bims-meract 2025-04-06 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–04–06
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies.
Resilience and vulnerabilities of tumor cells under purine shortage stress.
Integrative insights into the role of CAV1 in ketogenic diet and ferroptosis in pancreatic cancer.
TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy.
Targeting METTL3 mitigates venetoclax resistance via proteasome-mediated modulation of MCL1 in acute myeloid leukemia.
NUPR1 Promotes Radioresistance in Colorectal Cancer Cells by Inhibiting Ferroptosis.
Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription.
Atovaquone-induced activation of the PERK/eIF2α signaling axis mitigates metabolic radiosensitisation.
Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis.
Exploiting metabolic vulnerabilities through synergistic ferroptosis and disulfidptosis for breast cancer therapy.
Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism.
Syntaxin-6 mediated autophagy confers lenvatinib resistance in hepatocellular carcinoma.
SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis.
Targeting cTRIP12 counteracts ferroptosis resistance and augments sensitivity to immunotherapy in pancreatic cancer.
In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS -mutant cancer.
MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.
Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma.
Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer.
Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression.

bioRxiv. 2025 Mar 13. pii: 2025.03.10.642426. [Epub ahead of print]

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors perturb cellular metabolic activity, which imposes metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising antineoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cell metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids in cellular membranes. As a consequence of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to polyunsaturated fatty acids, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fat sources.

DOI: https://doi.org/10.1101/2025.03.10.642426
Nat Commun. 2025 Apr 03. 16(1): 3189

Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies.

Wei Ou, Xin-Xin Zhang, Bin Li, Ying Tuo, Ren-Xuan Lin, Peng-Fei Liu, Jian-Ping Guo, Hio-Cheng Un, Ming-Hao Li, Jia-Hao Lei, Xiao-Jing Gao, Fu-Fu Zheng, Ling-Wu Chen, Ling-Li Long, Zong-Ren Wang.

Localized prostate cancer (PCa) is highly variable in their response to therapies. Although a fraction of this heterogeneity can be explained by clinical factors or genomic and transcriptomic profiling, the proteomic-based profiling of aggressive PCa remains poorly understood. Here, we profiled the genome, transcriptome, proteome and phosphoproteome of 145 cases of localized PCa in Chinese patients. Proteome-based stratification of localized PCa revealed three subtypes with distinct molecular features: immune subgroup, arachidonic acid metabolic subgroup and sialic acid metabolic subgroup with highest biochemical recurrence (BCR) rates. Further, we nominated NANS protein, a key enzyme in sialic acid synthesis as a potential prognostic biomarker for aggressive PCa and validated in two independent cohorts. Finally, taking advantage of cell-derived orthotopic transplanted mouse models, single-cell RNA sequencing (scRNA-seq) and immunofluorescence analysis, we revealed that targeting NANS can reverse the immunosuppressive microenvironment through restricting the sialoglycan-sialic acid-recognizing immunoglobulin superfamily lectin (Siglec) axis, thereby inhibiting tumor growth of PCa. In sum, we integrate multi-omic data to refine molecular subtyping of localized PCa, and identify NANS as a potential prognostic biomarker and therapeutic option for aggressive PCa.

DOI: https://doi.org/10.1038/s41467-025-58569-w
bioRxiv. 2025 Mar 20. pii: 2025.03.19.644180. [Epub ahead of print]

Resilience and vulnerabilities of tumor cells under purine shortage stress.

Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.

Purine metabolism is a promising therapeutic target in cancer; however how cancer cells respond to purine shortage,particularly their adaptation and vulnerabilities, remains unclear. Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated these responses in prostate, lung and glioma cancer models. We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

DOI: https://doi.org/10.1101/2025.03.19.644180
Cell Death Discov. 2025 Apr 04. 11(1): 139

Integrative insights into the role of CAV1 in ketogenic diet and ferroptosis in pancreatic cancer.

Xue Liang, Ruofei Tian, Ting Li, Hao Wang, Yifei Qin, Meirui Qian, Jing Fan, Dan Wang, Hong-Yong Cui, Jianli Jiang.

Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.

DOI: https://doi.org/10.1038/s41420-025-02421-z
Cell Death Dis. 2025 Apr 03. 16(1): 240

TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy.

Wenhao Mao, Qian Jiang, Yadan Feng, Chen Peng, Hui Peng, Xuan Li, Lin Jiao, Li Zhang, Liwei Ma, Ting Sun.

