bims-glucam 2025-11-09 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–11–09
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure.
Olaparib targets ubiquitin D to promote autophagy in hepatocellular carcinoma by regulating glutamine metabolism.
Celastrol attenuates Th17 cell response through downregulating HDAC3/FOXO3/GLS1-dependent glutaminolysis.
Energy Metabolism and Cancer Pain: A Pathway to Innovative Treatment Strategies.
6-pentadecyl salicylic acid reduces cell proliferation in U373MG glioblastoma cells via glutamine uptake impairment.
Inducible effects of evodiamine on the uptake of glutamine in Caco-2 cells.
Norisoboldine restrains γδT17 cell activation and consequently alleviates psoriasis-like dermatitis in mice by selectively down-regulating glutaminolysis to decrease the level of α-ketoglutarate.
Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.
Tumor microenvironment and metabolic reprogramming: Unraveling the complex interplay in gastrointestinal tumor liver metastasis.
Circular RNAs as central regulators of metabolic reprogramming and immune responses in the breast cancer microenvironment: A comprehensive review.
Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
Nitroalkene inhibition of pro-inflammatory macrophage effector function via modulation of signaling metabolite levels.
Mitochondria-Targeted HA-Coated Nanosystem for ROS/CO Generation and Metabolic Reprogramming to Enhance Tumoricidal Macrophage Polarization.
Computational signatures of uncertainty are reflected in motor cortex excitatory neurochemistry.
The tumor microenvironment enhances the expression of cssDNA by modulating cell cycle signaling pathways via SKP2.
The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.
IGF2BP2 promotes malignant progression of ovarian cancer by regulating protein synthesis through liquid-liquid phase separation.

Nat Commun. 2025 Nov 03. 16(1): 9690

Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.

Yulseung Sung, Ya Chun Yu, Mirim Lee, Seonghun Lim, Yechan Lee, Mincheol Kang, Doru Kwon, Apeksha Parajulee, Junjeong Choi, Do Sik Min, Kuglae Kim, Wan Namkung, Yun-Hee Kim, Sang Myung Woo, Nam Doo Kim, Hee Chan Yoo, Jung Min Han.

The mitochondrial glutamine transporter SLC1A5_var plays a central role in the metabolic reprogramming of cancer cells by facilitating glutamine import into mitochondria for energy production and redox homeostasis. Despite its critical function, the development of effective and selective inhibitors targeting SLC1A5_var has remained a significant challenge. Here, we introduce iMQT_020, a selective allosteric inhibitor identified through structure-based screening. iMQT_020 disrupts the trimeric assembly of SLC1A5_var, causing metabolic crisis in cancer cells and selectively suppressing their growth. Mechanistically, iMQT_020 reduces glutamine anaplerosis and oxidative phosphorylation, resulting in a broad disruption of cancer metabolism. Additionally, iMQT_020 treatment epigenetically upregulates PD-L1 expression, enhancing the efficacy of combination therapies with anti-PD-L1 immune checkpoint inhibitors. These findings highlight the therapeutic potential of targeting SLC1A5_var as a critical metabolic vulnerability in cancer and demonstrate that targeting allosteric interprotomer interactions is a novel and promising therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-64730-2
Biochem Biophys Res Commun. 2025 Oct 30. pii: S0006-291X(25)01608-0. [Epub ahead of print]790 152892

Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure.

Ayato Maeda, Akihiro Nita, Toshiro Moroishi.

  Mechanical forces are increasingly recognized as critical regulators of immune cell function; however, the effects of static pressure on B cell biology remain poorly understood. In this study, we investigated how elevated atmospheric pressure influences B cell proliferation and metabolism. Using murine and human B cell lines cultured under normal or elevated static pressure, we found that increased pressure significantly enhances and sustains long-term B cell proliferation. Transcriptomic analysis revealed a downregulation of glycolytic pathways, corroborated by decreased glucose consumption. In contrast, glutamine consumption was elevated, indicating a metabolic shift toward glutaminolysis. Functional assays confirmed that both glutamine availability and glutaminase activity are essential for the pressure-induced proliferative response. These findings identify glutamine metabolism as a key mediator of B cell adaptation to mechanical pressure and suggest that static pressure is a previously underappreciated regulator of B cell function and immune metabolism.

Keywords:  B cells; Glutaminase; Glutamine metabolism; Immunometabolism; Mechanical pressure; Mechanotransduction; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bbrc.2025.152892
Expert Rev Anticancer Ther. 2025 Nov 06.

Olaparib targets ubiquitin D to promote autophagy in hepatocellular carcinoma by regulating glutamine metabolism.

Weijun Zhu, Fangfang Zhang, Haiyan Qu, Ningjun Li, Xi Chen, Wenhui Tu.

