bims-glucam 2026-02-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–02–01
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression.
RHOJ derived peptide promotes chemosensitivity by inhibiting glutamine metabolism in gastric cancer.
An integrative multi-omics study reveals glutamine metabolism dysregulation connecting Alzheimer's disease and age-related macular degeneration.
A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy.
Therapeutic Effect of Arginine, Glutamine and β-Hydroxy β-Methyl Butyrate Mixture as Nutritional Support on DSS-Induced Ulcerative Colitis in Rats.
The role of glutamine metabolism in cardiovascular diseases.
Inhibition of glutamine metabolism blocks tumor growth and sensitizes ccRCC to immune checkpoint blockade.
Metabolic Crosstalk in Triple-Negative Breast Cancer Lung Metastasis: Differential Effects of Vitamin D and E in a Co-Culture System.
Epigenetic and metabolic reprogramming support plasma cell differentiation in germinal centers.
Advances in redox imaging for cancer diagnosis and therapy.
Glutamine-driven upregulation of NPDC1 promotes colorectal cancer progression through PI3K/AKT signaling.
Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions.
The fall of the genome protectors triad: PBRM1, SETD2, and BAP1's impact on metabolism and immunity in clear cell renal cell carcinoma.
A Dual Glutathione-Depleting Nanoparticle Loaded with Porcine Pancreatic Elastase for Neoadjuvant Chemotherapy of Triple Negative Breast Cancer.
Enzyme-Responsive Hemostatic Elastin-like Polypeptides for Fibrin Stabilization and Coagulation Restoration in Thrombocytopenia.
Phosphate binders suppress glutaminase activity for treatment of cirrhosis and hepatic encephalopathy murine models.
Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.

Cancer Biol Ther. 2026 Dec 31. 27(1): 2621606

Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression.

Chunyan Wang, Hongyan Zhang, Chaonan Guan, Yuying Li, Shengli Yang, Lan Huang.

   BACKGROUND: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigates how glutamine metabolism affects CD276 protein stability and esophageal squamous cell carcinoma (ESCC) progression.
METHODS: CD276 and SLC1A5 expression were analyzed in 90 ESCC clinical tissues and TCGA/GEO datasets. CCK-8, colony formation, wound healing and transwell assays were performed in KYSE150 and KYSE450 cells. Autophagy was quantified by immunofluorescence and western blot. Mitochondrial reactive oxygen species (ROS) levels measured by flow cytometry. Rescue experiments used N-acetylcysteine (NAC) and chloroquine (CQ). Finally, antitumor effects of SLC1A5 inhibitor V9302 in the presence or absence of CD276 were evaluated in NOD/SCID mice (n = 5 per group) bearing KYSE150 xenografts.
RESULTS: CD276 and SLC1A5 upregulated in ESCC tissues (P < 0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively (P < 0.01). CQ but not MG-132 increased CD276 expression in ESCC cells. SLC1A5 stabilized CD276 protein without altering CD276 mRNA levels, by suppressing ROS-dependent autophagic degradation. NAC reversed ROS-induced CD276 degradation, while CQ abrogated CD276 downregulation upon glutamine metabolism inhibition. Inhibiting glutamine metabolism could reverse ESCC cell proliferation induced by CD276 overexpression. Moreover, combination of V9302 and CD276 knockout significantly reduced KYSE150 cell-derived xenograft tumor volume by 65.2% (95% CI 58.3-72.1%, P < 0.001) in NOD/SCID mice, without affecting mouse body weight (P > 0.05).
CONCLUSION: SLC1A5 enhances CD276 stability by suppressing ROS-autophagy signaling, promoting ESCC progression. Targeting glutamine metabolism to enhance CD276 degradation might be a novel therapeutic strategy for ESCC.

Keywords:  CD276; Esophageal squamous cell carcinoma; SLC1A5; autophagy; glutamine metabolism

DOI:  https://doi.org/10.1080/15384047.2026.2621606
J Transl Med. 2026 Jan 28.

RHOJ derived peptide promotes chemosensitivity by inhibiting glutamine metabolism in gastric cancer.

Jian Li, Huanqing Li, Fangzhou Ye, Jiayi Wang, Fan Li, Songhua Bei, Xiaohong Zhang, Jun Jiang, Li Feng.