Pancreatic cancer remains the most lethal human malignancy with limited clinical benefits from currently available anticancer treatments. Ferroptosis has recently attracted great attention as a potential antineoplastic strategy. However, the study of ferroptosis in PDAC remains insufficient. This study revealed that Methyltransferase like 3 (METTL3), as a key oncogenic factor, is frequently upregulated and inhibits ferroptosis by stabilizing SLC7A11 mRNA in PDAC. In addition, we identified a novel post-translational modification of METTL3 and characterized specific regulatory mechanisms of METTL3 protein degradation. The E3 ligase TRIM21 mediated K48-linked polyubiquitination of METTL3 at the K459 site, leading to the proteasomal degradation of METTL3, which prevented tumor progression by promoting ferroptosis. Interestingly, the TRIM21-METTL3 axics mediated ferroptosis effectively increased the expression of immune checkpoint PD-L1 and strengthened antitumor immunity in pancreatic cancer. Together, our findings first elucidated the detailed molecular mechanism of METTL3 degradation and revealed the pivotal role of the TRIM21-METTL3 axis in regulating ferroptosis and antitumor immunity, which may serve as a potential target for pancreatic cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07550-y
Cell Death Dis. 2025 Apr 01. 16(1): 233

Targeting METTL3 mitigates venetoclax resistance via proteasome-mediated modulation of MCL1 in acute myeloid leukemia.

Chang-Qing Jiao, Chen Hu, Meng-Hua Sun, Yan Li, Chao Wu, Fei Xu, Lei Zhang, Fu-Rong Huang, Jun-Jie Zhou, Ji-Fei Dai, Min Ruan, Wen-Chao Wang, Qing-Song Liu, Jian Ge.

Venetoclax, a selective BCL2 inhibitor, is extensively utilized in clinical settings for the treatment of acute myeloid leukemia (AML). However, its efficacy is often compromised by the development of drug resistance. Hence, identification of potential venetoclax combination treatment strategies is imperative to overcome this acquired resistance. In this study, we discovered that inhibition of METTL3 can synergistically enhance the anti-leukemic efficacy of venetoclax, and is capable of overcoming venetoclax resistance in in vivo experiments and various venetoclax resistance models. Mechanistic study revealed that STM2457 augmented venetoclax activity by downregulating MCL1 and MYC, thereby increasing apoptosis in leukemia cells induced by venetoclax. Further investigation demonstrated that STM2457 promotes the ubiquitination and subsequent protein degradation of MCL1 primarily through pharmaceutically targeting METTL3. Moreover, through molecular docking-based virtual screening, we identified isoliquiritigenin as a potential novel small molecule natural product targeting METTL3, which exhibited potential effects as an anti-leukemic agent.

DOI: https://doi.org/10.1038/s41419-025-07560-w
J Cell Mol Med. 2025 Apr;29(7): e70519

NUPR1 Promotes Radioresistance in Colorectal Cancer Cells by Inhibiting Ferroptosis.

Yimin Fang, Haiyan Chen, Yunhua Liu, Kai Jiang, Yucheng Qian, Jingsun Wei, Dongliang Fu, Hang Yang, Siqi Dai, Tian Jin, Tongtong Bu, Kefeng Ding.

  Radioresistance is a major clinical challenge and the underlying mechanism has not been thoroughly elucidated. In this study, a radioresistant (RR) cell line is established to explore the transcriptomic signatures of radioresistance in colorectal cancer (CRC). KEGG enriched pathway analysis demonstrated that ferroptosis is inactivated in RR cells. Further detection confirmed that radiotherapy can promote ferroptosis, and ferroptosis inactivation is one of the hallmarks of radioresistance in CRC. What's more, induction of ferroptosis can restore the radiosensitivity of CRC cells. Then, we performed RNA sequencing to compare gene expression between parental and RR cells, and cells pretreated with or without RSL3. Via high-throughput screening, NUPR1 was identified as a potential candidate for ferroptosis-mediated radioresistance in CRC. CRC cells can acquire radiation resistance by NUPR1-mediated ferroptosis suppression in the NUPR1-overexpressing cell line. More importantly, ZZW-115, an NUPR1 inhibitor, can sensitise RR cells to radiotherapy. Overall, our findings identify ferroptosis inactivation linked with resistance to radiotherapy. Besides, NUPR1 can promote radiation resistance by inhibiting ferroptosis, and targeting NUPR1 may be a potential strategy to relieve radioresistance associated with ferroptosis in CRC.