   BACKGROUND: To explore Ubiquitin D (UBD) and autophagy in hepatocellular carcinoma (HCC) and the key role of Olaparib targeting UBD in treating HCC.
RESEARCH DESIGN AND METHODS: Bioinformatics analysis was conducted to study UBD expression in HCC tissues. qRT-PCR and Western blot measured UBD mRNA/protein levels, autophagy markers, and Gln metabolism proteins in HCC tissues. Cellular thermal shift assay (CETSA) confirmed Olaparib-UBD interaction. A xenograft tumor model was established to observe tumor growth in mice, with qRT-PCR and western blot used to measure UBD expression levels in tumor tissues and Immunohistochemistry (IHC) used to assess expression of Microtubule-associated protein light chain 3 (LC3), sequestosome 1 (P62), solute carrier family 1 member 5 (SLC1A5), and glutaminase (GLS).
RESULTS: UBD was highly expressed in HCC tissues (p = 7.6e-11). UBD could negatively regulate autophagy levels by activating Gln metabolism. Olaparib could target and downregulate UBD expression, promoting HCC cell autophagy by regulating Gln metabolism pathways. Olaparib treatment in xenograft mice overexpressing UBD significantly reduced tumor growth (p < 0.05), inhibited Gln metabolism pathways, and enhanced HCC cell autophagy.
CONCLUSIONS: Olaparib targeted UBD to promote autophagy in HCC by inhibiting Gln metabolism pathways.

Keywords:  Autophagy; Olaparib; glutamine metabolism; hepatocellular carcinoma; ubiquitin D

DOI:  https://doi.org/10.1080/14737140.2025.2586736
Phytomedicine. 2025 Oct 25. pii: S0944-7113(25)01055-4. [Epub ahead of print]148 157418

Celastrol attenuates Th17 cell response through downregulating HDAC3/FOXO3/GLS1-dependent glutaminolysis.

Yan Liu, Wenjie Zhang, Yilei Guo, Zhifeng Wei, Yufeng Xia, Yue Dai.

   BACKGROUND: Preparations of Tripterygium wilfordii have long been used in China for the treatment of various autoimmune diseases. Celastrol, one of the primary active ingredients of T. wilfordii, was previously reported to attenuate the differentiation of Th17 cells which are closely related to the pathogenesis of autoimmune diseases, but its underlying mechanism remains to be identified.
PURPOSE: This study investigated the effect of celastrol on Th17 cell response and explored the mechanism of action based on cellular metabolism.
METHODS: Primary CD4+ T cells isolated from the mesenteric lymph nodes of C57BL/6 mice were stimulated with Th17 cell differentiation conditions. The Th17 cell proportion, mRNA expression of key transcription factor and cytokines, protein level of histone deacetylases (HDACs) as well as concentration of glutamine and its metabolites were detected by flow cytometry, real-time quantitative PCR (RT-qPCR), western blot and ELISA, respectively. The transcription factor for glutaminase 1 (GLS1) was predicted by database and verified by ChIP-qPCR and luciferase reporter assay. The binding of celastrol to HDAC was simulated by molecular docking and further verified by protein thermal stability detection, microscale thermophoresis and siRNA transfection. Colitis model was established in mice using dextran sulfate sodium (DSS).
RESULTS: In vitro, celastrol inhibited Th17 cell differentiation in a concentration-dependent manner. Metabolic screening revealed that celastrol preferentially downregulated glutaminolysis, as evidenced by increased intracellular glutamine levels and decreased GLS1 expression at both protein and mRNA levels. Exogenous supplement of glutamine or glutaminolysis products reversed the effect of celastrol, indicating that celastrol attenuates Th17 differentiation by inhibiting GLS1-dependent glutaminolysis. Database screening identified forkhead box 3 (FOXO3) as a key transcription factor regulating GLS1 expression. Celastrol interacted with HDAC3, reducing its activity and leading to increased acetylation and upregulation of FOXO3 expression. FOXO3, in turn, bound to the GLS1 promoter, resulting in downregulation of GLS1 expression. In mice with DSS-induced colitis, the inhibitory effect of celastrol on Th17 cell response was verified.
CONCLUSION: Celastrol mitigates the Th17 cell response by downregulating HDAC3/FOXO3/GLS-dependent glutaminolysis, highlighting its potential as a therapeutic agent for Th17 cell activation-related autoimmune diseases.

Keywords:  Celastrol; Forkhead box O3; Glutaminase 1; Glutaminolysis; Th17 cells

DOI:  https://doi.org/10.1016/j.phymed.2025.157418
Curr Top Med Chem. 2025 Nov 04.