Keywords:  Cisplatin; Gastric cancer; Glutamine metabolism; Peptide; ROS

DOI:  https://doi.org/10.1186/s12967-026-07731-z
J Alzheimers Dis. 2026 Jan 28. 13872877261418263

An integrative multi-omics study reveals glutamine metabolism dysregulation connecting Alzheimer's disease and age-related macular degeneration.

Shuang Wang, Chenting Wang, Hang Hong, Chunlan Tang, Jiancheng Yu, Qinwen Wang.

  BackgroundAlzheimer's disease (AD) and age-related macular degeneration (AMD) are two common neurodegenerative diseases with many similar pathological features, but their shared metabolic characteristics have not been fully elucidated.ObjectiveThis study aims to explore the shared metabolic pathways between AD and AMD using an integrated multi-omics strategy.MethodsWe incorporated Mendelian randomization (MR), bulk and single-cell transcriptomics, and targeted metabolomics to investigate the metabolic links.ResultsThrough MR, we found elevated genetically inferred glutamine concentrations were correlated with a lower likelihood of AD but a higher likelihood of AMD. Using transcriptomic profiling, we detected 19 common differentially expressed genes associated with glutamine and glutamate metabolism, such as GLS. Analysis of single-cell RNA sequencing data revealed that GLS displays distinct cell-type expression patterns. Targeted metabolomic profiling in APP/PS1 mice at 5 months of age provided additional evidence for alterations in glutamine metabolism. The degree of metabolic changes in the eyes was higher than that in the cortex and hippocampus, and the prominent eyes may be an early indicator of neurodegenerative metabolic dysfunction.ConclusionsOverall, these findings suggest that glutamine metabolism disorders represent a convergent mechanism between AD and AMD. Our findings shed light on the overlapping metabolic pathways linking AD and AMD, underscoring the value of ocular biomarkers as promising tools for early disease detection.

Keywords:  Alzheimer's disease; Mendelian randomization; age-related macular degeneration; targeted metabolomics; transcriptomics

DOI:  https://doi.org/10.1177/13872877261418263
Pharmaceuticals (Basel). 2025 Dec 22. pii: 23. [Epub ahead of print]19(1):

A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy.

Federica Barreca, Michele Aventaggiato, Mario Cristina, Luigi Sansone, Manuel Belli, Maria Beatrice Lista, Gaia Francisci, Sergio Valente, Dante Rotili, Antonello Mai, Matteo Antonio Russo, Marco Tafani.

  Background/Objectives: Metabolic reprogramming is an essential feature of tumors. Mitochondrial sirtuins SIRT3 and SIRT5 differently regulate glutamine metabolism with SIRT5 inhibiting glutaminase (GLS) and SIRT3 increasing glutamate dehydrogenase (GDH). Considering the important and interconnected role of glutamine, SIRT3 and SIRT5 for cancer growth and progression, our hypothesis is that a simultaneous modulation of SIRT3 and SIRT5 could represent a valid anti-tumoral strategy. Methods: wt and GLS1-silenced triple negative breast cancer spheroids were treated with 3-TYP, a selective SIRT3 inhibitor, and with MC3138, a new selective SIRT5 activator, both alone and in combination. The effects of such treatments on hypoxia, autophagy and mitophagy markers were determined by immunofluorescence and Western blot. Mitochondria morphology was studied by transmission electron microscopy (TEM) and mitochondrial ROS production by confocal analysis. Results: We observed that 3-TYP+MC3138 treatment decreased the size of spheroids by affecting HIF-1α, c-Myc, glutamine transporter SLC1A5 and autophagy (LC3II) and mitophagy (BNIP3) markers. Moreover, such treatments altered the morphology and conformation of the mitochondria. Finally, we also documented an increase in mitochondria reactive oxygen species (mtROS). Conclusions: The combined inhibition of SIRT3 and activation of SIRT5 greatly reduces the size of spheroids through the inhibition of hypoxic response, which is then followed by the alteration of the autophagic and mitophagic process and the toxic accumulation of mitochondrial ROS, representing a new anti-tumoral strategy.

