bims-meract 2025-07-06 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–07–06
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Lipidomics in Breast Cancer: Decoding Metabolic Reprogramming and Unlocking Therapeutic Opportunities.
Targeting the TRIM14/USP14 axis enhances radiotherapy efficacy by inducing GPX4 degradation and disrupting ferroptotic defense in HCC.
MTCH2 Deficiency Promotes E2F4/TFRC-Mediated Ferroptosis and Sensitizes Colorectal Cancer Liver Metastasis to Sorafenib.
SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.
Lipid droplet-associated hydrolase (LDAH) knockdown enhances TAG hydrolysis and promotes ovarian cancer progression and chemoresistance.
Histone serotonylation promotes pancreatic cancer development via lipid metabolism remodeling.
PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.
Identification of a ferroptosis related genes signature and GDF15 contributing to a new perspective for the diagnosis of CRPC.
Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.
A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer.
Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity.
Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma.
DNMBP-AS1/hsa-miR-30a-5p/PGC1α axis suppresses tumor progression of colorectal cancer by inhibiting PKM2-mediated Warburg effect and enhance anti-PD-1 therapy efficacy.
Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
Exploiting mitochondrial dysfunction to overcome BRAF inhibitor resistance in advanced melanoma: the role of disulfiram as a copper ionophore.
Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.
Trametinib thwarts activation of survival pathways induced by pro-ferroptotic drug conjugate ACXT-3102 resulting in enhanced pancreatic cancer cell death.
The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response.
Targeting glutamine metabolism as a potential target for cancer treatment.
The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer.
UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors.
Tumoral RCOR2 promotes tumor development through dual epigenetic regulation of tumor plasticity and immunogenicity.
Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.
ATB0,+-targeted nanoparticles trigger STAT3-ferroptosis regulatory axis for enhanced gastric cancer therapy.

Curr Drug Targets. 2025 Jun 24.

Lipidomics in Breast Cancer: Decoding Metabolic Reprogramming and Unlocking Therapeutic Opportunities.

Harshita Singhai, Sunny Rathee, Umesh K Patil.

  Lipidomics, a cutting-edge branch of metabolomics, provides a comprehensive understanding of the lipidome and its alterations in cellular and systemic processes. In breast cancer, a highly heterogeneous disease, lipidomics has emerged as a pivotal tool for exploring metabolic reprogramming, tumor progression, and therapeutic resistance. This review highlights the intricate relationship between lipid metabolism and breast cancer, with a focus on subtype-specific lipid dependencies, oxidative stress, and ferroptosis. Technological advancements, such as mass spectrometry and chromatography, have enabled precise profiling of lipid alterations, revealing distinct lipid signatures across breast cancer subtypes. Key enzymes like acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), along with lipid regulators like PPARγ, have been identified as central players in lipid-driven tumorigenesis. Lipidomic studies offer the potential for biomarker discovery and the development of lipid-targeted therapies. Despite challenges in standardization and integration with other omics approaches, lipidomics is poised to revolutionize breast cancer diagnostics and therapeutics, providing novel insights into the metabolic underpinnings of this complex disease.

Keywords:  Lipidomics; biomarkers; breast cancer; ferroptosis; lipid metabolism; mass spectrometry; metabolic reprogramming.

DOI:  https://doi.org/10.2174/0113894501387287250611095023
Cell Death Dis. 2025 Jul 01. 16(1): 481

Targeting the TRIM14/USP14 axis enhances radiotherapy efficacy by inducing GPX4 degradation and disrupting ferroptotic defense in HCC.

Xin Yue, Zhen Xiang, Yang Yi, Xuecen Wang, Weilin Zhou, Weijian Wu, Wenjing Qin, Yuxuan Zhao, Xianzhang Bu, Zhenwei Peng.

Radiation resistance constitutes a formidable impediment in the treatment paradigm for hepatocellular carcinoma (HCC). Deubiquitinases (DUBs) exhibit notable efficacy in modulating cellular responses to stress and exogenous interventions, endowed with the critical trait of being targetable, thus facilitating the execution of precise therapeutic strategies. Here, we demonstrate that broad-spectrum inhibition of thiol hydrolase-type DUBs markedly augments radiotherapy sensitivity in HCC cells. Based on this, via CRISPR-based screening, we identified USP14 as the principal DUB orchestrating radioresistance. Ferroptosis emerged as a pivotal form of radiation-induced cell death, with our study singularly illustrating that USP14 is instrumental in directing cellular defenses against ferroptosis via the targeting and stabilization of glutathione peroxidase (GPX4). Mechanistically, we found that radiation triggers the assembly of Tripartite motif-containing protein 14 (TRIM14) at the GPX4 locus, subsequently recruiting USP14. The TRIM14/USP14 complex facilitates the excision of pronounced K48-linked polyubiquitination at lysine residues 48 or 118 on GPX4, thereby preserving GPX4's structural integrity and antioxidative function to counteract ferroptosis. Intriguingly, TRIM14-mediated GPX4 stabilization is further amplified in radioresistant HCC, and subsequent radiation enables USP14-dependent blockade of GPX4 degradation. Consequently, pharmacological inhibition of USP14 substantially increases the susceptibility of HCC cells, thereby sensitizing patient-derived xenograft (PDX) tumors to radiotherapy. Concurrently, we explored the abscopal effect of radiotherapy and revealed that targeting USP14-enhanced ferroptosis augments antitumor immune responses post-radiation, suggesting a strategy to sustain therapeutic efficacy. In conclusion, our study uncovers the TRIM14/USP14 axis as a critical suppressor of radiation-induced ferroptosis and an actionable target to overcome radioresistance in HCC. These findings provide mechanistic insights and a translational framework for improving radiotherapy outcomes.

