bims-cesirm 2026-01-04 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–01–04
twenty-two papers selected by
Tigist Tamir, University of North Carolina

Circular RNA-based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer.
A tumor-derived lactate/ENO1 lactylation feedback loop facilitates osimertinib resistance of lung adenocarcinoma.
Improvements to Casanovo, a Deep Learning De Novo Peptide Sequencer.
Exploring the interplay between protein conformational changes and phosphorylation in a pancreatic cancer cell and stellate cell coculture system.
Harnessing m6A-regulated cholesterol biosynthesis helps impede tumor burden and stemness in high-garde serous ovarian carcinoma mesenchymal phenotype.
Synteny - a high throughput web tool to streamline causal gene prioritisation and provide insight into protein function.
Targeting Tumor Microenvironment-Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer.
Real-World Treatment Outcomes in Patients With Ga68-PSMA-PET Positive Metastatic Hormone-Sensitive Prostate Cancer With or Without Conventional Imaging Correlates.
ENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer.
DeepTESite: The Prediction of Protein Arginine Methylation Sites using Amino Acids Sequence Symmetric Position Encodings Based on Transformer Encoder.
Riboflavin-PLGA nanoparticles enhance the effectiveness of the pyruvate carboxylase inhibitor ZY-444 in targeting lipogenesis in colon and breast cancer.
Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer.
Extracellular Vesicle-Mediated Delivery of Antioxidant Enzymes: Emerging Insights and Translational Opportunities.
Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma.
Pharmacological Inhibition of Pyruvate Dehydrogenase Kinase 4 Enhances Insulin Sensitivity in Mouse Models of Diabetes and Obesity.
GAN-enhanced machine learning and metabolic modeling identify reprogramming in pancreatic cancer.
Improved preanalytical workflow for pancreatic tissue lipidomics: Insights into lipid stability and polar lipid recovery.
Characterization of Differential GPX4 Essentiality Between Intrahepatic and Extrahepatic Cholangiocarcinoma via Leveraging of a Large-Scale Functional Genomic Screen.
Cationic liposome-based silencing of thioredoxin reductase-1 for sensitization of MDA-MB 231 cells to gamma radiation.
NADK Governs Ferroptosis Susceptibility by Orchestrating NADPH Homeostasis.
Hyaluronic acid regulates cellular UDP-GlcNAc levels through CD44 to affect glycosylation and cell biological functions.
The Molecular Landscape and Utility of Multiomic Analyses in Triple-Negative Breast Cancer: Further Subtyping and Exploring Novel Biomarkers and Therapeutic Targets.

Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2504904123

Circular RNA-based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer.

Yudong Lin, Ruyue Wang, Fan Li, Zeyi Lu, Wenqin Luo, Haohua Lu, Zhehao Xu, Chang Xu, Yi Lu, Ziwei Zhu, Yang Li, Xudong Mao, Liqun Xia, Xiaojing Yu, Wenjing Su, Lifeng Ding, Gonghui Li.

  Androgen receptor (AR) signaling is essential for prostate cancer (PCa) cell growth and remains a key therapeutic target in castration-resistant PCa (CRPC). While circular RNAs (circRNAs) are increasingly recognized as important regulatory molecules, their roles in AR signaling during PCa progression remain poorly understood. This study identified circUTRN, an AR-inhibited circRNA that is upregulated following neoadjuvant hormonal therapy and downregulated in PCa tissues. circUTRN inhibits proliferation in both castration-sensitive and castration-resistant PCa. Mechanistically, circUTRN binds to acetyl-CoA carboxylase 1 (ACC1) and impairs the activity through both phosphorylation-dependent and independent pathways, thereby disturbing de novo fatty acid synthesis. The dynamic relation between circUTRN and ACC1 expression during PCa progression from treatment-naïve to therapeutic-resistant states highlights the metabolic vulnerability of fatty acid synthesis. Notably, we developed nanoparticles to deliver circUTRN in combination with AR signaling inhibitors (ARSIs). This approach effectively suppressed CRPC xenograft tumor growth, even in models resistant to next-generation ARSIs. This study reveals an AR-regulated circRNA involved in PCa progression and suggests a potential therapeutic strategy for treatment-resistant PCa.

Keywords:  acetyl-CoA carboxylase 1; androgen receptor; castration-resistant prostate cancer; circular RNA; fatty acid synthesis

DOI:  https://doi.org/10.1073/pnas.2504904123
Drug Resist Updat. 2025 Dec 26. pii: S1368-7646(25)00149-9. [Epub ahead of print]85 101346

A tumor-derived lactate/ENO1 lactylation feedback loop facilitates osimertinib resistance of lung adenocarcinoma.

Lu Gan, Qihai Sui, Mi-Die Xu, Fei Yang, Ming Li, Yitao Yuan, Yufu Lin, Xiuping Zhang, Guoshu Bi, Wei Jiang, Qun Wang, Wei Nie, Liang Liu, Fenghao Sun.