Keywords:  autophagy; glutamine metabolism; mitophagy; sirtuins; triple negative breast cancer

DOI:  https://doi.org/10.3390/ph19010023
Nutrients. 2026 Jan 09. pii: 208. [Epub ahead of print]18(2):

Therapeutic Effect of Arginine, Glutamine and β-Hydroxy β-Methyl Butyrate Mixture as Nutritional Support on DSS-Induced Ulcerative Colitis in Rats.

Elvan Yılmaz Akyüz, Cebrail Akyüz, Ezgi Nurdan Yenilmez Tunoglu, Meryem Dogan, Banu Bayram, Yusuf Tutar.

   BACKGROUND: Ulcerative colitis (UC) is characterized by chronic mucosal inflammation, oxidative stress, and disruption of intestinal metabolic homeostasis. Immunomodulatory nutrients such as arginine, glutamine, and β-hydroxy β-methylbutyrate (HMB) have shown potential benefits; however, their combined molecular effects on UC remain insufficiently defined.
OBJECTIVE: To investigate the individual and combined effects of arginine, glutamine, and HMB on inflammatory and metabolic gene expression, oxidative stress markers, and histopathological outcomes in a dextran sulfate sodium (DSS)-induced colitis model.
METHODS: Female Sprague Dawley rats were assigned to six groups: control, DSS, DSS + arginine, DSS + glutamine, DSS + HMB, and DSS + mixture. Colitis was induced using 3% DSS. Colon tissues were examined histologically, serum MDA, MPO, and GSH levels were quantified, and mRNA expression of IL6, IL10, COX2, NOS2, ARG2, CCR1, and ALDH4A1 was measured by RT-qPCR. Pathway enrichment analyses were performed to interpret cytokine and metabolic network regulation.
RESULTS: DSS induced severe mucosal injury, elevated MDA and MPO, reduced GSH, and significantly increased IL6, COX2, NOS2, ARG2, and CCR1 expression. Glutamine demonstrated the strongest anti-inflammatory and antioxidant effects by decreasing IL6 and COX2 and restoring GSH. Arginine primarily modulated nitric oxide-related pathways, whereas HMB increased ALDH4A1 expression and metabolic adaptation. The combination treatment produced more balanced modulation across inflammatory, chemokine, and metabolic pathways, consistent with enrichment results highlighting cytokine signaling and amino acid metabolism. Histopathological improvement was greatest in the mixture group.
CONCLUSIONS: Arginine, glutamine, and HMB ameliorate DSS-induced colitis through coordinated regulation of cytokine networks, oxidative stress responses, and metabolic pathways. Their combined use yields broader and more harmonized therapeutic effects than individual administration, supporting their potential as targeted immunonutritional strategies for UC. Rather than targeting a single inflammatory mediator, this study was designed to test whether combined immunonutrient supplementation could promote coordinated regulation of cytokine signaling, oxidative stress responses, and metabolic adaptation, thereby facilitating mucosal repair in experimental colitis.

Keywords:  DSS colitis; HMB; arginine; cytokine signaling; glutamine; inflammatory bowel disease; nutrigenomics

DOI:  https://doi.org/10.3390/nu18020208
Eur J Pharmacol. 2026 Jan 23. pii: S0014-2999(26)00082-8. [Epub ahead of print]1015 178600

The role of glutamine metabolism in cardiovascular diseases.

Yuqing Li, Haoqi Li, Zijie Cheng, Huimin Li, Yupeng Zhong, Xin Dong, Dan Wu, Qingxun Hu.

  Cardiovascular disease (CVD) is a major public health issue causing high mortality rates worldwide. Its pathogenesis is complex and diverse, its treatment costs are high, and it represents a serious threat to human health. In recent years, changes in amino acid metabolism have drawn widespread attention as a key part of regulating CVD. Among these amino acids, glutamine (Gln)-the most abundant free amino acid in the body - has gradually shown important potential in the cardiovascular system, both in terms of its metabolic activity and its role in functional regulation. As new technologies like spatiotemporal metabolomics and single-cell metabolic imaging have developed, they have provided new ways to systematically analyze the dynamic distribution and regulatory mechanisms of Gln in the tissue microenvironment. This paper reviews Gln's metabolic pathways in the body and how it works in maintaining cardiovascular balance and in disease states, including ferroptosis, oxidative stress (OS), and inflammatory regulation. It also looks at, based on current research, how Gln might help treat different CVD models and its potential value in practical use. Finally, this paper suggests that future research should combine metabolomics methods with higher temporal and spatial resolution. This will help further identify the key metabolic nodes and pathways of Gln in CVD development, and provide theoretical support and technical ways to develop precise treatment plans based on regulating amino acid metabolism.