DOI: https://doi.org/10.1038/s41419-025-07807-6
Adv Sci (Weinh). 2025 Jul 02. e00019

MTCH2 Deficiency Promotes E2F4/TFRC-Mediated Ferroptosis and Sensitizes Colorectal Cancer Liver Metastasis to Sorafenib.

Pu Xing, Jiangbo Chen, Hao Hao, Xiaowen Qiao, Xinying Yang, Kai Weng, Jie Chen, Lin Song, Tianqi Liu, Yifan Hou, Tongkun Song, Yumeng Ran, Bo Chen, Hong Yang, Wei Zhao, Zaozao Wang, Jiabo Di, Beihai Jiang, Xiangqian Su.

  Ferroptosis is a specific type of lipid peroxide-mediated cell death which is crucial in tumor suppression. While the mitochondrial carrier homolog 2 (MTCH2) is implicated in lipid homeostasis and mitochondrial metabolism, its role in ferroptosis and colorectal cancer (CRC) remains uncharacterized. Here, MTCH2 is identified as a crucial regulator of ferroptosis in CRC progression. Clinically, high expression of MTCH2 in CRC tissues predicts poor prognosis. Functionally, loss of MTCH2 inhibits azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumorigenesis in MTCH2cKO mice and leads to accumulation of ferrous ion and enhances ferroptosis of CRC in vitro and in vivo. Mechanistically, MTCH2 deficiency promotes the proteasome-dependent ubiquitination of E2F4 and attenuates transcriptional inhibition of transferrin receptor (TFRC) by E2F4, ultimately facilitating TFRC-mediated ferroptosis in CRC cells. Moreover, MTCH2 depletion combined with sorafenib treatment synergistically triggers ferroptosis, suppresses liver metastasis, and effectively eradicates tumors in liver metastasis foci. Taken together, This study reveals the mechanism of MTCH2 deficiency-induced ferroptosis to inhibit the progression of CRC and supports a potential therapeutic strategy targeting the MTCH2/E2F4/TFRC signaling axis in CRC patients with liver metastasis.

Keywords:  MTCH2; colorectal cancer; ferroptosis; liver metastasis; sorafenib

DOI:  https://doi.org/10.1002/advs.202500019
Leukemia. 2025 Jun 30.

SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.

Moran Wang, Ruiqi Zhu, Donald Small, Lan Lin, Li Li, Shengling Ma, Linghui Xia, Shanshan Luo, Wenjuan He, Jianming Yu, Junying Li, Ruowen Wei, Ao Zhang, Wei Shi, Yu Hu.

Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.

DOI: https://doi.org/10.1038/s41375-025-02673-9
Oncogenesis. 2025 Jul 02. 14(1): 22

Lipid droplet-associated hydrolase (LDAH) knockdown enhances TAG hydrolysis and promotes ovarian cancer progression and chemoresistance.

Bhawna Deswal, Sameera Nallanthighal, Elahe Nikpayam, Zenab Minhas, Antoni Paul, Young-Hwa Goo, Dong-Joo Cheon.

Lipid droplet-associated hydrolase (LDAH) is a lipid hydrolase abundantly expressed in adipose and ovarian tissues and macrophages. However, LDAH's functions in ovarian cancer are largely unknown. Analysis of publicly available patient datasets showed decreased LDAH expression in advanced stages of ovarian cancer, and low LDAH levels were associated with poor survival outcomes in ovarian cancer patients. Consistently, knockdown (KD) of LDAH in human ovarian cancer cell lines increased tumor cell proliferation but decreased endoplasmic reticulum (ER) stress and apoptosis upon cisplatin treatment. In addition, compared to scrambled control, LDAH KD ovarian cancer cells showed smaller lipid droplets (LDs), decreased triacylglycerol (TAG) content, and increased expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 A (CPT1A), and phospho-NF-kB. Our xenograft studies also showed increased tumor growth, increased ATGL expression, and decreased apoptosis after cisplatin treatment in LDAH KD tumors. ATGL overexpression increased cisplatin resistance and expression of CPT1A and phospho-NF-kB, whereas treatment of LDAH KD cells with an ATGL inhibitor attenuated the phenotype. Lastly, we observed that high ATGL levels were associated with shorter survival in ovarian cancer patients. Collectively, our results suggest that ovarian cancer cells downregulate LDAH expression, leading to enhanced ATGL-mediated TAG hydrolysis and increased tumor growth and chemoresistance.