Keywords:  NUPR1; colorectal cancer; ferroptosis; radiotherapy resistance

DOI:  https://doi.org/10.1111/jcmm.70519
Cell Rep. 2025 Apr 01. pii: S2211-1247(25)00258-X. [Epub ahead of print]44(4): 115487

Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription.

Wen-Juan Li, Yan-Chao Chen, Yi-An Lin, Yi-Qin Zou, Guo-Sheng Hu, Jing-Jing Yang, Xin-Yu Nie, Mei-Yan Li, Yi-Ran Wang, Yao-Hui He, Yan Zhao, Yu-Hua Tan, Xianming Deng, Wei-Ling He, Yan Cheng, Fang-Meng Fu, Wen Liu.

  Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in breast cancer cells. In turn, PRMT1 enhances the expression of HIF1α-driven glycolytic genes. Mechanistically, PRMT1 methylates HIF2β at arginine 42, facilitating the formation, chromatin binding, and the transcriptional activity of the HIF1α/HIF2β heterodimer. Genetic and pharmacological inhibition of PRMT1 suppresses HIF2β methylation, HIF1α/HIF2β heterodimer formation, chromatin binding, glycolytic gene expression, lactate production, and the malignant behaviors of breast cancer cells. Moreover, combination treatment with iPRMT1, a PRMT1 inhibitor, and menadione, an HIF1α/P300 interaction inhibitor, demonstrates synergistic effects in suppressing breast tumor growth. Clinically, PRMT1 and PRMT1-mediated HIF2β methylation were significantly elevated in breast tumors compared with adjacent normal tissues. In conclusion, our findings reveal the critical role of PRMT1-mediated arginine methylation in glycolytic gene expression, metabolic reprogramming, and breast tumor growth.

Keywords:  CP: Cancer; CP: Metabolism; HIF2β; arginine methylation; breast cancer; glycolytic gene expression; hypoxia; lactate production; menadione

DOI:  https://doi.org/10.1016/j.celrep.2025.115487
Cell Commun Signal. 2025 Apr 02. 23(1): 164

Atovaquone-induced activation of the PERK/eIF2α signaling axis mitigates metabolic radiosensitisation.

Jie Feng, Varun Pathak, Niall M Byrne, Sarah Chambers, Tongchuan Wang, Rayhanul Islam, Reinhold J Medina, Jonathan A Coulter.

   BACKGROUND: Hypoxia, a key feature of most solid tumours, including head and neck cancer, reduces radiotherapy efficacy by promoting radiation resistance through micro-environmental and genomic alterations. Addressing these resistance mechanisms is crucial, as radiotherapy remains central to managing locally advanced disease. Atovaquone, a mitochondrial electron transport chain complex III inhibitor, is reported to reduce tumour hypoxia in preclinical models, however, this response does not consistently enhance radiation sensitivity. This work examines the potential of atovaquone to modify the hypoxic response in models of head and neck squamous cell carcinoma (HNSCC), uncovering an adaptive resistance mechanism driven by integrated stress response (ISR) signaling that limits the radiosensitising potential of this approach.
METHODS: The bioenergetic response of HNSCC cells to atovaquone was assessed using the Seahorse XFe96 Analyzer with the XF Cell Mito Stress Test. Radiation dose modifying effects of atovaquone were tested by clonogenic survival assays, while ROS yields were analysed by flow cytometry. Western blotting and quantitative reverse transcription-PCR were employed to study activation of ISR signaling and the overall influence of atovaquone on the hypoxic response. Finally, the role of the ISR activation in modulating radiosensitivity was investigated using both siRNA and pharmacological inhibition of eIF2α, a central regulator of the ISR.
RESULTS: Herein we report that atovaquone significantly disrupts mitochondrial respiration, triggering phosphorylation of eIF2α, a pivotal regulator of the ISR, and a master regulator of protein synthesis. Notably, atovaquone also increased the autophagic load under hypoxia, while autophagy inhibition significantly enhanced apoptosis, improving radiation sensitivity. Combined eIF2α inhibition and atovaquone promotes cell cycle redistribution and significantly enhances mitochondrial ROS production and compared to atovaquone alone, restoring atovaquone mediated radiosensitisation.
CONCLUSIONS: Our data highlight dual counter opposing impacts of atovaquone, serving as a hypoxic radiosensitiser though oxidative phosphorylation (OXPHOS) inhibition, but also in promoting stress induced ISR signaling, conferring resistance to radiation treatment. Importantly, if ISR activation is impeded, the metabolic radiosensitising properties of atovaquone is restored. These data provide a new insight to a molecular response that could help counteract hypoxia-induced radioresistance.