  Enhanced glycolysis and lactate accumulation are shared features of human cancers. Lactylation is a lactate-derived posttranslational modification. So far, the impact of lactylation on resistance to osimertinib (a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)) in patients with lung adenocarcinoma (LUAD) remains indistinct. Here, we performed 4D label-free proteomics analysis of LUAD tissues from advanced-stage EGFR-mutant patients treated with surgery with or without neoadjuvant osimertinib to reveal a global lactylation profile and explore the role and molecular mechanism of protein lactylation in resistance to osimertinib. Through scanning the lactylated proteome, we discovered that α-Enolase 1 (ENO1), which acts as a key glycolytic enzyme, underwent lactylation at lysine 89 (K89) in LUAD tissues. The levels of ENO1 lactylation were notably attenuated in LUAD tissues after effective osimertinib treatment and were notably elevated in osimertinib-resistant LUAD cells. We found that monocarboxylate transporters (MCTs) facilitated lactate uptake into LUAD cells for ENO1 lactylation primarily through a p300/CREB-binding protein C (CBP)-dependent mechanism. ENO1 facilitated metabolic reprogramming and lactate production and interacted with several key metabolic enzymes, such as pyruvate kinase M1 (PKM1), pyruvate kinase M2 (PKM2), lactate dehydrogenase B (LDHB), and malate dehydrogenase 2 (MDH2), thus forming a tumor-derived lactate/ENO1 lactylation feedback loop, eventually contributing to osimertinib resistance in LUAD. In the in vivo orthotopic xenograft osimertinib-resistant models, targeted suppression of the tumor-derived lactate/ENO1 lactylation feedback loop effectively ameliorated resistance to osimertinib. Collectively, our findings provide the basis for targeting lactate/lactate-associated signaling to combat resistance to osimertinib.

Keywords:  ENO1; Lactylation; Lung adenocarcinoma; MCT; Osimertinib resistance; P300/CBP

DOI:  https://doi.org/10.1016/j.drup.2025.101346
J Proteome Res. 2025 Dec 30.

Improvements to Casanovo, a Deep Learning De Novo Peptide Sequencer.

Gwenneth Straub, Varun Ananth, William E Fondrie, Chris Hsu, Daniela Klaproth-Andrade, Marina Pominova, Michael Riffle, Justin Sanders, Bo Wen, Lingwen Xu, Melih Yilmaz, Michael J MacCoss, Sewoong Oh, Wout Bittremieux, William Stafford Noble.

  Casanovo is a state-of-the-art deep learning model for de novo peptide sequencing from mass spectrometry and proteomics data. Here, we report on a series of enhancements to Casanovo, aimed at improving the interpretability of the scores assigned to predicted peptides, generalizing the software for use in database searches, speeding up training and prediction runtimes, and providing workflows and visualization tools to facilitate adoption of Casanovo and interpretation of its results. Our goal is to make Casanovo accurate and easy to use for applications such as metaproteomics, antibody sequencing, immunopeptidomics, and the discovery of novel peptide sequences in standard proteomics analyses. Casanovo is available as open source at https://github.com/Noble-Lab/casanovo.

Keywords:  de novo; deep learning; mass spectrometry; sequencing

DOI:  https://doi.org/10.1021/acs.jproteome.5c00706
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2511839122

Exploring the interplay between protein conformational changes and phosphorylation in a pancreatic cancer cell and stellate cell coculture system.

Haiyan Lu, Yuan Liu, Hung-Yu Chiang, Hua Zhang, Xudong Shi, Lingjun Li.

  A global exploration of the complex interplay between protein conformational changes and phosphorylation events in cell-cell interactions is crucial for understanding the dynamic nature of protein modifications. This understanding is essential for developing novel targeted therapies for pancreatic cancer, particularly in the context of interactions between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). However, protein conformational changes that occur during PCCs-PSCs interactions remain poorly studied, and the relationship between these changes and phosphorylation is not well understood. Here, we present a comprehensive mass spectrometry-based study investigating the interplay between protein conformational alterations and phosphorylation in a coculture system of pancreatic ductal adenocarcinoma cells (PANC-1) and PSCs. Our results demonstrate that 435 proteins exhibiting conformational changes were detected during the coculture of PANC-1 with PSCs, primarily involving proteins associated with the tricarboxylic acid (TCA) cycle, glycolysis/gluconeogenesis, and carbon metabolism. Our findings also highlight a potential association between phosphorylation and protein conformational changes. Moreover, we identified five potential conformational targets, including ACLY, ACO1, ACO2, IDH1, and OGDH, which may provide valuable insights into the molecular pathways underlying gemcitabine resistance in pancreatic cancer. Overall, these results offer insights into protein conformational changes and their potential link to phosphorylation in the context of cancer-stromal cell interactions, paving the way for structure-based, targeted therapeutic strategies for pancreatic cancer treatment.

Keywords:  cell–cell interactions; mass spectrometry; pancreatic cancer; phosphorylation; structural proteomics

DOI:  https://doi.org/10.1073/pnas.2511839122
Mol Med. 2025 Dec 29.

Harnessing m6A-regulated cholesterol biosynthesis helps impede tumor burden and stemness in high-garde serous ovarian carcinoma mesenchymal phenotype.

Aravindan Narayanan, Kiran Dhenge, Sharmila A Bapat.