Energy Metabolism and Cancer Pain: A Pathway to Innovative Treatment Strategies.

Halisa Paerhati, Minhao Zhang, Lianbing Gu.

  Cancer is a widespread disease that often causes severe pain, significantly reducing patients' quality of life and increasing the overall burden of the illness. Managing cancer pain effectively remains a major clinical challenge. Metabolism is a fundamental biological process that involves both the breaking down of substances to produce energy (catabolism) and the building of complex molecules (anabolism). Cancer cells exhibit altered energy metabolism, including glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism. Emerging research suggests that these metabolic changes can amplify cancer pain through specific signalling pathways, such as AMPK and PI3K/AKT. Targeting these metabolic pathways offers a promising approach for pain relief. This review explores the link between cancer pain and energy metabolism, highlighting potential new therapeutic strategies aimed at metabolic targets.

Keywords:  Cancer pain; energy metabolism; glutamine metabolism; lipid metabolism; glycolysis; oxidative phosphorylation; signalling pathways; therapeutic targets.

DOI:  https://doi.org/10.2174/0115680266430740251020110940
Toxicol Mech Methods. 2025 Nov 06. 1-9

6-pentadecyl salicylic acid reduces cell proliferation in U373MG glioblastoma cells via glutamine uptake impairment.

Laura I Méndez, Andrea Ocharán-Mercado, Luisa C Hernández-Kelly, Jaqueline Loaeza-Loaeza, Daniel Hernández-Sotelo, Francisco Castelán, Libia Vega, Marie-Paule Felder-Schmittbuhl, Arturo Ortega.

  Glioblastoma cells exhibit a pronounced dependence on glutamine uptake, primarily via the alanine‑serine‑cysteine transporter 2, since its deletion prevents glioma growth, making this transporter an attractive therapeutic target. This study aimed to evaluate 6‑pentadecyl salicylic acid, a natural antineoplastic and immunomodulatory compound, for its ability to impair alanine‑serine‑cysteine transporter 2‑mediated glutamine transport and by these means reduce glioblastoma cells viability. Human U373MG glioma cells and primary chick cerebellar Bergmann glia (non‑malignant control) were exposed to increasing concentrations of 6SA for 24 h. Viability, measured by the MTT assay, declined in a dose‑dependent manner in U373MG cells while Bergmann glia remained largely unaffected (p < 0.001). L-[³H]-glutamine uptake assays revealed that 100 µM 6SA functioned as a potent inhibitor, increasing the Michaelis constant (KM) more than four-fold (from 7.11 mM to 31.79 mM). This indicates a mixed-type or competitive inhibition mechanism that dramatically reduces the transporter's apparent affinity for glutamine and prevents saturation within the tested substrate range. Additionally, quantitative PCR showed a dose‑dependent down‑regulation of ASCT2 mRNA, suggesting post‑transcriptional control. Blind docking of 6SA onto the cryo‑EM ASCT2 structure identified nine peripheral cavities that could serve as allosteric sites, however, these predictions are computational and require experimental validation; binding to these sites would stabilize a low‑affinity transporter conformation, consistent with the kinetic data. Collectively, 6‑pentadecyl salicylic acid selectively impairs glutamine transport and viability in glioblastoma cells while sparing normal glial cells, supporting its potential as a lead compound for alanine‑serine‑cysteine transporter 2 ‑targeted glioma therapy.

Keywords:  6-pentadecyl salicylic acid glutamine; U373MG cells; cell proliferation; glioblastoma; glutamine transporters

DOI:  https://doi.org/10.1080/15376516.2025.2579574
J Ethnopharmacol. 2025 Oct 30. pii: S0378-8741(25)01530-2. [Epub ahead of print]356 120838

Inducible effects of evodiamine on the uptake of glutamine in Caco-2 cells.

Sho Somehara, Fumika Mizuno, Tomoaki Ishida, Hajime Mizukami, Toshiaki Makino.

   ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM) and traditional Japanese Kampo medicine, the symptoms associated with malabsorption syndrome correspond to "spleen deficiency", which can be treated with the prescriptions containing spleen-tonifying drugs. However, there is a lack of scientific evidence for this effect.
AIM OF THE STUDY: We hypothesized that one potential mechanisms of action of spleen-tonifying drugs is to enhance nutrient transporter function in the gastrointestinal epithelium. Glutamine is an amino acid that aids in intestinal function. In addition, we develop crude drugs with this efficacy and to clarify the active ingredients and their mechanisms of action.
MATERIALS AND METHODS: We screened 99 crude drugs used in Kampo preparations to identify those that promote the uptake of glutamine into human colon-derived Caco-2 cells.
RESULTS: We found 7 active crude drugs on the promotion of glutamine uptake, however, no activity was observed for the representative spleen-tonifying drugs such as Ginseng Radix and Astragali Radix. Instead of spleen-tonifying drugs, we observed that the extract of Euodiae Fructus (dried fruit of Tetradium ruticarpum) had the strongest effect on glutamine uptake. Euodiae Fructus extract induced mRNA expression of the amino acid transporter B0 (ATB0), also known as system alanine-serine-cysteine transporter 2 or solute carrier 1A. The active ingredient in Euodiae Fructus was evodiamine, and when Caco-2 cells were incubated with medium containing evodiamine (3 μM) for 24 h, the glutamine uptake and the mRNA expression of ATB0 were significantly induced by 1.6-times and 4.1-times, respectively. The inducible effects of evodiamine were significantly suppressed by each inhibitor of protein tyrosine kinase, protein kinase C, phosphatidylinositol-3 kinase, or epidermal growth factor receptor (EGFR). Evodiamine induced mRNA expression level of EGFR.
CONCLUSIONS: It is incorrect to interpret the spleen-tonifying effect as an effect of enhanced glutamine uptake. Evodiamine, an ingredient of Euodiae Fructus, promotes glutamine absorption in intestinal cells to improve malabsorption syndrome.

Keywords:  Caco-2 cells; Epidermal growth factor receptor; Euodiae fructus; Evodiamine; Glutamine uptake

DOI:  https://doi.org/10.1016/j.jep.2025.120838
J Adv Res. 2025 Oct 24. pii: S2090-1232(25)00838-0. [Epub ahead of print]

Norisoboldine restrains γδT17 cell activation and consequently alleviates psoriasis-like dermatitis in mice by selectively down-regulating glutaminolysis to decrease the level of α-ketoglutarate.

Yue He, Chenxi Li, Junchen Fan, Yanrong Zhu, Yilei Guo, Zhifeng Wei, Yue Dai, Yufeng Xia.

   INTRODUCTION: Psoriasis, an inflammatory skin disease characterized by aberrant type 17 immunity, is effectively treated with monoclonal antibodies targeting IL-17, though with notable side effects. Given that γδT17 cells represent the primary sources of IL-17 in the dermis of psoriasis patients, targeting these cells to inhibit IL-17 expression constitutes a potential therapeutic strategy for psoriasis.
OBJECTIVE: To examine the effects and mechanisms of Norisoboldine (NOR) on γδT17 cell activation in psoriasis-like dermatitis mice.
METHODS: Imiquimod was used to induce mouse psoriasis-like dermatitis model, and bioinformatics analysis and multiple molecular biological methods were employed to evaluate the proportion of γδT17 cells and signals activation.
RESULTS: NOR alleviates imiquimod-induced psoriasis-like dermatitis in mice by restraining γδT17 cell activation. In γδT17 cells, NOR selectively down-regulated glutaminolysis and overexpression of glutaminolysis rate-limiting enzyme glutaminase 1 (GLS1) dampened the attenuation of NOR against γδT17 cell activation. Exogenous addition of glutamine and combination with GLS1 inhibitor BPTES significantly repressed and promoted γδT17 cell activation, respectively. Through exogenous supplementation of glutamate and its downstream metabolites, including fumaric acid, succinic acid, and isocitric acid, along with the interference of glutamate dehydrogenase and isocitrate dehydrogenase 1/2, we found that NOR selectively decreased the level of α-ketoglutarate (α-KG) to suppress γδT17 cell activation. The decrease of α-KG level led to downregulation of lysine-specific histone demethylase 6B expression, which in turn restrained demethylation of histone H3K27 in RORγt promoter, ultimately restraining γδT17 cell activation.
CONCLUSION: NOR can limit γδT17 cell activation to alleviate psoriasis-like dermatitis in mice by suppressing glutaminolysis, down-regulating the levels of α-KG, inhibiting the expression of KDM6b, and consequently increasing the trimethylation level of histone H3K27 in RORγt promoter. These findings attest to the beneficial effect of NOR in inhibiting γδT17 cell activation and offer a potential therapeutic approach for psoriasis.

Keywords:  Glutaminolysis; Norisoboldine; Psoriasis; α-Ketoglutarate; γδT17 cells

DOI:  https://doi.org/10.1016/j.jare.2025.10.043
Front Oncol. 2025 ;15 1673513

Ammonium metabolism rewiring in the prostate cancer microenvironment: Mechanisms and clinical prospects.

Zihao Ye, Hao Wu, Zhanhao Li, Ruizhe Ye, Yingliang Rao, Bin Liu, Baoshan Gao.