Keywords:  Autophagy; ER stress; Hypoxia; Radiosensitisation

DOI:  https://doi.org/10.1186/s12964-025-02160-9
bioRxiv. 2025 Mar 13. pii: 2025.03.11.642569. [Epub ahead of print]

Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis.

Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.

Nucleotides are essential for nucleic acid synthesis, signaling, and metabolism, and can be synthesized de novo or through salvage. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target for cancer therapy. However, resistance frequently emerges, highlighting the need for a deeper understanding of nucleotide regulation. Here, we harness uridine salvage and CRISPR-Cas9 screening to reveal regulators of de novo pyrimidine synthesis. We identify several factors and report that pyrimidine synthesis can continue in the absence of coenzyme Q (CoQ), the canonical electron acceptor in de novo synthesis. We further investigate NUDT5 and report its conserved interaction with PPAT, the rate-limiting enzyme in purine synthesis. We show that in the absence of NUDT5, hyperactive purine synthesis siphons the phosphoribosyl pyrophosphate (PRPP) pool at the expense of pyrimidine synthesis, promoting resistance to chemotherapy. Intriguingly, the interaction between NUDT5 and PPAT appears to be disrupted by PRPP, highlighting intricate allosteric regulation. Our findings reveal a fundamental mechanism for maintaining nucleotide balance and position NUDT5 as a potential biomarker for predicting resistance to chemotherapy.

DOI: https://doi.org/10.1101/2025.03.11.642569
J Adv Res. 2025 Mar 29. pii: S2090-1232(25)00212-7. [Epub ahead of print]

Exploiting metabolic vulnerabilities through synergistic ferroptosis and disulfidptosis for breast cancer therapy.

Yu Liang, Haibo Lan, Qiuyu Li, Mengdan Gao, Minyi Liu, Ziting Xu, Yang Gao, Li Zhang, Yingjia Li, Bingxia Zhao.

   INTRODUCTION: Ferroptosis represents a promising therapeutic approach for breast cancer treatment. However, cancer cells can develop resistance through the SLC7A11-GSH-GPX4 axis, wherein increased SLC7A11 expression enhances cystine uptake, replenishes GSH, and reactivates GPX4. Notably, cells with high SLC7A11 expression become vulnerable to disulfidptosis under glucose-deprived conditions.
OBJECTIVES: We aimed to develop a dual-mode therapeutic strategy that simultaneously induces ferroptosis and disulfidptosis by targeting both lipid peroxidation and glucose metabolism in breast cancer cells.
METHODS: Fe-Cu-SS metal-organic frameworks (MOFs) loaded with BAY876 (FCSP@876 MOFs) were synthesized to enhance ferroptosis and trigger disulfidptosis in breast cancer cells. The MOFs were characterized using transmission electron microscopy (TEM), Fourier-transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and UV-Vis spectroscopy. In vitro experiments demonstrated that FCSP@876 MOFs increased reactive oxygen species (ROS) levels and lipid peroxidation while depleting NADPH. Western blotting and actin filament staining confirmed the underlying mechanisms. In vivo xenograft experiments in BALB/c mice assessed the synergistic effects of ferroptosis and disulfidptosis induction.
RESULTS: During ferroptosis induction, cancer cells exhibited an adaptive upregulation of SLC7A11 expression. FCSP@876 MOFs effectively counteracted this resistance mechanism by simultaneously inducing ferroptosis and restricting glucose uptake through BAY876, leading to NADPH depletion and subsequent disulfidptosis. Both in vitro and in vivo experiments demonstrated the enhanced therapeutic efficacy of this dual-mode strategy compared with single-mode treatments.
CONCLUSION: This study successfully developed a novel therapeutic strategy that combines ferroptosis and disulfidptosis using FCSP@876 MOFs, offering a promising approach for overcoming ferroptosis resistance in breast cancer therapy.