  Post-transcriptional RNA modifications have emerged as critical regulators of stemness, cellular plasticity, adaptation to stress and transformation. Amongst these the N6-methyladenosine (m6A) modification orchestrates a wide range of physiological processes; yet its contribution to metabolic regulation remains poorly addressed. In the present study, differential proteomics revealed enrichment of core components of the m6A machinery, viz. WTAP (writer) and IGF2BP3 (reader) in stem-like cells of the mesenchymal subtype of High-Grade Serous Ovarian Carcinoma (HGSC). Intriguingly, components of de novo cholesterol biosynthesis were also enriched. In investigating the suggested link between m6A regulation and sterol metabolism, we established a m6A-dependent stabilization of transcripts encoding rate-limiting de novo cholesterol biosynthetic enzymes by IGF2BP3 towards sustaining cholesterol production. Disruption of this cross-regulation by pharmacological inhibition impaired cell survival, self-renewal, and migration. Analyses of datasets from The Cancer Genome Atlas (TCGA) assigned a clinical significance to this regulatory axis through correlation of elevated expression of de novo cholesterol biosynthetic genes with poor progression-free survival of serous ovarian carcinoma patients. IGF2BP3 knock down, and chemical blockade of de novo cholesterol biosynthesis, both alone or in combination, achieved attenuated disease progression, in vivo. Effectively, our study links RNA modifications with metabolic reprogramming in the HGSC mesenchymal subtype through delineation of a m6A-IGF2BP3-cholesterol biosynthesis axis-mediated regulation of tumor cell stemness and aggression.

Keywords:  De novo cholesterol biosynthesis; High-grade serous ovarian carcinoma; M6A RNA modification; Mesenchymal subtype; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s10020-025-01413-0
Sci Rep. 2025 Dec 29. 15(1): 44761

Synteny - a high throughput web tool to streamline causal gene prioritisation and provide insight into protein function.

Harry B Cutler, Jacqueline Stöckli, Søren Madsen, Stewart W C Masson, Oliver K Fuller, Tom Buckingham Shum, David E James.

  Accounting for human genetic evidence can improve the outcomes and impact of basic medical research studies. However, current approaches are incompatible with the high volume of disease-associated genes that require mechanistic interrogation and risk overlooking important phenotypic associations. Synteny responds to an urgent need in systems biology, scaling human genetic analysis to match the throughput of modern omics technologies. This approach prioritises candidates with the strongest human disease relevance and unearths functionally important proteins ( https://bigproteomics.shinyapps.io/Synteny/ ).

Keywords:  Candidate prioritisation; Causal genes; Disease-associated genes; Human genetic data; Proteomics; Systems biology; Transcriptomics

DOI:  https://doi.org/10.1038/s41598-025-28473-w
Mol Cancer Ther. 2025 Dec 30. OF1-OF10

Targeting Tumor Microenvironment-Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer.

Brian M Shinder, Young Sun Lee, Ninghui Mao, Nazifa Salsabeel, Zeda Zhang, Harmanpreet Kaur, Xiaoping Chen, Qing Chang, Elisa de Stanchina, Anuradha Gopalan, Charles L Sawyers, Brett S Carver.

Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)-targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAF) promotes antiandrogen resistance through human epidermal growth factor receptor 3 (HER3)-AKT signaling. In this study, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. IHC analysis of radical prostatectomy specimens from patients with prostate cancer treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition, independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, Zeno did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment-derived NRG1 affects responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN wild-type prostate cancers.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0505
Clin Genitourin Cancer. 2025 Nov 25. pii: S1558-7673(25)00176-4. [Epub ahead of print]24(1): 102476

Real-World Treatment Outcomes in Patients With Ga68-PSMA-PET Positive Metastatic Hormone-Sensitive Prostate Cancer With or Without Conventional Imaging Correlates.

Wadih Issa, Maureen Aliru, Song Zhang, Damla Gunenc, Changchuan Jiang, Qian Qin, Suzanne Cole, Waddah Arafat, Jue Wang, Daniel Yang, Neil Desai, Aurelie Garant, Raquibul Hannan, Orhan K Oz, Solomon Woldu, Yair Lotan, Claus Roehrborn, Kevin Courtney, Andrew Z Wang, Tian Zhang.

   BACKGROUND: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is highly sensitive, enabling detection of disease not visualized on conventional imaging, and leading to a new disease state: PSMA-avid/CT-negative metastatic prostate cancer. The optimal management and treatment outcomes for this group remain poorly defined. We investigated whether treatment intensification with androgen receptor signaling inhibitors (ARSI) provides additional benefit for these patients.
METHODS: We conducted a retrospective study of patients with metastatic hormone-sensitive prostate cancer (mHSPC) diagnosed via standard-of-care PSMA PET/CT imaging (Ga68 gozetotide/PSMA-11) at our institution. Patients were stratified based on whether PSMA-avid lesions (SUVmax > 2.5) had correlates on conventional imaging: PSMA (+)/CT (-) versus PSMA (+)/CT (+). We compared prostate-specific antigen progression-free survival (PSA PFS) and castration resistance-free survival (CRFS) between cohorts. OS was not assessed.
RESULTS: Among 159 patients, 81 (51%) had PSMA (+)/CT (-) and 78 (49%) had PSMA (+)/CT (+) disease. With a median follow up of 23 months, patients with PSMA (+)/CT (-) mHSPC had significantly longer PSA PFS (hazard ratio [HR] 0.31, P = .01) and CRFS (HR 0.08, P < .001). Within the PSMA (+)/CT (-) cohort, ARSI intensification did not improve CRFS compared to androgen deprivation therapy (ADT) monotherapy (HR 0.32, P = .33).
CONCLUSIONS: Patients with PSMA (+)/CT (-) mHSPC exhibit a more favorable prognosis with reduced risk of PSA progression and castration resistance compared to those with PSMA (+)/CT (+) disease. However, among patients treated with ADT alone, CRFS was similar across groups, suggesting that the benefit of ARSI intensification in PSMA (+)/CT (-) patients requires prospective validation.