  Ammonium metabolism represents a critically understudied yet pivotal driver of prostate tumorigenesis and tumor microenvironment (TME) remodeling. The interplay between tumor metabolic reprogramming and the tumor microenvironment has emerged as a critical frontier in oncology research. While previous studies on prostate cancer metabolism have predominantly focused on lipid metabolism and the Warburg effect, the role of ammonium metabolism, particularly the urea cycle in tumor immune regulation remains insufficiently explored. This metabolic reprogramming constitutes a central node connecting catabolic nutrient breakdown to anabolic biosynthesis by integrating upstream amino acid deamination and transamination reactions with downstream pathways, generating key intermediates including α-ketoglutarate, coenzyme A, and citrate that concurrently fuel the tricarboxylic acid cycle and macromolecular synthesis. Crucially, oncogenic drivers such as Myc and p53 modulate this flux through epigenetic regulation of core enzymes such as glutaminase, glutamine synthetase and ornithine transcarbamylase, thereby channeling metabolism toward tumor progression. The immunomodulatory consequences manifest through dual mechanisms including TME immunosuppression driven by M2 macrophage polarization and immune evasion mediated via glutathione dependent redox homeostasis disruption. Beyond its established role in modulating redox homeostasis, ammonium metabolic reprogramming may additionally trigger novel cell death modalities such as ferroptosis by GSH/GPX4 axis. This emerging pathway offers promising therapeutic avenues for prostate cancer intervention. Synthesizing mechanistically validated insights from in vivo or in vitro models and clinical trials of ammonium-targeting inhibitors, this review proposes novel therapeutic strategies and candidate biomarkers. Moreover, the unique citrate and polyamine metabolism characteristics of prostate cancer may be impacted by these processes, offering promising avenues for future treatments.

Keywords:  ADT; SLC; TME; ammonium metabolism; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2025.1673513
Crit Rev Oncol Hematol. 2025 Nov 01. pii: S1040-8428(25)00389-0. [Epub ahead of print]216 105001

Tumor microenvironment and metabolic reprogramming: Unraveling the complex interplay in gastrointestinal tumor liver metastasis.

Song Wang, Zheng Ma, Lianghong Lv, Qian Yu, Shanglong Liu, Yun Lu.

  Gastrointestinal tumors (GITs) are among the most prevalent and lethal malignancies worldwide, with liver metastasis (LM) being a major contributor to poor patient prognosis, contributing to recurrence in a substantial proportion (approximately 37 %) of patients undergoing radical gastrectomy. Dismally, the prognosis for GI-LM (Gastrointestinal tumors Liver Metastasis) patients remains exceedingly poor, with survival rates beyond five years languishing below 10 %. Recent studies have highlighted the critical role of tumor metabolic reprogramming and its interaction with the tumor microenvironment (TME) in the progression of gastrointestinal tumor liver metastasis. Tumor cells undergo metabolic alterations, such as enhanced glycolysis, increased glutamine metabolism, and altered lipid metabolism, to meet the demands of rapid proliferation. These metabolic changes also reshape the liver microenvironment by secreting metabolites (e.g., lactate, succinate), promoting immune suppression, angiogenesis, and stromal remodeling, thereby facilitating liver metastasis. Conversely, the liver microenvironment, including immune cells, stromal cells, and extracellular matrix components, influences tumor cell metabolism through nutrient competition, cytokine signaling, and hypoxia-driven mechanisms, creating a bidirectional interaction. This review summarizes the molecular mechanisms underlying the interplay between tumor metabolic reprogramming and the microenvironment in gastrointestinal tumor liver metastasis, explores how metabolic changes drive TME remodeling to promote metastasis, and discusses emerging therapeutic strategies targeting these mechanisms. The aim is to provide new insights for precision medicine in treating gastrointestinal tumor liver metastasis.

Keywords:  Gastrointestinal tumors; Immune evasion; Liver metastasis; Metabolic reprogramming; Stromal interactions; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105001
Biomed Pharmacother. 2025 Oct 31. pii: S0753-3322(25)00876-5. [Epub ahead of print]193 118682

Circular RNAs as central regulators of metabolic reprogramming and immune responses in the breast cancer microenvironment: A comprehensive review.

Negar Sadat Sherafat, Amirhossein Mardi, Faezeh Absalan, Amirreza Mehmandar-Oskuie.