DOI: https://doi.org/10.1038/s41389-025-00566-1
Nat Commun. 2025 Jul 01. 16(1): 5947

Histone serotonylation promotes pancreatic cancer development via lipid metabolism remodeling.

Sang Lin, Sheng Tan, Yonglin Peng, Aziguli Tulamaiti, Wenfei Du, Keshuo Ding, Changyu Chen, Jun Wu, Hua Li, Wei Xu, Jielin Sun, Xue-Li Zhang, Zhi-Gang Zhang, Xiaodong Zhao.

Neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has emerged to play parallel roles in both neurobiology and oncology. Apart from receptor-mediated signaling transduction pattern, serotonin can be covalently integrated into histone (the post-translational modification known as histone serotonylation) and serve as an epigenetic mark associated with permissive gene expression. However, how histone serotonylation influences tumorigenesis is yet to be understood. In this study, we observe the higher levels of histone serotonylation (H3K4me3Q5ser) and transglutaminases 2 (TGM2, the enzyme catalyzing serotonylation) in both pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines in comparison with their normal counterparts, and inhibition of histone serotonylation suppresses PDAC development. Mechanistically, we demonstrate that TGM2-mediated histone serotonylation at promoter of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC development by lipid metabolism remodeling. Collectively, this study reveals histone serotonylation as an important driver of PDAC tumorigenesis.

DOI: https://doi.org/10.1038/s41467-025-61197-z
Cancer Res. 2025 Jul 03.

PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.

Beatriz Parejo-Alonso, David Barneda, Sara Maria David Trabulo, Sarah Courtois, Sara Compte-Sancerni, Jelena Zurkovic, Laura Ruiz-Cañas, Quan Zheng, Jiajia Tang, Matthias M Gaida, Ulf Schmitz, Pilar Irun, Laure Penin-Peyta, Shanthini Mary Crusz, Petra Jagušt, Pilar Espiau-Romera, Alba Royo-García, Andrés Gordo-Ortiz, Mariia Yuneva, Meng-Lay Lin, Shenghui Huang, Ming-Hsin Yang, Angel Lanas, Bruno Sainz, Christoph Thiele, Christopher Heeschen, Patricia Sancho.

The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3475
Sci Rep. 2025 Jul 01. 15(1): 21624

Identification of a ferroptosis related genes signature and GDF15 contributing to a new perspective for the diagnosis of CRPC.

Yuanyuan Shao, Xiaoli Li, Jiaolong Liu, Zhongjian Qiu, Taijian Zhang, Nan Li, Jianmeng Hu, Fuding Lu, Zhiguo Zhu.

  Prostate cancer (PCa) is a highly prevalent malignancy among men. Castration-resistant prostate cancer (CRPC) is the main pathological type leading to the death of patients. Due to the lack of effective early diagnostic biomarkers, the treatment of CRPC is often lagging. Ferroptosis is a new discovered pathway of cell death. The diagnostic value of ferroptosis-related genes for CRPC is still uncertain. In this study, we identified 10 differently expressed FRGs between 145 hormone-sensitive PCa (HSPC) and 49 CRPC. A novel ferroptosis-related genes (FRGs) signature was constructed using seven FRGs (ABCC5, ACSL1, AKR1C3, CAMKK2, GDF15, PDSS2, and ZFP36), which could distinguish CRPC from HSPC with area under the ROC curve (AUC) = 0.93. This result was confirmed in an independent validation cohort with AUC = 0.90, F1 score = 0.85. Among the seven FRGs, GDF15 independently predicted CRPC with the good performance (AUC = 0.84). Moreover, GDF15 could effectively distinguish PCa from normal tissues (AUC = 0.79 and 0.83 in two cohorts). Two distinct ferroptosis profiles were discovered, and FRGs signature and GDF15 could also effectively distinguish them. GDF15 expression level shows an inverted U-shape with disease progression (normal, HSPC, CRPC). Although GDF15 expression was decreased in CRPC cells, overexpression of GDF15 still facilitates CRPC cells migration and invasion in vitro. Our findings suggest that this novel FRGs signature and GDF15 could be robust biomarkers for predicting CRPC in clinical practice.

Keywords:  Biomarker; Castration-resistant prostate cancer; Diagnostic; Ferroptosis; GDF15

DOI:  https://doi.org/10.1038/s41598-025-97045-9
ACS Chem Biol. 2025 Jul 02.

Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.

Stephen B Ruiz, Daniel E Tylawsky, Janki Shah, Michelle Saoi, Brandon Cuevas, Shanay Desai, Boglarka Racz, Ana Marie Perea, Arianna R Izawa-Ishiguro, Justin Cross, Daniel A Heller.