Keywords:  AR treatment intensification; Androgen deprivation therapy; Androgen receptor inhibitor intensification

DOI:  https://doi.org/10.1016/j.clgc.2025.102476
Cell Death Dis. 2025 Dec 27.

ENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer.

Yongning Li, Hao Wang, Liwen Chen, Yanyu Gong, Dijie Zheng, Futang Li, Changhao Wu, Zhiwei He, Chao Yu.

Pancreatic ductal adenocarcinoma is a highly malignant solid tumor of the digestive tract, and chemoresistance to gemcitabine is an important cause of shortened survival time in patients. Upregulation of deoxypyrimidine synthesis is one of the important reasons for pancreatic cancer cells to be resistant to gemcitabine, however, the specific mechanism leading to increased deoxypyrimidine synthesis in pancreatic cancer cells is still unclear. Ribonucleotide reductase M2 subunit (RRM2) is overexpressed through unclear mechanisms in many types of human cancer significantly affects sensitivity to various chemotherapy treatments. Here, we found that high expression of enolase-1 (ENO1) is closely related to gemcitabine resistance in pancreatic cancer patients. Cellular experiments and in vivo experiments confirmed that ENO1 increases the resistance of pancreatic cancer to gemcitabine without relying on its glycolytic enzyme activity. Mechanistically, ENO1 competitively binds to RRM2 with ubiquitin E3 ligase STUB1, thereby weakening the ubiquitination and degradation of RRM2 by STUB1. This ENO1-mediated aggregation of RRM2 protein increases the synthesis of dNTPs in pancreatic cancer cells, enhancing the resistance of pancreatic cancer to gemcitabine. Our study reveals a role of ENO1 in pancreatic cancer via RRM2-STUB1 axis and provides a scientific basis for the development of new therapeutic strategies targeting ENO1.

DOI: https://doi.org/10.1038/s41419-025-08061-6
IEEE Trans Comput Biol Bioinform. 2026 Jan 01. PP

DeepTESite: The Prediction of Protein Arginine Methylation Sites using Amino Acids Sequence Symmetric Position Encodings Based on Transformer Encoder.

Xihong Yuan, Chizhuo Ma, Zhichao Lei, Chuzheng Wang.

Methylation is a type of Post-translational modification, which is closely associated with various diseases. The methylation sites prediction is very important for revealing methylation molecular mechanism. The deep learning model Transformer and the Multi-Head Attention Mechanism have been applied and have demonstrated promising performance in sites prediction. However, the position encoding of Transformer model don't consider the structure particularity of protein sequences, and the Multi-Head Attention Mechanism insufficiently focuses on unidirectional flow of information within extensive genomic sequences, resulting in the challenging of accuracy and position encoding computation. To solve the above problems, we propose DeepTESite model based on Transformer Encoder. In our DeepTESite model, Amio Acids Sequence Symmetric Position Encodings is first proposed based on the methylation symmetry hypothesis that arginine methylation of some histones show a certain spatial or functional symmetry in specific sequences for halving the position encoding computation. Then the Bidirectional Multi-Head Attention Mechanism is applied to extract features in sequential and spatial information. The comprehensive experiments demonstrate that our DeepTESite outperforms existing state-of-the-art methylation sites prediction methods, which achieves an accuracy of 87.88% and enhances computational complexity. Experimental results based on our proposed DeepTESite in phosphorylation site prediction further show significant improvement compared to other models. These findings suggest that first proposed Amio Acids Sequence Symmetric Position Encodings is reasonable and provides a promising solution for protein arginine methylation sites prediction.

DOI: https://doi.org/10.1109/TCBBIO.2025.3650228
Sci Rep. 2025 Dec 30.

Riboflavin-PLGA nanoparticles enhance the effectiveness of the pyruvate carboxylase inhibitor ZY-444 in targeting lipogenesis in colon and breast cancer.

Siraprapa Siritutsoontorn, Preeyanuch Manohong, Natthapat Sawektreeratana, Chutima Kuhakarn, Kanlaya Prapainop Katewongsa, Sarawut Jitrapakdee.

  Targeting cancer metabolism has become a promising strategy for cancer treatment. Pyruvate carboxylase (PC) is an anaplerotic enzyme that replenishes tricarboxylic acid cycle intermediates. PC is overexpressed in several types of human cancers, especially in aggressive cancers, including breast and colon cancer, where it promotes growth, survival, and metastasis. Recently, N4-((5-(4-(benzyloxy)phenyl)-2-thiophenyl)methyl)-N2-isobutyl-2,4-pyrimidinediamine (ZY-444) has been reported to possess anti-cancer activity by inhibiting PC activity in breast cancer. In this study, we expanded the potential of ZY-444 to highly aggressive colon cancer, HT-29 and HCT116, and further enhanced its efficacy using nanodelivery systems. The results reveal that ZY-444 not only inhibits the clonogenic growth of these colon cancer cells but also downregulates the expression of several key lipogenic enzymes, accompanied by a marked reduction in triglyceride and cholesterol levels. To improve its efficacy, ZY-444 was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a surface coated with riboflavin (Rf)-functionalized chitosan (CSRf), a ligand known to target Rf transporters. The ZY-444-loaded PLGA nanoparticles exhibited a spherical morphology with an approximate size of 300 nm and a positive zeta potential, demonstrating their suitability for drug delivery applications. Compared with the free compound, ZY-444 encapsulated in nanoparticles demonstrated markedly enhanced efficacy being 11-, 14-, and 19-fold more potent in inhibiting the clonogenic growth of HT-29, HCT116, and MDA-MB-231 cells, respectively. In addition, the encapsulated form was over 10 times more effective at suppressing the migration and invasion of HCT116 and MDA-MB-231 cells. Encapsulated ZY-444 also more strongly inhibited the expression of lipogenic enzymes, further reinforcing its effect on lipid metabolism. Collectively, these findings underscore the potential of ZY-444-loaded PLGA nanoparticles as a promising drug delivery system for suppressing colon and breast cancer through targeted inhibition of the de novo lipogenesis pathway.