Keywords:  Biological mechanisms; Cardiovascular disease; Cellular metabolism; Detection; Glutamine

DOI:  https://doi.org/10.1016/j.ejphar.2026.178600
J Transl Med. 2026 Jan 24.

Inhibition of glutamine metabolism blocks tumor growth and sensitizes ccRCC to immune checkpoint blockade.

Guofeng Ma, Huiqing Jia, Xintao Tian, Guipeng Wang, Xiangyan Zhang, Zhiyuan Mi, Yuefeng Jia, Liping Wang, Zhijuan Liang, Da Li, Xin Mao, Ye Liang, Haitao Niu.



Keywords:  Glutaminase inhibitor; Glutamine antagonist; Immune checkpoint blockade; PD-L1; ccRCC

DOI:  https://doi.org/10.1186/s12967-026-07705-1
Cancers (Basel). 2026 Jan 18. pii: 294. [Epub ahead of print]18(2):

Metabolic Crosstalk in Triple-Negative Breast Cancer Lung Metastasis: Differential Effects of Vitamin D and E in a Co-Culture System.

Balquees Kanwal, Saranya Pounraj, Rumeza Hanif, Zaklina Kovacevic.

  Background: Triple-negative breast cancer (TNBC) is more likely to metastasise to the lungs than other breast cancer (BrCa) types, yet the molecular interactions within the tumour microenvironment (TME) at secondary sites remain poorly understood. Methods: This pilot study aimed to explore the metabolic crosstalk between MDA-MB-231 TNBC cells and MRC-5 lung fibroblasts within a co-culture system to replicate the lung metastatic TME. Co-cultures were also treated with Vitamin D or Vitamin E to evaluate the effects of these nutraceuticals on the metabolic crosstalk between TNBC cells and fibroblasts. Results: Our findings demonstrate that co-culture induced the activation of fibroblasts into cancer-associated fibroblasts (CAFs), evidenced by increased α-SMA and FAP expression. Metabolic profiling revealed that TNBC cells in co-culture displayed increased expression of enzymes associated with oxidative phosphorylation (OXPHOS) and glutamine metabolism, while fibroblasts exhibited a metabolic profile consistent with glycolysis and lactate metabolism. Vitamin D inhibited lactate metabolism and HIF-1α expression in fibroblasts while suppressing TCA cycle activity in cancer cells, suggesting a potential role in disrupting oncogenic metabolic crosstalk. Conversely, Vitamin E treatment was associated with increased expression of TCA cycle and oxidative metabolism-related markers in BrCa cells without significantly affecting fibroblast glycolysis. Such differential metabolic responses may contribute to metabolic heterogeneity within the tumour microenvironment. Conclusions: These results provide valuable insights into the metabolic dynamics of TNBC metastases in the lung TME and demonstrate that Vitamins D and E exert distinct effects on metabolic crosstalk between cancer cells and fibroblasts. These findings may have significant implications for the potential supplementation of Vitamins D and E in patients with metastatic TNBC and justify further in-depth analysis.

Keywords:  breast cancer; co-culture model; lung fibroblasts; triple-negative breast cancer (TNBC); tumour microenvironment; vitamin D; vitamin E

DOI:  https://doi.org/10.3390/cancers18020294
J Exp Med. 2026 Mar 02. pii: e20250569. [Epub ahead of print]223(3):

Epigenetic and metabolic reprogramming support plasma cell differentiation in germinal centers.

Yuliang Wang, Xinyi Yang, Mengting Lou, Tiantian Chen, Wen Li, Cuifang Yang, Le Zhang, Zhenming Cai, Yuren Fan, Sulan Zhai, Shengze Zhang, Yunli Wang, Xiaoming Wang, Jingjing Chen.