Although ferroptosis resistance is prevalent among many cancer cell types, precisely how ferroptosis surveillance mechanisms are induced remains elusive due to the heterogeneity of the cellular mutational status and metabolic states. Here, we find that phospholipase PAFAH2 regulates ferroptosis through its unique ability to specifically detoxify membrane-bound oxidized phospholipids in KEAP1 mutant and NRF2-active cancer cells. We show that the genetic or chemical perturbation of PAFAH2 is sufficient to sensitize KEAP1 mutant lung adenocarcinoma cells to ferroptosis. Lipidomic analyses reveal that PAFAH2 inhibition shifts the cellular lipidome to a distinctly ferroptosis state characterized by the enrichment of key phospholipids previously identified to be important in ferroptosis, like ether-linked phosphatidylethanolamines. Finally, we comparatively assessed the antitumor efficacy of PAFAH2 inhibitor monotherapy versus cotreatment with a nanoparticle-stabilized GPX4 inhibitor formulation. Our findings support that the broad applicability of PAFAH2 inhibition can be used in ferroptosis induction and abrogation of ferroptosis resistance across cancer types.

DOI: https://doi.org/10.1021/acschembio.5c00273
J Clin Invest. 2025 Jul 01. pii: e193171. [Epub ahead of print]135(13):

A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer.

Samyuktha Suresh, James M Ford.

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, presents a clinical challenge in developing effective treatment options. In this issue of the JCI, Zeng et al. demonstrate a provocative and promising therapeutic strategy for TNBC by leveraging the metabolic vulnerabilities presented by methylthioadenosine phosphorylase (MTAP) deletion to genotoxic stress inducers, such as poly (ADP-ribose) polymerase inhibitors (PARPi). They found that combining MTAP deletion or inhibition with PARPi was highly effective in brain metastatic TNBC where the methionine-limited environment further enhanced this combination. This approach underscores the importance of targeting metabolic vulnerabilities in the development of personalized cancer therapies.

DOI: https://doi.org/10.1172/JCI193171
Nat Commun. 2025 Jul 01. 16(1): 5563

Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.

Huiwang Zhan, Dhiman Sankar Pal, Jane Borleis, Yu Deng, Yu Long, Chris Janetopoulos, Chuan-Hsiang Huang, Peter N Devreotes.

Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.

DOI: https://doi.org/10.1038/s41467-025-60596-6
Nat Commun. 2025 Jul 01. 16(1): 5616

Exploitable mechanisms of antibody and CAR mediated macrophage cytotoxicity.

Tianyi Liu, Meng Zhang, Tatyanah Farsh, Haolong Li, Audrey Kishishita, Abhilash Barpanda, Stanley G Leung, Jun Zhu, Hyuncheol Jung, Junjie Tony Hua, Xiaolin Zhu, Alexander B Kim, Young Ah Goo, Minsoo Son, Jaenyeon Kim, Aish Subramanian, Martin Sjöström, Katherine C Fuh, Jocelyn S Chapman, Julia Carnevale, Luke A Gilbert, Aparna Lakkaraju, Peter M Bruno, David Quigley, Arun P Wiita, Felix Y Feng, Carl J DeSelm.

Macrophages infiltrate solid tumors and either support survival or induce cancer cell death through phagocytosis or cytotoxicity. To uncover regulators of macrophage cytotoxicity towards cancer cells, we perform two co-culture CRISPR screens using CAR-macrophages targeting different tumor associated antigens. Both identify ATG9A as an important regulator of this cytotoxic activity. In vitro and in vivo, ATG9A depletion in cancer cells sensitizes them to macrophage-mediated killing. Proteomic and lipidomic analyses reveal that ATG9A deficiency impairs the cancer cell response to macrophage-induced plasma membrane damage through defective lysosomal exocytosis, reduced ceramide production, and disrupted caveolar endocytosis. Depleting non-cytotoxic macrophages using CSF1R inhibition while preventing ATG9A-mediated tumor membrane repair enhances the anti-tumor activity of therapeutic antibodies in mice. Thus, macrophage cytotoxicity plays an important role in tumor elimination during antibody or CAR-macrophage treatment, and inhibiting tumor membrane repair via ATG9A, particularly in combination with cytotoxic macrophage enrichment through CSF1R inhibition, improves tumor-targeting macrophage efficacy.

DOI: https://doi.org/10.1038/s41467-025-60745-x
Nat Commun. 2025 Jul 01. 16(1): 5511

Identification of the Notch ligand DLK1 as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma.

Nai-Yun Sun, Suresh Kumar, Yoo Sun Kim, Diana Varghese, Arnulfo Mendoza, Rosa Nguyen, Reona Okada, Karlyne Reilly, Brigitte Widemann, Yves Pommier, Fathi Elloumi, Anjali Dhall, Daiki Taniyama, Mayank Patel, Etan Aber, Cristina F Contreras, Rosandra N Kaplan, Katja Kiseljak-Vassiliades, Margaret E Wierman, Dan Martinez, Jennifer Pogoriler, Amber K Hamilton, Sharon J Diskin, John M Maris, Robert W Robey, Michael M Gottesman, Jaydira Del Rivero, Nitin Roper.

While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516).