Keywords:  Breast cancer; Colon cancer; Nanoparticles; PLGA; Pyruvate carboxylase; ZY-444

DOI:  https://doi.org/10.1038/s41598-025-29207-8
Elife. 2025 Dec 29. pii: RP104545. [Epub ahead of print]14

Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer.

Jessica Armand, Sungsoo Kim, Kibum Kim, Eugene Son, Minah Kim, Kevin Kalinsky, Hee Won Yang.

  CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are standard for hormone receptor-positive (HR+) metastatic breast cancer. However, most patients eventually develop resistance and discontinue treatment, and there is currently no consensus on effective second-line strategies. Using preclinical HR+ human breast cancer models with acquired resistance to CDK4/6i, we demonstrate that maintaining CDK4/6i therapy, either alone or combined with CDK2 inhibitors (CDK2i), slows the growth of resistant tumors by prolonging G1 progression. Mechanistically, sustained CDK4/6 blockade in drug-resistant cells reduces E2F transcription and delays G1/S via a noncanonical, posttranslational regulation of retinoblastoma protein (Rb). Durable suppression of both CDK2 activity and growth of drug-resistant cells requires co-administration of CDK2i with CDK4/6i. Moreover, cyclin E overexpression drives resistance to the combination of CDK4/6i and CDK2i. These findings elucidate how continued CDK4/6 blockade constrains resistant tumors and support clinical strategies that maintain CDK4/6i while selectively incorporating CDK2i to overcome resistance.

Keywords:  breast cancer; cancer biology; cyclin-dependent kinase; drug resistance; human; mouse; targeted therapy

DOI:  https://doi.org/10.7554/eLife.104545
Antioxidants (Basel). 2025 Dec 14. pii: 1504. [Epub ahead of print]14(12):

Extracellular Vesicle-Mediated Delivery of Antioxidant Enzymes: Emerging Insights and Translational Opportunities.

Junyu Wang, Yakun Li, Robin P F Dullaart, Peter Olinga, Han Moshage.

  Oxidative stress is a key contributor to the onset and progression of diverse pathological conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), neurodegeneration, cardiovascular disorders, and cancer. Conventional antioxidant therapies, such as small-molecule scavengers or systemic enzyme administration, are limited by poor stability, inefficient delivery, and off-target effects. Extracellular vesicles (EVs), particularly exosomes, are increasingly recognized as natural carriers of antioxidant enzymes (AOEs), including catalase, superoxide dismutases, glutathione peroxidases, peroxiredoxins, and thioredoxin. These vesicles not only protect enzymes from degradation but also enable targeted delivery to recipient cells, where they can actively modulate redox homeostasis. In this review, we summarize current evidence for AOEs as bona fide EV cargo, outline mechanisms that govern their selective packaging and transfer, and highlight their roles in intercellular communication under physiological and pathological conditions. We also discuss emerging therapeutic applications of both natural and engineered EVs for redox modulation, along with the challenges of quantifying enzymatic activity, ensuring reproducibility, and scaling clinical translation. By integrating insights from cell biology, redox signaling, and translational research, we propose that EV-mediated AOE delivery represents a promising next-generation strategy for combating oxidative stress-related diseases.

Keywords:  antioxidant enzymes (AOEs); extracellular vesicles (EVs); intercellular communication; oxidative stress; redox signaling; therapeutic delivery

DOI:  https://doi.org/10.3390/antiox14121504
Nat Commun. 2025 Dec 31.

Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma.

Yunzhan Li, Zekun Li, Qin Li, Dongxiao Sun, Bo Ni, Mingjun Tan, Ashley E Shay, Min Wang, Chenyang Meng, Guangcong Shen, Boyang Fu, Yueying Shan, Shiqi Zhang, Rifah Rownak Tanshee, Tianxing Zhou, Yongjie Xie, Kun-Ming Chen, Bin Qiao, Yunkun Dang, Scot R Kimball, Guanshi Zhang, Girish H Rajacharya, Pankaj K Singh, Xiuchao Wang, Jihui Hao, Shengyu Yang.

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.

DOI: https://doi.org/10.1038/s41467-025-68099-0
J Obes Metab Syndr. 2025 Dec 31.

Pharmacological Inhibition of Pyruvate Dehydrogenase Kinase 4 Enhances Insulin Sensitivity in Mouse Models of Diabetes and Obesity.