The germinal center (GC) is a specialized structure that ensures the production of high-quality antibodies. Although recent studies have pinpointed the existence of a pre-plasma cell (prePC) population within mouse GC B cells, it remains unclear how these prePCs mechanistically differentiate into PCs. Additionally, there is a lack of validation of these findings in human cells. Here, we demonstrate CD205 is highly expressed in prePCs both in mouse and in human. The histone H3 lysine 27 demethylase Kdm6b, not Kdm6a, potently enhances the differentiation of prePCs into bona fide PCs by removing repressive H3K27me3 marks at the Irf4 locus. Interestingly, prePCs favor glutamine metabolism, which provides α-ketoglutarate as a substrate for the demethylation reaction of Kdm6b. Thus, prePCs require metabolic and epigenetic reprogramming to differentiate into PCs in the GC.

DOI: https://doi.org/10.1084/jem.20250569
J Clin Biochem Nutr. 2026 Jan;78(1): 14-18

Advances in redox imaging for cancer diagnosis and therapy.

Hironobu Yasui, Kazuhiro Kato, Tomoki Bo, Osamu Inanami.

  Cancer remains a leading cause of global morbidity and mortality, necessitating continuous innovations in diagnosis and therapy. Redox biology, the balance between reactive oxygen species production and antioxidant defenses, plays a central role in tumor initiation, progression, and therapeutic response. Elevated reactive oxygen species levels drive DNA damage, genomic instability, and tumor-promoting signaling, whereas adaptive antioxidant responses promote survival, therapeutic resistance, and recurrence. Chemotherapy and radiotherapy partly exert their cytotoxic effects through reactive oxygen species generation. However, tumors with enhanced redox-buffering capacity often evade reactive oxygen species-mediated killing. Ferroptosis, iron-dependent cell death driven by lipid peroxidation, is a key redox-linked pathway that synergizes with radiotherapy, offering new radiosensitization strategies. Redox imaging is a non-invasive approach to map oxidative and reductive dynamics in tumors. This review outlines the unique strengths of advancements, including optical imaging with redox-sensitive probes, positron emission tomography tracers targeting glutamine metabolism or system Xc -, magnetic resonance imaging with nitroxide-based probes and dynamic nuclear polarization, and electron paramagnetic resonance imaging. Together, these developments underscore the potential of redox imaging as a research and clinical tool. By enabling functional tumor characterization, patient stratification, and treatment monitoring, redox-based imaging provides a framework for precision oncology and development of redox-modulating therapies.

Keywords:  cancer; imaging; radiotherapy; reactive oxygen species; redox

DOI:  https://doi.org/10.3164/jcbn.25-211
J Transl Med. 2026 Jan 24.

Glutamine-driven upregulation of NPDC1 promotes colorectal cancer progression through PI3K/AKT signaling.

Qing Qin, Dapeng Zhang, Yusai Xie, Fan Zhang, Yulan Huang, Renchao Deng, Minli Yang, Lili Zhang, Houjie Liang, Rongchen Shi.



Keywords:  Colorectal cancer; Glutamine; KRAS mutation; NPDC1

DOI:  https://doi.org/10.1186/s12967-026-07733-x
MedComm (2020). 2026 Feb;7(2): e70585

Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions.

Ruimiao Qian, Jun Ge, Ni Fan, Zheng Sun, Chengcheng Zhao, Yujiao Sun, Yingpeng Li, Yunfei Li, Hui Fu.

  Natural products, originating from diverse biological sources, serve as a critical reservoir of bioactive compounds for cancer intervention across prevention, treatment, and supportive care. Their mechanisms extend beyond direct cytotoxicity to include modulation of tumor metabolism-such as glucose, lipid, and glutamine pathways-and the tumor microenvironment (TME), highlighting their multifaceted role in oncology. However, a systematic synthesis of how natural products concurrently target metabolic reprogramming and immune-stromal components across different clinical phases remains lacking. This review delineates the therapeutic applications of natural products-such as flavonoids, alkaloids, and terpenoids-across the clinical continuum, including perioperative support, concurrent chemoradiotherapy, maintenance therapy, and metastasis suppression. We detail their actions in disrupting core metabolic pathways and elucidate their influence on TME components like cancer-associated fibroblasts, extracellular matrix, and immune cells including tumor-associated macrophages and T lymphocytes. Furthermore, we discuss innovative delivery strategies-including nanocarriers and codelivery systems-that enhance bioavailability and enable synergistic combination with chemotherapy or immunotherapy. By integrating mechanistic insights with clinical translation strategies, this work provides a comprehensive framework for employing natural products in biomarker-driven, precision oncology regimens, supporting their evolving role in multimodal cancer care.

