramming of cells.

DOI: https://doi.org/10.1038/s41368-025-00408-1
Cell Death Dis. 2026 Feb 05.

c-Myc/GRPEL1 maintains fatty acid synthesis via FASN to support PDAC cell proliferation.

Jing Wang, Liyuan Zhang, Keke Chen, Fangze Wei, Wendi Li, Chanjuan Cui, Feng Chen, Bing Wei, Tao Huang, Hezhi Fang, Wei Cui.

Pancreatic ductal adenocarcinoma (PDAC) cells undergo mitochondrial metabolic reprogramming to support their proliferation. However, the mechanisms by which mitochondrial protein quality control (MPQC) regulates cell metabolism remain unclear. Here, we found that c-Myc promotes PDAC cell proliferation by transcriptionally upregulating the expression of GRPEL1, an essential MPQC component. Mechanistically, c-Myc-regulated GRPEL1 maintains oxidative phosphorylation (OXPHOS) and minimizes ROS accumulation, thereby facilitating de novo fatty acid (FA) synthesis through the transcriptional upregulation of fatty acid synthase (FASN) expression. Targeting the c-Myc/GRPEL1 axis to block FASN-regulated FA synthesis inhibited PDAC cell proliferation and tumor growth in both cell models and patient-derived organoids (PDOs), whereas FA supplementation partially reversed this inhibitory effect. Clinically, c-Myc expression is positively associated with the levels of MPQC components in pancreatic ductal cells, with GRPEL1 ranking among the top hits. Furthermore, c-Myc, GRPEL1, and FASN are all expressed at higher levels in PDAC tissues than in peri-tumoral pancreatic tissues, and both c-Myc and GRPEL1 expression levels are positively correlated with that of FASN. These findings suggest that therapeutic inhibition of FA synthesis may be promising for treating PDAC patients with active c-Myc/GRPEL1/FASN signaling. Overall, this study demonstrates that FA synthesis mediated by the c-Myc/GRPEL1/FASN axis is essential for PDAC growth.

DOI: https://doi.org/10.1038/s41419-026-08439-0
Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]

Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.

Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.

  Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.

Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
ACS Appl Mater Interfaces. 2026 Feb 06.

Co-disruption of GPX4 and DHODH Ferroptosis Defense Systems via Excipient-Free Self-Assembled Nanoassemblies for Enhanced Ferroptosis Therapy in Triple-Negative Breast Cancer.

Tianyi Xia, Chen Liu, Qian Lin, Min Jiang, Quanyi Jin, Ding Guo, Xuan Zhu, Nian Liu.

  Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive phenotype and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is evolving as a highly promising approach to combat TNBC. However, tumor cells deploy redundant ferroptosis defense systems including glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) systems to evade this lethal process. Here, doxorubicin (DOX) and teriflunomide (Tfm) were used as therapeutic building blocks for the self-assembly of tumor-targeting, excipient-free nanoassemblies (DoT) that enhance ferroptosis induction in TNBC. After being trapped in cancer cells, the FDA-approved antitumor drug DOX could not only disrupt the GPX4 defense system by inhibiting Nrf2 but also ignite an intracellular reactive oxygen species storm to unleash a lipid peroxidation spark. Simultaneously, Tfm further devastated the intracellular ferroptosis defense system by suppressing DHODH and crippling the radical-trapping antioxidant capacity, thus evoking robust ferroptotic cell death in TNBC cells. The work presents a synergistic co-disruption strategy against dual ferroptosis defense systems, exhibiting significant potential for clinical applications.

Keywords:  dihydroorotate dehydrogenase (DHODH); ferroptosis defense systems; glutathione peroxidase 4 (GPX4); self-assembled nanoassembly; triple-negative breast cancer

DOI:  https://doi.org/10.1021/acsami.5c23291