Min-Ji Kim, Bitna Ha, Ran Ryeong Kim, Jung-Yi Lee, Chae Won Lim, Jin Hee Ahn, In-Kyu Lee, Jae-Han Jeon.

   Background: Insulin resistance is a central feature of type 2 diabetes mellitus (T2DM), which remains a major global health burden with limited therapies that directly address upstream molecular defects. Pyruvate dehydrogenase kinase 4 (PDK4), a regulator of glucose and lipid metabolism, has emerged as a promising therapeutic target. Here, we evaluated the metabolic effects of GM-10395, an orally available PDK4 inhibitor, in preclinical models of insulin resistance.
Methods: We evaluated the metabolic effects of GM-10395, an orally available PDK4 inhibitor, in preclinical models of insulin resistance. In alpha mouse liver 12 (AML12) hepatocytes, we assessed protein kinase B (AKT) phosphorylation, mitochondrial reactive oxygen species (ROS), and oxygen consumption rate (OCR). In vivo, long-term oral administration of GM-10395 (8 weeks in KKAy mice [n=6 per group] and 5 weeks in diet-induced obesity [DIO] mice [n=6 per group]) was evaluated for effects on glucose tolerance, glycosylated hemoglobin, lipid profiles, and liver histology.
Results: GM-10395 restored AKT phosphorylation, reduced ROS generation, and normalized OCR in palmitate-treated AML12 cells. In both KKAy and DIO mice, GM-10395 significantly improved glucose tolerance and reduced hepatic steatosis. Serum lipid analysis revealed reductions in low-density lipoprotein cholesterol and triglycerides, with histology confirming decreased lipid deposition. Enhanced insulin signaling, evidenced by increased phosphorylated AKT (pAKT)/total AKT (tAKT) ratios in liver, muscle, and adipose tissues, was consistently observed.
Conclusion: GM-10395 improves systemic glucose and lipid homeostasis by restoring insulin sensitivity via PDK4 inhibition. These results support GM-10395 as a promising oral therapeutic candidate for insulin resistance in T2DM.

Keywords:  Fatty liver; Insulin resistance; Phosphorylation; Pyruvate dehydrogenase kinase 4; Type 2 diabetes mellitus

DOI:  https://doi.org/10.7570/jomes25086
PLoS Comput Biol. 2026 Jan 02. 22(1): e1013862

GAN-enhanced machine learning and metabolic modeling identify reprogramming in pancreatic cancer.

Tahereh Razmpour, Masoud Tabibian, Arman Roohi, Rajib Saha.

Pancreatic ductal adenocarcinoma is one of the deadliest forms of cancer, presenting significant clinical challenges due to poor prognosis and limited treatment options. Understanding the metabolic reprogramming that drives this disease is crucial for identifying new therapeutic targets and improving patient outcomes. We developed a novel computational framework integrating genome-scale metabolic modeling with machine learning to identify metabolic signatures and therapeutic vulnerabilities in pancreatic cancer. To address the inherent class imbalance in cancer datasets, we generated synthetic healthy samples using a Wasserstein Generative Adversarial Network with Gradient Penalty, implementing a rigorous three-step biological filtration process to ensure their validity. This approach enabled the creation of a balanced dataset for robust comparison of healthy versus cancerous metabolic states. Our machine learning classifier achieved 94.83% accuracy in distinguishing between these states, demonstrating the effectiveness of our integrated approach. Systems-level analysis revealed three key dysregulated pathways: heparan sulfate degradation, O-glycan metabolism, and heme degradation. We identified impaired lysosomal degradation of heparan sulfate proteoglycans as a potential contributor to disease pathogenesis, providing a mechanistic explanation for the previously observed association between lysosomal storage disorders and pancreatic cancer. Additionally, nervonic acid transport emerged as the most discriminative reaction between healthy and cancerous states, with gene-level analysis highlighting fatty acid binding proteins, fatty acid transporters, and acyl-CoA synthetases as key molecular drivers of metabolic reprogramming. Our multi-level approach connected genetic drivers to functional metabolic consequences, revealing coordinated upregulation of fatty acid transport and activation processes. These findings enhance our understanding of pancreatic cancer metabolism and present potential therapeutic targets, demonstrating the value of integrated computational approaches in cancer research.

DOI: https://doi.org/10.1371/journal.pcbi.1013862
J Lipid Res. 2025 Dec 26. pii: S0022-2275(25)00231-7. [Epub ahead of print] 100968

Improved preanalytical workflow for pancreatic tissue lipidomics: Insights into lipid stability and polar lipid recovery.

Karol Parchem, Malena Manzi, Robert Jirásko, Ondřej Peterka, Zuzana Lásko, Ondřej Kuda, Michal Holčapek.

  Tissue lipidomics is a rapidly advancing field in clinical and biomedical research that provides crucial information on the lipid-driven molecular mechanisms underlying physiological and pathological conditions. However, accurate mass spectrometry-based analysis requires careful preanalytical handling due to the metabolic activity of tissue and analyte heterogeneity. Here, we introduce a robust tissue processing workflow with the pancreas as a model of a highly metabolically active organ. First, we evaluate lipid stability in porcine pancreatic tissue stored on ice, observing significant lysophospholipid formation after 60-120 minutes. Then, we compare sample handling using ice versus liquid nitrogen for both porcine and mouse pancreatic tissues, illustrating that processing temperature affects low-abundant lipid class levels, with liquid nitrogen providing better preservation. To enhance polar lipidome analysis, we optimize a hexane-methanol liquid-liquid extraction protocol and find that the addition of 2% (v/v) water to methanol yields the most effective recovery and reproducibility. Finally, the workflow is applied to mouse pancreatic tissue samples, enabling the identification of 209 polar lipid species across 10 classes, with 124 species quantified. Among these, hexosylceramides show clear sex-specific variation.