  Circular RNAs (circRNAs) are becoming more widely acknowledged for their role in breast cancer (BC) and have emerged as significant regulators of a variety of biological processes. By sponging microRNAs (miRNAs), these covalently closed noncoding RNAs can function as competing endogenous RNAs (ceRNAs), encode peptides, and control the expression of parental genes. CircRNAs influence various cellular behaviors through these mechanisms. In vivo, they affect tumor growth and metastasis, while in vitro, they regulate BC cell proliferation, migration, invasion, and apoptosis. Certain circRNAs regulate fatty acid synthesis and uptake, leading to enhanced oxidative phosphorylation in mitochondria. They also modify glucose metabolism by controlling critical glycolytic enzymes and transporters, and stimulate lipid biosynthesis. Others use miRNA-mediated signaling axes to change the expression of glutamine transporters and metabolic enzymes, which in turn affects glutamine metabolism. Additionally, circRNAs influence important signaling pathways such as PI3K/AKT/mTOR, which promote improved cell survival and resistance to drugs. Certain circRNAs in the tumor microenvironment support the recruitment of myeloid-derived suppressor cells (MDSCs), encourage M2 macrophage polarization, and alter immune checkpoints by influencing T-cell activity and PD-L1 expression. Numerous circRNAs are promising biomarkers because of their strong correlations with clinicopathological parameters, treatment response, and prognosis. The classification, biological roles, immunoregulatory functions, and therapeutic potential of circRNAs in BC are compiled in this review.

Keywords:  Breast cancer; Circular RNAs (circRNAs); Competing endogenous RNAs (ceRNAs); Drug resistance; Immune modulation; Metabolic reprogramming; MicroRNA (miRNA); PI3K/AKT/mTOR pathway; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2025.118682
Nat Commun. 2025 Nov 04. 16(1): 9664

Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.

Berwini B Endaya, Lukáš Kučera, Dan-Diem Thi Le, Jessica B Spinelli, Andrea Brožková, Dominika Luptáková, Kryštof Klíma, Gabriela L Oliveira, Petra Brisudová, Klára Boháčová, Štěpána Boukalová, Renata Zobalová, František Kolář, Karel Chalupsky, Klára Dohnalová, Arash Yarmohammadi-Barzegar, Šárka Dvořáková, Evgeniya Biryukova, Marta Kaliaeva, Vladimír Havlíček, Radislav Sedláček, Jan Procházka, Libor Vítek, Sunghyouk Park, Pavel Martásek, Zdeněk Krška, Paulo J Oliveira, Michael V Berridge, Jiří Neužil.

Liver is endowed with high regenerative activity, so that the tissue regrows in mouse after partial hepatectomy within days. We reason that this requires de novo pyrimidine synthesis to support rapid progression via the cell cycle. We find that suppression of de novo pyrimidine synthesis prevents proliferation in regenerating liver, suppressing liver regrowth. Tracing studies and spatial metabolomics reveal a metabolic shift such that ammonia, normally detoxified to urea in the periportal region under homeostasis, is redirected for generating aspartate and carbamoyl phosphate periportally, and glutamine pericentrally, and these products are utilized as precursors by the de novo pyrimidine synthesis pathway. Our research uncovers a metabolic reprogramming leading to utilization of a toxic byproduct for anabolic pathways that are essential for liver regeneration.

DOI: https://doi.org/10.1038/s41467-025-65451-2
Front Physiol. 2025 ;16 1426102

Nitroalkene inhibition of pro-inflammatory macrophage effector function via modulation of signaling metabolite levels.

Emily R Stevenson, James P O'Brien, Allison M Manuel, Crystal E Uvalle, Gregory J Buchan, Steven J Mullett, Karina Lockwood, Tomeka Suber, Bruce A Freeman, Stacy L Gelhaus.

   Introduction: Classically activated innate immune cells undergo a metabolic switch to aerobic glycolysis to support effector function. We report that the small-molecule nitroalkene 10-n-octadec-9-enoic acid (NO2-OA) attenuates the Warburg- like phenotype of aerobic glycolysis in lipopolysaccharide (LPS)-activated macrophages, thus inhibiting pro-inflammatory signaling.
Methods: RAW264.7 and bone marrow derived macrophage were treated with LPS with and without NO2-OA or 1400W. Pro-inflammatory cytokines were measured by ELISA and protein expression was determined by immunoblot. Central carbon metabolites with and without 13C stable isotope tracing were measured using liquid chromatography-high resolution mass spectrometry.
Results: Overall, the present observations indicate that nitroalkene-induced changes in central carbon metabolism contribute to the anti-inflammatory actions of this class of multi-target lipid signaling mediators. Comparison of macrophage responses to NO2-OA with the inducible nitric oxide synthase (NOS2 and iNOS) inhibitor 1400W affirms that NO2-OA inhibition of NOS2 expression and activity alone was not sufficient to account for the decreases in pro-inflammatory cytokine expression. NO2-OA treatment reduced intracellular succinate levels, which may be attributed to a concomitant reduction in intracellular itaconate and reliance on glutamine, thereby contributing to hypoxia-inducible factor 1α (HIF1α) destabilization observed in LPS-activated macrophages.
Conclusion: The current data provide additional perspective on the actions of this small-molecule electrophile, which is currently in a Phase 2 clinical trial for the treatment of obesity-related chronic pulmonary inflammation and associated airway dysfunction.