DOI: https://doi.org/10.1038/s41467-025-60649-w
Cell Death Discov. 2025 Jul 02. 11(1): 299

DNMBP-AS1/hsa-miR-30a-5p/PGC1α axis suppresses tumor progression of colorectal cancer by inhibiting PKM2-mediated Warburg effect and enhance anti-PD-1 therapy efficacy.

Tianxiao Wang, Wenxin Zhang, Jiafeng Liu, Xiang Mao, Xinhai Wang, Jiyifan Li, Yuxin Huang, Zimei Wu, Haifei Chen, Huanying Shi, Huijie Qi, Lu Chen, Qunyi Li.

The Warburg effect, which is aerobic glycolysis, constitutes a major driver of various cancer progression. Therefore, we aimed to examine the role of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC1α) and its competing endogenous RNA (ceRNA) network in colorectal cancer (CRC) metabolic reprogramming. We used bioinformatics analysis and dual-luciferase reporter gene experiments and identified the DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA network. Additionally, we investigate the impact of PGC1α expression alterations on CRC proliferation and metabolic reprogramming. Moreover, we studied the influence of PGC1α on pyruvate kinase M2 (PKM2), and CRC malignant behavior manifestation. Our study has uncovered a significant association between the DNMBP-AS1/hsa-miR-30a-5p/PGC1α ceRNA network and CRC patient prognosis. Additionally, PGC1α overexpression impeded CRC growth, reduced glycolytic capacity, and enhanced anti-PD-1 therapy efficacy. PGC1α inhibited tumor cell glycolysis by downregulating the WNT/β-catenin pathway depending on peroxisome proliferator-activated receptor gamma (PPARγ), thereby suppressing PKM2. The PPARγ agonist rosiglitazone could hinder CRC proliferation and glycolytic activity. Combined with the PGC1α agonist ZLN005, it exhibits synergistic effects for treating CRC. Moreover, we verified that ZLN005 significantly potentiated PD-1 induced tumor suppression in xenograft mice. Finally, we demonstrated that PGC1α and PKM2 expression patterns in tumor tissues were closely related to patient prognosis. Moreover, we constructed a predictive model to predict the 5-year survival events in CRC patients using random forest model. Our results offer novel perspectives on the role of DNMBP-AS1/hsa-miR-30a-5p/PGC1α network in controlling CRC proliferation, metabolism and immune responses. Furthermore, our investigation reveals that using rosiglitazone combined with PGC1α agonist presents a promising therapeutic approach for managing CRC.

DOI: https://doi.org/10.1038/s41420-025-02561-2
Sci Adv. 2025 Jul 04. 11(27): eadx4562

Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.

Anna Pellattiero, Charlotte Quirin, Federico Magrin, Mattia Sturlese, Alberto Fracasso, Nikolaos Biris, Stéphanie Herkenne, Laura Cendron, Evripidis Gavathiotis, Stefano Moro, Andrea Mattarei, Luca Scorrano.

The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.

DOI: https://doi.org/10.1126/sciadv.adx4562
Cell Death Dis. 2025 Jul 01. 16(1): 482

Exploiting mitochondrial dysfunction to overcome BRAF inhibitor resistance in advanced melanoma: the role of disulfiram as a copper ionophore.

Bolun Zhao, Fazhan Ban, Yuehua Li, Qiong Shi, Sen Guo, Xiuli Yi, Huina Wang, Tianwen Gao, Chunying Li, Guannan Zhu.

Resistance to targeted therapies poses a significant challenge in advanced melanoma with BRAF mutations. Even with a BRAF + MEK inhibitor combination, about 70% of patients experience disease progression within two years, highlighting the need for novel strategies beyond MAPK signaling inhibition. This study investigates whether mitochondrial dysfunction induced by the copper ionophore disulfiram (DSF) can effectively counteract resistance to BRAF inhibitors. We established two BRAF inhibitor (BRAFi)-resistant melanoma cell lines using BRAF mutant 451Lu and UACC62. In vivo experiments were conducted using subcutaneous implantation in nude mice. Cell viability and colony formation assays assessed treatment efficacy, while mitochondrial morphology was evaluated via transmission electron microscopy. Mitochondrial respiration was measured using a Seahorse metabolic analyzer, and oxidative stress was assessed through flow cytometry and confocal microscopy. RNA sequencing identified downstream factors regulated by intracellular copper levels, and the CRISPR-Cas9 system was used to knock out candidate genes in BRAFi-resistant cells for mechanistic validation. We provided evidence that DSF induced cell death in BRAFi-resistant melanoma in a copper-dependent manner, severely impairing mitochondrial structure and function through increased oxidative stress. RNA-seq and immunoblotting revealed that thioredoxin-interacting protein (TXNIP) expression significantly increased in response to DSF. TXNIP knockout reduced DSF-induced cytotoxicity by mitigating oxidative stress. These findings were supported by in vivo experiments. Furthermore, we demonstrated that the oxidative damage mediated by TXNIP involved its interaction with thioredoxin 2 (TRX2). In conclusion, targeting mitochondrial function with disulfiram effectively inhibits BRAFi-resistant melanoma cells, independent of MAPK signaling blockage. These results point to the potential of combining disulfiram with BRAF inhibitors as a promising strategy to overcome BRAFi resistance.