Keywords:  Lipid fractionation; Mass spectrometry; Pancreas; Sample preparation; Supercritical fluid chromatography; Tissue lipidomics

DOI:  https://doi.org/10.1016/j.jlr.2025.100968
Int J Mol Sci. 2025 Dec 12. pii: 11990. [Epub ahead of print]26(24):

Characterization of Differential GPX4 Essentiality Between Intrahepatic and Extrahepatic Cholangiocarcinoma via Leveraging of a Large-Scale Functional Genomic Screen.

Ye Rim Lee, Chaeyoung Seo, Md Abdullah, Su Hyun Baek, Seung Jin Lee.

  Ferroptosis has emerged as a promising therapeutic vulnerability of diverse malignancies, yet the regulatory circuits adopted by each in cholangiocarcinoma (CCA) subtypes remain incompletely understood. We integrated the genome-wide CRISPR-Cas9 loss-of-function screens and transcriptomic profiles of the Cancer Dependency Map and then systematically assessed the essentiality of ferroptosis suppressor genes (FSGs) in the intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. Nineteen and 16 essential FSGs were identified in iCCA and eCCA, respectively, among which GPX4 exhibited a significantly higher dependency in iCCA. Pharmacological inhibition of GPX4 with RSL3 markedly reduced cell viability and induced lipid peroxidation in iCCA cell lines, whereas eCCA cell lines displayed pronounced resistance associated with elevated GPX4 expression. A transcriptomic comparison revealed enrichment of WNT signaling in eCCA. Co-treatment with the tankyrase inhibitor XAV-939 and RSL3 enhanced growth inhibition of eCCA cells, indicating that WNT signaling contributed to ferroptosis resistance. These findings indicate that iCCA exhibits a preferential dependency on GPX4, whereas WNT-β-catenin signaling mediates resistance in eCCA. Collectively, the results clarify the molecular basis of subtype-specific ferroptosis vulnerability and offer a rationale for combinatorial therapeutic strategies that integrate GPX4 and WNT pathway inhibition when treating refractory eCCA.

Keywords:  DepMap; WNT; bioinformatics; cholangiocarcinoma; enzyme-inhibited ferroptosis; glutathione peroxidase 4

DOI:  https://doi.org/10.3390/ijms262411990
Biochim Biophys Acta Mol Cell Res. 2025 Dec 26. pii: S0167-4889(25)00205-8. [Epub ahead of print]1873(2): 120100

Cationic liposome-based silencing of thioredoxin reductase-1 for sensitization of MDA-MB 231 cells to gamma radiation.

Sandeep B Shelar, Manidipa Basu, P A Hassan, K C Barick.

  Thioredoxin reductase 1 (TrxRd1) is a widely conserved antioxidant enzyme that maintains cellular redox homeostasis by reducing oxidized thioredoxin 1 (Trx1). Overexpression of TrxRd1 has been directly linked to radioresistance in cancer cells. In this study, we examined the impact of cationic liposome-mediated knockdown of TrxRd1 on the radiosensitization of MDA-MB 231 breast cancer cells. Cationic liposomes were formulated using dihexadecyldimethylammonium bromide (DDAB) as a surfactant and soy lecithin as the lipid component, employing a supercooled micelle-based method. These liposomes were complexed with plasmid DNA encoding a short hairpin RNA targeting TrxRd1 (shTrxRd1) via electrostatic interactions. Lipoplex formation (DDAB-shTrxRd1) was confirmed by assessing changes in hydrodynamic size, surface charge, and isothermal titration calorimetry. Cellular uptake was demonstrated by cytosolic localization of propidium iodide (PI) and expression of green fluorescent protein (GFP), while reduced TrxRd1 mRNA levels confirmed gene silencing. TrxRd1 knockdown led to elevated reactive oxygen species (ROS) levels in gamma-irradiated cells. This was accompanied by decreased cell viability, reduced colony formation, and increased apoptosis, indicating enhanced radiosensitization of MDA-MB 231 cells following TrxRd1 suppression and gamma radiation exposure. In summary, targeting TxrRd1 by cationic liposome gene silencing provide improved radiosensitization of breast cancer cells through augmenting ROS accumulation.

Keywords:  Gene knockdown; Lipoplexes; Radiosensitization; Reactive oxygen species; Thioredoxin reductase 1

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120100
Antioxidants (Basel). 2025 Nov 24. pii: 1396. [Epub ahead of print]14(12):

NADK Governs Ferroptosis Susceptibility by Orchestrating NADPH Homeostasis.

Xinyi Chen, Yingying Zhang, Dandan Song, Fei Gui, Yuejia Cao, Yu Hong, Rong Chen, Yang Song, Chunhong Di, Jun Yang, Xiaohua Tan.