Keywords:  cancer metabolic reprogramming; immune modulation; natural products; precision medicine; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.70585
Front Cell Dev Biol. 2025 ;13 1713830

The fall of the genome protectors triad: PBRM1, SETD2, and BAP1's impact on metabolism and immunity in clear cell renal cell carcinoma.

Mathieu Johnson, Sandra Turcotte.

  The loss of chromosome 3p and the inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) were identified in clear cell renal cell carcinomas (ccRCC) over three decades ago. Since then, mutations in genes for the three chromatin modulators, polybromo 1 (PBRM1), SET domain-containing 2 (SETD2), and BRCA1-associated protein-1 (BAP1), have been recognized as common in ccRCC. Although these genomic alterations are central to understanding ccRCC's development, other deregulated cellular processes are also prominent in these tumors. Metabolic reprogramming is a key hallmark of this disease, characterized by various changes linked to the stabilization of hypoxia-inducible factors (HIF), including increased aerobic glycolysis, elevated lipid levels, and glutamine dependence for cell survival. Additionally, HIF-α stabilization plays a crucial role in regulating the immune system, thereby enhancing CD8+ T lymphocyte cytotoxicity. Immune checkpoint inhibitors (ICI) are now used as first-line treatments to target the often highly infiltrated tumor microenvironment of ccRCC. However, the effectiveness of ICI varies and is difficult to predict. Although emerging studies are beginning to provide insight, evidence suggests roles for PBRM1, SETD2, and BAP1 in metabolic regulation and in shaping the tumor immune microenvironment in ccRCC. Here, we review recent advances in this field and examine their impact on the management of ccRCC.

Keywords:  BAP1; PBRM1; SETD2; VHL; ccRCC; metabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2025.1713830
ACS Nano. 2026 Jan 26.

A Dual Glutathione-Depleting Nanoparticle Loaded with Porcine Pancreatic Elastase for Neoadjuvant Chemotherapy of Triple Negative Breast Cancer.

Yanming Xia, Shuxian Xu, Yutong Wu, Xiaocheng Ma, Linxiu Peng, Yan Lu, Xiaopeng Han, Chao Qin, Lifang Yin.

  Neoadjuvant chemotherapy remains a central clinical strategy for triple negative breast cancer (TNBC), yet the lack of tumor-specific targets often results in variable treatment responses. Porcine pancreatic elastase (PPE), a natural protease with selective antitumor activity, is significantly limited by the tumor microenvironment, particularly due to elevated glutathione (GSH) levels. To address the limited therapeutic potential of PPE, we constructed PMC@HA nanoparticles by coencapsulating PPE within a bimetallic Cu/Zn nanocarrier and integrating the glutaminase inhibitor CB-839. The Cu/Zn carrier not only consumes intracellular GSH but also displays peroxidase-like catalytic behavior, generating cytotoxic •OH. CB-839 impedes mitochondrial GSH biosynthesis, enhances PPE-mediated hydrolysis and CD95 death domain release, and drives reactive oxygen species buildup in tumor cells. Furthermore, the combined action of PPE and CB-839 leads to lipid peroxide accumulation, mitochondrial collapse, and intensified tumor cell apoptosis. This multifunctional nanoplatform achieves strong tumor suppression and initiates immunogenic cell death, resulting in immune activation. When applied as a neoadjuvant regimen in conjunction with surgery, PMC@HA significantly decreases postoperative recurrence and distant metastasis in TNBC. This combinatorial approach may improve chemosensitivity and limit metastatic progression, thereby potentially extending long-term survival in patients with TNBC.

Keywords:  Apoptosis; Bimetallic Nanoparticles; Neoadjuvant Chemotherapy; Porcine Pancreatic Elastase; Triple Negative Breast Cancer

DOI:  https://doi.org/10.1021/acsnano.5c16112
J Am Chem Soc. 2026 Jan 28.

Enzyme-Responsive Hemostatic Elastin-like Polypeptides for Fibrin Stabilization and Coagulation Restoration in Thrombocytopenia.