Keywords:  glutamine metabolism; inflammation; macrophage; metabolism; nitroalkene fatty acid

DOI:  https://doi.org/10.3389/fphys.2025.1426102
ACS Appl Mater Interfaces. 2025 Nov 06.

Mitochondria-Targeted HA-Coated Nanosystem for ROS/CO Generation and Metabolic Reprogramming to Enhance Tumoricidal Macrophage Polarization.

Na Peng, Chun Song, Xiaoting Liu, Michał Nowicki, Roman Szewczyk, Yanyang Wang, Yi Liu.

  Tumor-associated macrophage (TAM) polarization is related to mitochondrial function, stability, and ROS production. The development of a mitochondria-targeted nanosystem with immunomodulatory impact on TAM repolarization is crucial for macrophage-targeted immunotherapy. First, zirconium(IV) coordinated with tetra-kis(4-caboxyphenyl) porphyrin to synthesize PCN-224, which encapsulated CO-releasing molecule 401 (CORM-401) via the hollow structures (PCN-CORM), and then, an amphiphilic copolymer containing triphenylphosphine (TPP) was synthesized to load PCN-CORM via self-assembly and surface-coated with hyaluronic acid (HA) to obtain the mitochondria-targeted nanosystem (HA@MR@PCN-CORM). Mediated by HA and TPP motifs, HA@MR@PCN-CORM efficiently targeted mitochondria of TAMs via HA-CD44 interaction and re-exposed TPP groups by digesting HA and caused reactive oxygen species (ROS) and carbon dioxide (CO) storm under a laser irradiation of 660 nm (20 mW cm-2), and the killing rate of M2-like TAMs reached 66.8% at a PCN-224 concentration of 15 μg/mL. Moreover, HA@MR@PCN-CORM, through depletion of GSH, inhibition of glutamine metabolism, and metabolic reprogramming, resulted in an increased ratio of M1/M2-type TAMs from 0.29 to 1.20 and an in vivo tumor volume inhibition rate of 93.4% with synergistically enhanced infiltration of CD3+/CD4+, CD3+/CD8+ T lymphocytes, and DCs in tumor tissues. The nanosystem was exhibited as a promising strategy for depletion and modulation of TAMs in an immunosuppressive tumor microenvironment for antitumor therapy.

Keywords:  antitumor immunotherapy; metabolic reprogramming; mitochondria-targeted; polarization; tumor-associated macrophages

DOI:  https://doi.org/10.1021/acsami.5c15795
Nat Commun. 2025 Nov 04. 16(1): 9737

Computational signatures of uncertainty are reflected in motor cortex excitatory neurochemistry.

Nazia Jassim, Peter Thestrup Waade, Owen Parsons, Frederike H Petzschner, Catarina Rua, Christopher T Rodgers, Simon Baron-Cohen, John Suckling, Christoph Mathys, Rebecca P Lawson.

How individuals process and respond to uncertainty has important implications for cognition and mental health. Here, we use computational phenotyping to examine inter-individual differences in uncertainty processing in relation to neurometabolites and trait anxiety in humans. We introduce a categorical state-transition extension of the Hierarchical Gaussian Filter to model individuals' evolving beliefs about transition probabilities in a four-choice probabilistic sensorimotor learning task with a reversal. Using 7-Tesla Magnetic Resonance Spectroscopy, we measure neurotransmitter levels in the primary motor cortex. Model-based results reveal dynamic belief updating in response to environmental changes. We further find region-specific relationships between baseline primary motor cortex glutamate+ glutamine levels and prediction errors and volatility beliefs. High trait anxiety is associated with faster post-reversal responses. This study establishes a direct neurochemical correlate of hierarchical belief updating, identifying motor cortex glutamate + glutamine as an important neural marker of inter-individual differences in uncertainty processing.

DOI: https://doi.org/10.1038/s41467-025-64702-6
Sci Rep. 2025 Nov 05. 15(1): 38760

The tumor microenvironment enhances the expression of cssDNA by modulating cell cycle signaling pathways via SKP2.

Dandan Shao, Jinghao Wang, Kexuan Zou, Yatao Chen, Pengfei Zhang, Jie Song.