  Ferroptosis, a regulated cell death pathway driven by iron-dependent lipid peroxidation, is modulated by cellular antioxidant systems, particularly the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. NAD kinase (NADK), the only enzyme converting NAD+ to NADP+ located in cytoplasm, fuels NADPH-dependent antioxidant defenses. However, its role in ferroptosis regulation remains not fully explored. Using ferroptosis-sensitive HT1080 cells, we employed pharmacological inhibition (thioNAM), siRNA-mediated knockdown, and plasmid-driven overexpression of NADK to dissect its impact on ferroptosis. Complementary interventions with nicotinamide mononucleotide (NMN), glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1) were used to map metabolic interactions. Cell viability, redox metabolites (NADPH and GSH), oxidative stress markers (ROS, MDA), and protein expression were quantified. ThioNAM depleted NADP(H) and sensitized cells to RSL-3-induced ferroptosis, which was reversible with Ferrostatin-1. NADK knockdown produced similar results, reducing NADP(H) levels and amplifying lipid peroxidation. Conversely, NADK overexpression restored NADPH/GSH levels and rescued ferroptosis. NADK was essential for G6PD- and ME1-mediated NADPH production and ferroptosis resistance. Administration of ThioNAM or knockdown of NADK abolished the ferroptosis-rescuing effects of NMN, whereas NADK overexpression enhanced NMN's ability to rescue ferroptosis by maintaining redox homeostasis. NADK is a metabolic hub in ferroptosis regulation, bridging NMN-driven NAD+ salvage to NADPH synthesis via G6PD/ME1. Targeting NADK offers novel strategies for diseases associated with ferroptosis.

Keywords:  NAD kinase 1; NADPH; ferroptosis; lipid peroxidation; redox homeostasis

DOI:  https://doi.org/10.3390/antiox14121396
J Biol Chem. 2025 Dec 27. pii: S0021-9258(25)02963-1. [Epub ahead of print] 111111

Hyaluronic acid regulates cellular UDP-GlcNAc levels through CD44 to affect glycosylation and cell biological functions.

Yue Wang, Tomoya Isaji, Tiangui Wu, Takuro Ono, Tsukushi Saito, Yoshiyuki Kuroda, Tomohiko Fukuda, Jianguo Gu.

  Hyaluronic acid (HA) is a key component of the extracellular matrix. Higher HA levels are strongly associated with poor prognosis in advanced cancer. Notably, the biosynthesis of N-glycans, O-GlcNAc, and HA all depend on UDP-GlcNAc as the essential donor substrate. Therefore, there may be functional relationships among different glycan types, although the specific mechanisms behind these interactions remain unclear. We established knockout (KO) cell lines for hyaluronan synthase 2 (HAS2) and CD44 in HeLa and PANC-1 cell lines, which express relatively high levels of HAS2. Results from cell proliferation, Transwell, wound-healing, and colony assays showed that proliferation, migration, and clonogenic capacity were significantly reduced in HAS2- or CD44-KO cells compared to wild-type cells. Lectin blot and HPLC analyses revealed increased levels of intracellular UDP-GlcNAc, O-GlcNAcylation, and GlcNAc-branched N-glycans in HAS2 KO cells. These changes were reversed by adding exogenous HA to HAS2 KO cells or by restoring HAS2 expression. Interestingly, HA effects were not observed in CD44 KO cells, indicating the key role of CD44 in mediating these HA-induced changes. Additionally, CD44 KO significantly reduced β-catenin levels and cell migration, which could be rescued with a β-catenin activator. Our findings suggest that cells sense extracellular HA levels through CD44, to induce CD44-dependent β-catenin signaling, potentially regulating fructose-6-phosphate amidotransferase, a rate-limiting enzyme in the hexosamine biosynthetic pathway responsible for the synthesis of UDP-GlcNAc. These results provide a potential mechanistic connection between extracellular HA and intracellular glycosylation, offering new insights into the diverse roles of HA in cell biology.

Keywords:  CD44; Hyaluronic acid; N-glycan; O-GlcNAcylation; UDP-GlcNAc

DOI:  https://doi.org/10.1016/j.jbc.2025.111111
Cancers (Basel). 2025 Dec 16. pii: 4003. [Epub ahead of print]17(24):

The Molecular Landscape and Utility of Multiomic Analyses in Triple-Negative Breast Cancer: Further Subtyping and Exploring Novel Biomarkers and Therapeutic Targets.

Conan Juan, Yan Peng.

  Triple-negative breast cancer (TNBC) has the poorest prognosis among all breast cancer subtypes, largely due to the lack of targeted therapies and its resistance to both chemotherapy and immunotherapy. A deeper understanding of TNBC biology is therefore critical for identifying therapeutic targets. Molecular subtyping of TNBC, first introduced over a decade ago, has significantly advanced our knowledge of the disease's biology. However, tumor heterogeneity remains a major factor contributing to poor clinical outcomes and treatment resistance. The integration of multiomic technologies, including genomic, transcriptomic, proteomic, and metabolomic analyses, offers a powerful approach to further dissect tumor heterogeneity and accelerate the discovery of new biomarkers and therapeutic targets. This review aims to highlight the potential utility and evolving role of multiomics (-omics) in improving our understanding of TNBC biology-particularly tumor heterogeneity-ultimately facilitating the development of novel therapies and actionable strategies to treat the disease.

Keywords:  biomarkers; multiomics; therapeutic targets; triple-negative breast cancer; tumor heterogeneity

DOI:  https://doi.org/10.3390/cancers17244003