Yang Sun, Sunghyun Kang, Malvina Heiniger, Ivan Urosev, Rosario Vanella, Adrian Bertschi, Michael A Nash.

Hemorrhage remains a leading cause of mortality in trauma and surgery, and treatment options are limited for thrombocytopenic patients with impaired platelet function. Current plasma-derived hemostatic products face challenges, including limited supply, storage requirements, and infectious risk. Here we report a recombinant protein-based hemostat designed to enhance clot mechanics through enzyme responsiveness and self-assembly, which integrates biophysical design principles with clot-targeted drug delivery. We rationally designed a library of enzyme-responsive glutamine (Q)-containing block elastin-like polypeptides (Q-block-ELPs) that reinforce fibrin clots through phase separation and covalent cross-linking. Q-block-ELPs incorporate glutamine residues within a peptide motif recognized by coagulation factor XIIIa, enabling site-specific grafting into fibrin networks during clot formation. By tuning polymer length, Q-block valency, and lower critical solution temperature (LCST) behavior, we engineered Q-block-ELPs to phase separate at body temperature and integrate into the fibrin architecture. In vitro, Q-block-ELPs increase fibrin network density and stiffness. In a thrombocytopenic mouse model, systemic administration reduced blood loss and accelerated clot formation. This strategy delivers a programmable, pathogen-free platform for systemic bleeding control, bridging biophysical protein design with translational hemostatic therapy, and addressing an urgent need for platelet-deficient bleeding disorders.

DOI: https://doi.org/10.1021/jacs.5c18009
Biochem Pharmacol. 2026 Jan 24. pii: S0006-2952(26)00083-3. [Epub ahead of print]246 117752

Phosphate binders suppress glutaminase activity for treatment of cirrhosis and hepatic encephalopathy murine models.

Ze-Ning Chen, Zhi-Xing Liu, Chen-Kai Huang, Lu Yu, Yu-Long Ji, Yang-Feng Lv, Qing-Rong Liang, Qun Tang.

  Hyperactivated glutaminase1 (GLS1) promotes the progression of cirrhosis via the reprogramming of hepatic stellate cells (HSCs). Hepatic encephalopathy (HE), the main complication of cirrhosis characterized by abnormal ammonia metabolism, is also associated with increased glutaminase activation in intestinal epithelial cells (IECs). The enzymatic activity of glutaminase depends on inorganic phosphate (Pi). In this study, a retrospective study of serum Pi levels was performed in 185 cirrhosis-HE patients. The pharmacology and pharmacodynamics of Pi binders (sevelamer and lanthanum carbonate) were evaluated in CCl4-induced cirrhosis and both type A and C HE murine models. The biological events downstream of Pi binders were evaluated via glutamate rescue in activated HSCs and GLS1-overexpressing IECs. We found that serum Pi is an independent risk factor for cirrhosis progression to HE. Both binders stimulated HSC senescence and rebalanced interorgan ammonia, alleviating cirrhosis and HE and reversing liver dysfunction. They had better therapeutic effects than L-ornithine L-aspartate (OA). Pi deprivation weakened glutaminase enzymatic activity, lowering collagen and Alpha-smooth muscle actin (α-SMA) production in HSCs and ammonia production in both wild-type and GLS1-overexpressing IECs. Since Pi deprivation alleviates glutaminolysis and ammonia production by decreasing glutaminase activity, Pi binders might hold great promising to treat cirrhosis and HE.

Keywords:  Cirrhosis; Glutaminase 1; Hepatic encephalopathy; Liver function; Phosphate binder

DOI:  https://doi.org/10.1016/j.bcp.2026.117752
Biomolecules. 2026 Jan 20. pii: 171. [Epub ahead of print]16(1):

Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.

Mariagrazia Mancuso, Federico Mezzalira, Beatrice Vignoli, Elisa Greotti.

  Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca2+ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca2+-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca2+ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca2+-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca2+ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca2+-centered mitochondria-glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer's disease.

Keywords:  Alzheimer’s disease; astrocyte–neuron communication; excitotoxicity; glutamate homeostasis; glutamatergic synapse; metabolic coupling; mitochondrial Ca2+ signaling; mitochondrial signaling; neuronal hyperexcitability; synaptic vulnerability

DOI:  https://doi.org/10.3390/biom16010171