Keywords:  Disulfidptosis; Ferroptosis; Glucose dependency; SLC7A11

DOI:  https://doi.org/10.1016/j.jare.2025.03.052
J Cancer Res Clin Oncol. 2025 Mar 28. 151(3): 126

Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism.

Qiu-Yu Zhao, Wen-Jun Liu, Jian-Guang Wang, He Li, Jia-Lu Lv, Yumeng Wang, Chun Wang.

   OBJECTIVES: Lung cancer is a leading cause of global cancer mortality. Clinical observations reveal that histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is accompanied by mutations in TP53 and RB1. By applying gradually increasing cisplatin concentrations to mimic the escalating drug pressure within the tumor microenvironment, this study investigated the link between phenotypic transformation to SCLC in cisplatin-resistant human lung adenocarcinoma cells and alterations in cellular energy production pathways.
MATERIALS AND METHODS: We established two cisplatin-resistant NSCLC cell lines with varying resistance levels. RNAseq analyses identified TP53 and RB1 gene mutations. Comprehensive functional assays were performed to characterize A549/DDP1 μg/mL and A549/DDP3 μg/mL cells, focusing on proliferation and migratory capabilities. Cellular bioenergetics were assessed through glycolysis and oxidative phosphorylation analyses. Western blotting was employed to examine epithelial-mesenchymal transition (EMT), glucose metabolism, and lipid metabolism markers. Cell cycle distribution was analyzed by flow cytometry. Additionally, a xenograft mouse model was developed for in vivo validation.
RESULTS: TP53 and RB1 mutations were associated with cisplatin concentration-dependent phenotypic transformation, with A549/DDP cells acquiring a more aggressive SCLC-like phenotype (In the article we call the A549/DDPSCLC cells). Analysis of cell bioenergetics profiling and Western blot analyses revealed enhanced glucose metabolism in A549/DDP1 μg/mL cells, while A549/DDPSCLC cells exhibited predominant lipid metabolism. Compound3K and Etomoxir specifically inhibit the activity of PKM2 and CPT1A, respectively, with Etomoxir demonstrating substantially inhibited A549/DDPSCLC cells growth and more cell cycle arrest in the G0/G1 phase. Combinatorial of Compound3K and Etomoxir effectively induced cell death in A549/DDPSCLC phenotype cells in vitro. Etomoxir alone or combined with Compound3K significantly inhibited tumor growth in vivo, with enhanced efficacy in the combination group.
CONCLUSIONS: This study provides the first evidence of cisplatin concentration-dependent metabolic reprogramming during NSCLC-to-SCLC transformation. We identified a phenotypic transition from NSCLC to SCLC accompanied by a metabolic shift from glucose to fatty acid metabolism, offering new insights into therapeutic strategies for treatmentresistant lung cancer.

Keywords:   RB1 ; TP53 ; Fatty acid metabolism; Glucose metabolism; NSCLC; Phenotype

DOI:  https://doi.org/10.1007/s00432-025-06164-3
Oncogene. 2025 Apr 03.

Syntaxin-6 mediated autophagy confers lenvatinib resistance in hepatocellular carcinoma.

Guo-Pei Zhang, Ze-Bing Song, De-Hua Chen, Yang Yu, Fei-Feng Wu, Ming Kuang, Shao-Qiang Li.

Lenvatinib is the first-line therapy for inoperable HCC. However, intrinsic and acquired drug resistance occurs during the treatment period. Autophagy is an adaptive response that favors tumor survival under stress. In the present study, we aim to reveal the unknown autophagic engagement in lenvatinib resistance. Lenvatinib-resistant HCC cell lines and xenograft mouse HCC models were established to identify the key regulator of lenvatinib resistance in HCC. By in vitro functional restoration assays and autophagic flux detection, we demonstrated that the Syntaxin-6 (STX6) -mediated autophagy induced lenvatinib resistance of HCC cells. Mechanistically, Co-immunoprecipitation assay and mass spectrometry indicated that the interactions of STX6 with Beclin1, VTI1A, and VAMP3 facilitated autophagy, leading to the lenvatinib resistance. Additionally, STX6 enhanced the ability of proliferation, migration, and invasion of HCC in vitro and in vivo. Clinically, STX6 expression was significantly elevated in HCC tissues compared to it in para-tumor tissues. High STX6 expression predicted poor outcomes for patients following resection. Moreover, high expression of STX6 displayed low preventive efficacy of lenvatinib as a postoperative adjuvant treatment for HCC patients with a high risk of recurrence. Collectively, we identified that STX6-mediated autophagy plays a crucial role in lenvatinib resistance in HCC, providing a potential therapeutic target to overcome lenvatinib resistance for HCC patients.