DOI: https://doi.org/10.1038/s41419-025-07766-y
Cell Commun Signal. 2025 Jul 01. 23(1): 307

Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.

Yiyi Shou, Ruiqi Liu, Hao Xiong, Keke Xu, Xiaoyan Chen, Luanluan Huang, Yitian Zhang, Hailong Sheng, Haibo Zhang, Yanwei Lu.

  Cancer cells experience metabolic reprogramming to enhance the synthesis of nitrogen and carbon, facilitating the production of macromolecules essential for tumor proliferation and growth. A central strategy in this process involves reducing catabolic activities and managing nitrogen, thereby improving the efficiency of nitrogen utilization. The urea cycle (UC), conventionally recognized for its role in detoxifying excess nitrogen in the liver, is pivotal in this metabolic transition. Beyond the hepatic environment, the differential expression of UC enzymes facilitates the utilization of nitrogen for the synthesis of metabolic intermediates, thereby addressing the cellular metabolic requirements, especially under conditions of nutrient scarcity. In oncogenic contexts, the expression and regulation of UC enzymes undergo substantial modification, promoting metabolic reprogramming to optimize nitrogen assimilation into cellular biomass. This reconfigured UC not only enhances tumor cell survival but also plays a pivotal role in the reorganization of the tumor microenvironment (TME), thereby aiding in immune evasion. This review examines the mechanistic underpinnings of urea cycle dysregulation (UCD) in cancer, highlighting its dynamic roles across various tumor types and stages, as well as the therapeutic implications of these alterations. Understanding how UC relaxation promotes metabolic flexibility and immune evasion may help develop novel therapeutic strategies that target tumor metabolism and enhance anti-cancer immunity.

Keywords:  Cancer metabolism; Cancer treatment; Metabolic reprogramming; Tumor immunogenicity; Urea cycle

DOI:  https://doi.org/10.1186/s12964-025-02328-3
Mol Cancer Ther. 2025 Jul 03.

Trametinib thwarts activation of survival pathways induced by pro-ferroptotic drug conjugate ACXT-3102 resulting in enhanced pancreatic cancer cell death.

Kumar S Bishnupuri, Kenneth F Newcomer, Qingqing Gong, Rony Takchi, Li Ye, Suwanna Vangveravong, Lauren Ross, Brian A Van Tine, William G Hawkins, Dirk Spitzer.

Ferroptosis has recently been described as an iron-dependent subroutine of programmed cell death (PCD). Cancers driven by oncogenic Ras mutations, such as pancreatic ductal adenocarcinoma (PDAC), are particularly vulnerable to ferroptosis and are thus promising candidates for antineoplastic drugs targeting this unique form of PCD. Our group has developed a cancer-specific drug conjugate (ACXT-3102), consisting of a pro-apoptotic sigma-2 ligand as a delivery moiety (SV119), linked to an inhibitor of the cystine antiporter xCT (dm-Erastin), an established inducer of ferroptosis. We hypothesized that ACXT-3102 would trigger apoptosis and ferroptosis via its discrete chemical components, representing a new approach to clinical therapy for PDAC. In vitro, cell viability assays corroborated our earlier findings that ACXT-3102 is a potent inducer of cancer cell death. The sigma-2 delivery component of ACXT-3102 induced canonical markers of apoptosis, including cleaved caspase-3/7 and poly (ADP-ribose) polymerase (PARP), whereas the dm-Erastin cargo component induced canonical markers of ferroptosis, including lipid peroxidation and consumption of glutathione peroxidase 4 (GPX4). These changes resulted in the accumulation of reactive oxygen species (ROS). Subsequently, we found that ACXT-3102-mediated cell death was accompanied by activation of MAPK/ERK signaling, presumably via ROS-dependent degradation of dual-specificity phosphatase 6 (DUSP6), a negative MAPK/ERK phosphorylation regulator. We suspected this was a compensatory reaction and that ACXT-3102-induced cancer cell death would be augmented by inhibition of MAPK/ERK signaling. We successfully combined ACXT-3102 with trametinib (MEK inhibitor) to enhance the overall efficacy of treatment in vitro and in vivo, presumably by targeting ACXT-3102-induced upregulation of MAPK/ERK.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-1032
J Exp Clin Cancer Res. 2025 Jul 03. 44(1): 186

The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response.

Mingming Sun, Qi Yan, Xinru Zhai, Xintong Dai, Chenxin Yang, Huifang Zhao, Sizhen Lai, Jiyan Wang, Lian Li, Zhen Li, Yanping Li, Taoyuan Wang, Tao He, Jun Xue, Zhenghu Jia, Chunze Zhang, Shuai Zhang, Changliang Shan.

  Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions and functions in cancer. However, whether 6PGD serves non-metabolic functions in regulating cancer progression and drug response has not been reported. Here, we found that highly expressed 6PGD contributes to colorectal cancer (CRC) tumor growth and tumor metastasis. Mechanistically, 6PGD binds to ALKBH5 and inhibits its activity through the non-metabolic activity of 6PGD; this increases m6A modification levels and the stability of MDM2 mRNA and decreases the p53 protein stability, subsequently activating the expression of CCNA2 and HMGA2, which are responses to CRC tumor growth and tumor metastasis. Collectively, these findings reveal the multi-functionality of 6PGD in promoting CRC tumor growth, tumor metastasis, and drug responses through its non-metabolic activity.

Keywords:  6-phosphogluconate dehydrogenase (6PGD); Colorectal cancer (CRC); Metastasis; Non-metabolic activity; Proliferation

DOI:  https://doi.org/10.1186/s13046-025-03450-3
J Exp Clin Cancer Res. 2025 Jul 01. 44(1): 180

Targeting glutamine metabolism as a potential target for cancer treatment.

Wenxuan Zou, Zitao Han, Zihan Wang, Qian Liu.

  Metabolic reprogramming is a hallmark of cancer cells, and the advent of "glutamine addiction" in numerous tumors signifies a pivotal advancement for precision-targeted therapy. This review demonstrates that glutamine metabolism is a pivotal factor in the development of malignant phenotypes in tumors by modulating multifaceted regulatory networks (Hippo/YAP, mTORC1 signaling pathway, and non-coding RNAs). These networks play a crucial role in the reprogramming of glutamine metabolism, which in turn affects various hallmarks of cancer, including cancer cell proliferation, ROS-mediated inhibition of apoptosis, and EMT-associated invasive metastasis. With respect to targeted therapeutic strategies, the focus on key transporters and metabolizing enzymes (ASCT2/GLS1) provides a theoretical foundation for the development of multi-targeted combination therapeutic regimens based on the inhibition of glutamine metabolism. A body of research has demonstrated that the metabolic processes of glutamine regulate a variety of immune system functions, including T cell depletion/activation, the polarization of TAMs, and the function of NK cells. This regulatory relationship, termed the metabolic-immune axis, is a crucial factor in the development of immune escape mechanisms by tumors. The study further suggests that a combination of targeted intervention strategies, involving the modulation of glutamine metabolism, has the potential to reshape the immune microenvironment and enhance the efficacy of CAR-T cell therapy. It is important to note that glutamine metabolism also affects tumor stroma formation by remodeling cancer-associated fibroblasts (CAFs). In response to therapeutic resistance mechanisms, tumor cells form adaptive escapes through ASNS and GAD metabolic branch activation, glucose/lipid metabolic compensation, and ATF4 transcriptional stress networks. This review systematically integrates the critical role of glutamine metabolism in tumor development and therapeutic resistance, providing new perspectives and translational pathways for the development of precision therapeutic strategy selection based on metabolic plasticity modulation.

Keywords:  Anticancer targets; Drug resistance; Glutamine metabolism; Immune evasion; Malignant progression of tumors

DOI:  https://doi.org/10.1186/s13046-025-03430-7
Front Cell Dev Biol. 2025 ;13 1584630

The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer.

Qijing Wang, Kai Li, Liang Li, Qin Li, Yanyu Qi, Kai Liu, Hang Yuan, Ping Lin.

  Cancer represents a serious threat to human health and life. Despite recent advances in the cancer therapy that significantly extend patient survival, many individuals still undergo drug resistance, even to multiple chemotherapeutic drugs, known as multidrug resistance (MDR). MDR causes the treatment failure and promotes the risk of tumor recurrence and metastasis, which has been a critical clinical challenge. The molecular mechanisms for cancer cells developing MDR are complex and largely unclarified. ATP-binding cassette (ABC) transporters-mediated enhanced drug efflux and glucose metabolic reprogramming have been recently identified as key factors that limit drug efficacy. In addition to regulating glucose metabolism, several glycolytic enzymes exhibit aberrant cellular localization, including translocation to the nucleus, cell membrane or mitochondria, which imparts their non-classical pro-oncogenic functions to facilitate tumor progression and MDR. In this review, we summarize the roles and molecular insights of glycometabolic enzymes in MDR progression and discuss existing therapeutic strategies of targeting glucose metabolic enzymes for overcoming MDR.

Keywords:  cancer metabolism; cancer therapy; glucose metabolism; glycolysis; multidrug resistance

DOI:  https://doi.org/10.3389/fcell.2025.1584630
Proc Natl Acad Sci U S A. 2025 Jul 08. 122(27): e2500562122

UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors.

Yongkang Zou, Zhaoxiang Wang, Qiang Jiang, Xia Kong, Xiaohe Ma, Zhengyan Liang, Zhiguo Wang, Beiying Chen, Jiao Yuan, Jiayue Wen, Sheng Ye, Yubin Yan, Binbin Li, Xing-Dong Xiong, Xin-Guang Liu, Zhiwei He, Yafei Cai, Junzhi Zhou.

  Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of UFL1 or UBA5, or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.