Circular single-stranded DNA (cssDNA), an emerging nucleic acid vector, exhibits significant clinical potential for treating genetic disorders, enabling gene editing, and advancing oncotherapy. Its unique attributes, including high stability, structural simplicity, conformational flexibility, and low molecular mass, establish it as a promising gene therapy tool. Our study reveals that cssDNA demonstrates superior expression efficiency over conventional plasmids across diverse tumor cell lines. Notably, cssDNA expression is enhanced under certain tumor microenvironment (TME) conditions (glucose deficiency, glutamine deficiency and hypoxia) compared to normal condition. Mechanistically, these TME conditions induce significant cell cycle perturbations, particularly pronounced G1 arrest. Intriguingly, transfected cssDNA expression peaks during the late G2/M phase, immediately preceding entry into the G1 phase. We further identify S-phase kinase-associated protein 2 (SKP2) as a critical regulator of cssDNA expression under TME conditions. SKP2 inhibition directly or indirectly notably enhances the expression levels of cssDNA. These findings confirm cssDNA's advantages as a gene expression vector and how specific TME conditions modulate its expression via cell cycle and SKP2-dependent mechanisms in vitro. This work provides a scientific foundation for cssDNA-based cancer therapy and opens new avenues for future clinical translation.

DOI: https://doi.org/10.1038/s41598-025-22477-2
Biochim Biophys Acta Rev Cancer. 2025 Oct 31. pii: S0304-419X(25)00233-1. [Epub ahead of print]1880(6): 189491

The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.

Woo Hyun Park.

  Mitochondria, far from being mere cellular powerhouses, act as central command hubs dictating cell fate by integrating metabolic cues with life-or-death decisions. In cancer, these organelles undergo profound functional and structural reprogramming to support relentless proliferation, survival, and adaptation to stress. This metabolic plasticity, however, creates unique vulnerabilities exploitable for therapeutic gain. This comprehensive review synthesizes recent insights into the multifaceted roles of mitochondria in cancer, focusing on how inhibiting their core functions can trigger diverse cell death pathways and modulate the tumor microenvironment. This paper delves into the central role of mitochondria in orchestrating various forms of regulated cell death (RCD), including apoptosis, ferroptosis, necroptosis, and the newly defined cuproptosis. A primary focus is placed on the dual nature of mitochondrial reactive oxygen species (ROS), which can promote tumorigenesis but can also be pharmacologically elevated to catastrophic levels, triggering oxidative stress-induced demise. This review systematically categorizes and discusses a burgeoning pharmacopeia of mitochondrial inhibitors-targeting the electron transport chain (ETC), metabolic enzymes like glutaminase, protein homeostasis, and ion channels-and analyzes their mechanisms of action, preclinical evidence, and clinical translation status. Furthermore, this paper examines how these agents can overcome chemoresistance and synergize with existing treatments, including the exciting interface with immunotherapy, where mitochondrial fitness is paramount for robust anti-tumor T-cell responses and the induction of immunogenic cell death (ICD). By dissecting the complex interplay between mitochondrial inhibition, metabolic disruption, oxidative stress, and cell death, this review highlights the immense promise of mitochondria-targeted therapies and charts the course for future innovations in oncology.

Keywords:  Cancer metabolism; Immunotherapy; Mitochondria; Oxidative stress; Regulated cell death; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189491
Cell Rep. 2025 Nov 04. pii: S2211-1247(25)01282-3. [Epub ahead of print]44(11): 116511

IGF2BP2 promotes malignant progression of ovarian cancer by regulating protein synthesis through liquid-liquid phase separation.

Xueyou Xiong, Xuan Wang, Zhenlong Wang, Feixue Chen, Yaqian Shi, Xiyi Chen, Weijian Gong, Xuemei Jia, Juan Xu.

  Ovarian cancer (OC) is the most lethal gynecological malignancy, and high expression of IGF2BP2 is significantly associated with poor prognosis. Intracellular macromolecules regulate diverse biological functions via liquid-liquid phase separation (LLPS). However, whether IGF2BP2 undergoes LLPS and promotes tumor progression in OC through spatiotemporal coordination remains elusive. Here, we demonstrate that IGF2BP2 forms condensates through LLPS in OC cells, which recruit target RNAs and translation initiation factors to enhance de novo protein synthesis. Both N6-methyladenosine (m6A)-modified RNA binding and acetylation of IGF2BP2 promote its LLPS. However, substitution of five lysines and one glycine with glutamine within the m6A-binding pocket of IGF2BP2 blocks acetylation and disrupts its LLPS, which in turn dampens global protein synthesis and abolishes the oncogenic activity of IGF2BP2 in OC. Our findings reveal that IGF2BP2-driven LLPS promotes OC progression by enhancing protein synthesis, highlighting its potential as a therapeutic target.

Keywords:  CP: cancer; CP: molecular biology; IGF2BP2; LLPS; liquid-liquid phase separation; m(6)A; ovarian cancer; translation

DOI:  https://doi.org/10.1016/j.celrep.2025.116511