DOI: https://doi.org/10.1038/s41388-025-03371-7
EMBO J. 2025 Mar 31.

SIRT5-mediated desuccinylation of PPA2 enhances HIF-1alpha-dependent adaptation to hypoxic stress and colorectal cancer metastasis.

Xiang Zhang, Yuqin Di, Youpeng Wang, Jiale Qin, Lvlan Ye, Xiangqiong Wen, Zunfu Ke, Ziyang Wang, Weiling He.

  Metastasis is the primary cause of death in patients with colorectal cancer (CRC). Hypoxia is a hallmark of solid tumors that promotes cellular metabolic adaptation and dissemination. However, the mechanisms linking hypoxia-regulated metabolic adaptation to CRC metastasis remain unclear. Here, we found that inorganic pyrophosphatase 2 (PPA2) suppresses metastatic progression of CRC via its phosphatase function. PPA2 expression levels are reduced in CRC specimen and correlate with enhanced response to hypoxia by promoting hypoxia-inducible factor-1 (HIF-1) signaling to promote CRC cell glycolysis and dissemination. Mechanistically, PPA2 decreases HIF-1alpha stability through non-canonical ubiquitin-mediated proteasomal degradation via recruitment of E3 ligase NEDD4. Furthermore, PPA2 directly dephosphorylates NEDD4 at threonine 758 residue, resulting in its activation. Under hypoxic stress, NAD-dependent protein deacetylase sirtuin-5 promotes the dissociation of PPA2 and NEDD4 by inducing PPA2 desuccinylation at lysine 176, contributing to the improved stability of HIF-1alpha under hypoxic conditions. Our findings reveal a tumor-suppressive role of PPA2 in HIF-1alpha-dependent colorectal cancer, providing a potential therapeutic target and prognostic strategy.

Keywords:  HIF-1α; Hypoxia; Metastatic Colorectal Cancer; NEDD4; PPA2 Succinylation

DOI:  https://doi.org/10.1038/s44318-025-00416-1
Drug Resist Updat. 2025 Mar 22. pii: S1368-7646(25)00040-8. [Epub ahead of print]81 101240

Targeting cTRIP12 counteracts ferroptosis resistance and augments sensitivity to immunotherapy in pancreatic cancer.

Hongyi Lin, Shuncang Zhu, Yinhao Chen, Jinpeng Lu, Chengke Xie, Chengyu Liao, Xiaoxiao Huang, Ge Li, Yongding Wu, Zhiyuan Li, Jianfei Hu, Xinquan Lin, Yifeng Tian, Qiaowei Li, Zuwei Wang, Shi Chen.

   AIMS: Current therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) have limited efficacy in increasing patient survival rates, largely due to ferroptosis resistance and immunosuppression. The aim of this study is to identify molecular mechanisms associated with ferroptosis resistance and immunosuppression in PDAC tumour cells.
METHODS: Circular RNA sequencing (circRNA-seq) was performed on clinical samples to identify potential circRNAs that mediate ferroptosis resistance. C11-BODIPY staining, FerroOrange staining, the glutathione ratio, malondialdehyde quantification, and transmission electron microscopy were employed to assess ferroptosis. RNA pulldown, mass spectrometry, RNA immunoprecipitation, and coimmunoprecipitation assays were conducted to investigate the molecular mechanisms involved. A HuNSG mouse xenograft tumour model was utilized to validate therapeutic agents.
RESULTS: A circRNA derived from TRIP12 (cTRIP12) was identified in PDAC samples resistant to ferroptosis. cTRIP12 knockdown increased the sensitivity of PDAC cells to ferroptosis and immunotherapy. Subsequent mechanistic studies revealed that cTRIP12 specifically binds to the O-linked N-acetylglucosamine transferase (OGT) protein and increases intracellular O-GlcNAcylation levels, leading to increased protein levels of ferritin heavy chain (FTH) and PD-L1 in tumour cells. Notably, high cTRIP12 expression suppressed ferroptosis sensitivity and increased immune resistance in PDAC cells by functioning as a protein scaffold through its interaction with OGT and protein kinase R-like endoplasmic reticulum kinase (PERK). cTRIP12 inhibition induced ferroptosis in PDAC cells by reducing FTH and PD-L1 expression and synergistically increased the immunotherapy efficacy. In vivo animal experiments confirmed that the triple therapy consisting of GSK2656157, erastin, and anti-CTLA-4 effectively suppressed the progression of PDAC in tumours with high cTRIP12 expression.
CONCLUSION: We elucidated the molecular mechanisms underlying the simultaneous occurrence of ferroptosis resistance and immune suppression in PDAC patients. Our study provides a novel therapeutic strategy that could promote ferroptosis in tumour cells and increase immunotherapy efficacy.