Keywords:  UFMylation; hypoxia; posttranslational modification; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2500562122
J Clin Invest. 2025 Jul 03. pii: e188801. [Epub ahead of print]

Tumoral RCOR2 promotes tumor development through dual epigenetic regulation of tumor plasticity and immunogenicity.

Lei Bao, Ming Zhu, Maowu Luo, Ashwani Kumar, Yan Peng, Chao Xing, Yingfei Wang, Weibo Luo.

  Gain of plasticity and loss of MHC-II enable tumor cells to evade immune surveillance contributing to tumor development. Here, we showed that the transcriptional corepressor RCOR2 is a key factor that integrates two epigenetic programs surveilling tumor plasticity and immunogenicity. RCOR2 was upregulated predominantly in tumor cells and promoted tumor development in mice through reducing tumor cell death by CD4+/CD8+ T cells and inducing cancer stemness. Mechanistically, RCOR2 repressed RNF43 expression through LSD1-mediated demethylation of histone H3 at lysine 4 to induce activation of Wnt/β-catenin and tumor stemness. Simultaneously, RCOR2 inhibited CIITA expression through HDAC1/2-mediated deacetylation of histone H4 at lysine 16, leading to MHC-II silencing in tumor cells and subsequent impairment of CD4+/CD8+ T cell immunosurveillance, thereby promoting immune evasion. RCOR2 loss potentiated anti-PD-1 therapy in mouse models of cancer and correlated with better response to anti-PD-1 therapy in human patients. Collectively, these findings uncover a "two birds with one stone" effect for RCOR2, highlighting its potential as a valuable target for improved cancer therapy.

Keywords:  Adult stem cells; Cancer immunotherapy; Immunology; MHC class 2; Oncology

DOI:  https://doi.org/10.1172/JCI188801
Nat Commun. 2025 Jul 01. 16(1): 5554

Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.

Nioosha Nekooie Marnany, Alwyn Dady, Isabelle Duband-Goulet, Frédéric Relaix, Roberto Motterlini, Roberta Foresti, Sylvie Dufour, Jean-Loup Duband.

Metabolic reprograming has been linked to epithelial-to-mesenchymal transition (EMT) in cancer cells, but how it influences EMT in normal cells remains largely unknown. Here we explored how metabolism impacts delamination and migration of avian trunk neural crest cells, an important progenitor cell population of the vertebrate embryo. We report that delamination exhibits a quiescent metabolic phenotype whereas migration is characterized by OXPHOS-driven metabolism coupled to distinct expression of metabolic, EMT and developmental genes. While glucose and glutamine are required for delamination and migration, we uncover a specific role for glutamine and its catabolizing enzyme glutaminase in the unfolding of NCC delamination. Namely, glutamine is required for nuclear accumulation of glutaminase, which interacts and cooperates with Wnt signaling to regulate EMT gene expression and cell cycle during delamination. Our data indicate that similarly to cancer cells, embryonic cells engage metabolic enzymes for non-canonical signaling functions to connect metabolism with EMT.

DOI: https://doi.org/10.1038/s41467-025-58573-0
Colloids Surf B Biointerfaces. 2025 Jun 28. pii: S0927-7765(25)00425-4. [Epub ahead of print]255 114918

ATB0,+-targeted nanoparticles trigger STAT3-ferroptosis regulatory axis for enhanced gastric cancer therapy.

Hailun Zheng, Xiaoyan Mao, Zhiwei Chen, Linying Wang, Fuxiang Shangguan, Zihao Tao, Jinyao Ye, Weilan Cao, Qing Yao, Lili Yan, Ruijie Chen, Shihui Bao, Longfa Kou.

  Chemotherapy remains one of the main treatments for gastric cancer, but the efficacy of 5-fluorouracil (5-FU) is limited by drug resistance. Ferroptosis is a unique mode of regulated cell death characterized by iron accumulation and lipid peroxidation, and its induction by aberrant STAT3 signaling may contribute to chemotherapy resistance. Cryptotanshinone (Cpt) is a bioactive compound extracted from Salvia miltiorrhiza that acts as a STAT3 inhibitor and has shown efficacy against several malignancies, endowing its potential as an agent to overcome the chemotherapy of gastric cancer. Importantly, cancer cells-especially drug-resistant cells-often upregulate amino acid transporters to import indispensable nutrients that support rapid proliferation, and therefore these transporters could guide the target delivery of chemotherapeutics for enhanced delivery efficiency. Here, we developed an amino acid transporter-targeted nanoplatform (F/C@Trp-NPs) co-loaded with 5-FU and Cpt to target the SLC6A14 (ATB0,+) transporter, which is abnormally upregulated in gastric cancer cells, and evaluated its anticancer effects. The F/C@Trp-NPs significantly inhibited gastric cancer cell proliferation in vitro, consistent with the in vivo results. This study provides a promising new therapeutic strategy for gastric cancer.

Keywords:  ATB(0,+); Chemoresistance; Gastric cancer; Nanoparticles; STAT3

DOI:  https://doi.org/10.1016/j.colsurfb.2025.114918