Keywords:  Circular RNA; Ferroptosis; Immunotherapy; O-GlcNAcylation; Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.drup.2025.101240
bioRxiv. 2025 Mar 21. pii: 2025.03.20.644389. [Epub ahead of print]

In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS -mutant cancer.

Matthew Decker, Benjamin J Huang, Timothy Ware, Christopher Boone, Michelle Tang, Julia Ybarra, Aishwarya C Ballapuram, Katrine A Taran, Pan-Yu Chen, Marcos Amendáriz, Camille J Leung, Max Harris, Karensa Tjoa, Henry Hongo, Sydney Abelson, Jose Rivera, Nhi Ngo, Dylan M Herbst, Radu M Suciu, Carlos Guijas, Kimia Sedighi, Taylor Andalis, Elysia Roche, Boer Xie, Yunlong Liu, Catherine C Smith, Elliot Stieglitz, Micah J Niphakis, Benjamin F Cravatt, Kevin Shannon.

Normal and oncogenic Ras proteins are functionally dependent on one or more lipid modifications 1,2 . Whereas K-Ras4b farnesylation is sufficient for stable association with the plasma membrane, farnesylated H-Ras, K-Ras4a, and N-Ras traffic to the Golgi where they must undergo palmitoylation before regulated translocation to cell membranes. N-Ras palmitoylation by the DHHC family of palmitoyl acyl transferases (PATs) and depalmitoylation by ABHD17 serine hydrolases is a dynamic process that is essential for the growth of acute myeloid leukemias (AMLs) harboring oncogenic NRAS mutations 3-6 . Here, we have tested whether co-targeting ABHD17 enzymes and Ras signal output would cooperatively inhibit the proliferation and survival of NRAS -mutant AMLs while sparing normal tissues that retain K-Ras4b function. We show that ABD778, a potent and selective ABHD17 inhibitor with in vivo activity, selectively reduces the growth of NRAS -mutant AML cells in vitro and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901) 7,8 . Similarly, ABD778 and PD901 significantly extended the survival of recipient mice transplanted with three independent primary mouse AMLs harboring an oncogenic Nras G12D driver mutation. Resistant leukemias that emerged during continuous drug treatment acquired by-pass mutations that confer adaptive drug resistance and increase mitogen activated protein kinase (MAPK) signal output. ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib 9 , the K/N-Ras G12C inhibitor sotorasib 10 , and the FLT3 inhibitor gilteritinib 11 . Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other NRAS -mutant cancers.

DOI: https://doi.org/10.1101/2025.03.20.644389
J Pharmacol Exp Ther. 2025 Mar;pii: S0022-3565(24)42179-4. [Epub ahead of print]392(3): 100530

MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.

Ziqi Chen, Hekang Ding, Yunlong Zhu, Shuai Sun, Zhenyu Song, Li Zhang, Chaozhao Liang, Lingfan Xu.

  MicroRNAs play a crucial role in regulating tumor progression and invasion. Nevertheless, the expression of miRNA-335 in prostate cancer (PCa) and its clinical significance remain unelucidated. Here, we report that miRNA-335 functions as a tumor suppressor by regulating expression of glutaminase 1 (GLS1), a key enzyme of glutamine metabolism pathway, in PCa. In this study, we show that the expression of miRNA-335 is downregulated in PCa tissues. The level of miRNA-335 is even lower in highly invasive PCa cell lines. Furthermore, enhancing the expression of miRNA-335 inhibits PCa cell migration and invasion in vitro. Additionally, we identify GLS1 as the downstream effector, governed by miRNA-335 via 3'-untranslated region, and the direct regulation is verified by dual luciferase reporter assay. MiRNA-335 interrupts glutamine catabolism by inhibiting GLS1 enzymatic activity. Overexpression of miRNA-335 markedly suppresses tumor growth of PCa in vivo. To sum up, our results indicate that miRNA-335 acts as a tumor suppressor and has an important role in restraining the metastasis of PCa cells by targeting GLS1. These discoveries indicate that miRNA-335 could serve as a new prospective therapeutic target for PCa. SIGNIFICANCE STATEMENT: miRNA-335, a metabolism-related microRNA, is a potential therapeutic target for prostate cancer by interfering with glutaminase 1 activity.

Keywords:  Glutaminase 1; Glutamine; MicroRNA; MicroRNA-335; Prostate cancer; miRNA-335

DOI:  https://doi.org/10.1016/j.jpet.2024.100530
J Clin Invest. 2025 Apr 01. pii: e191422. [Epub ahead of print]135(7):

Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma.

Qun Chen, Hao Yuan, Michael S Bronze, Min Li.

Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive tumor microenvironment (TME) characterized by elevated lactate levels, which contribute to immune evasion and therapeutic resistance. In this issue of the JCI, Sun, Zhang, and colleagues identified nonhistone ENSA-K63 lactylation as a critical regulator that inactivates PP2A, activates STAT3/CCL2 signaling, recruits tumor-associated macrophages (TAMs), and suppresses cytotoxic T cell activity. Targeting ENSA-K63 lactylation or CCL2/CCR2 signaling reprograms the TME and enhances the efficacy of immune checkpoint blockade (ICB) in PDAC preclinical models. This work provides critical insights into the metabolic-immune crosstalk in PDAC and highlights promising therapeutic strategies for overcoming immune resistance and improving patient outcomes.

DOI: https://doi.org/10.1172/JCI191422
Immunity. 2025 Mar 21. pii: S1074-7613(25)00096-2. [Epub ahead of print]

Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer.

Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L Chan, Bo Wei, Philip L Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, David G Edwards, Livia S Eberlin, Xiang H-F Zhang.

  The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of omega-6 fatty acids or inhibiting fatty acid elongation for AA synthesis restores anti-tumor immunity and re-sensitizes the resistant tumors to anti-PD-1 and chemotherapy treatment. In human patients, AA metabolism-related pathways correlates with neutrophil enrichment. Overall, we demonstrate how lipid accumulation in TNBC cells leads to immune suppression and therapy resistance.

Keywords:  arachidonic acid; extracellular vesicles; immunotherapy; neutrophils; triple negative breast cancer

DOI:  https://doi.org/10.1016/j.immuni.2025.03.002
J Clin Invest. 2025 Apr 01. pii: e189197. [Epub ahead of print]135(7):

Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression.

Shike Wang, Houfu Guo, Reo Fukushima, Masahiko Terajima, Min Liu, Guan-Yu Xiao, Lenka Koudelková, Chao Wu, Xin Liu, Jiang Yu, Emma Burris, Jun Xu, Alvise Schiavinato, William K Russell, Mitsuo Yamauchi, Xiaochao Tan, Jonathan M Kurie.

  Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2-modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain α3 (Col6a3), a component of the Col6 heterotrimeric molecule, as a candidate LH2 substrate. In gain- and loss-of-function studies, high Col6a3 levels increased tumor growth and metastatic activity and enhanced the proliferative, migratory, and invasive activities of LUAD cells. LH2 coimmunoprecipitated with Col6a3, and LH2 glucosylated Col6 in an in vitro reaction. Glucosylation increased the integrin-binding and promigratory activities of Col6 in LUAD cells. Col6a3 K2049 was deglucosylated in GGT-inactive tumor samples, and mutagenesis of Col6a3 K2049 phenocopied Col6a3 deficiency or LH2 GGT domain inactivation in LUAD cells. Thus, LH2 glucosylates Col6 to drive LUAD progression. These findings show that the GGT domain of LH2 is protumorigenic, identify Col6 as a candidate effector, and provide a rationale to develop pharmacological strategies that target LH2's GGT domain in cancer cells.

Keywords:  Cell biology; Collagens; Integrins; Lung cancer; Oncology

DOI:  https://doi.org/10.1172/JCI189197