bims-glucam 2026-06-07 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–06–07
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic Reprogramming Coordinates Mannose and Glutamine Metabolism to Maintain Glucose Homeostasis During Glycosuria.
Immunohistochemical evaluation of glutaminase-1 enzyme in oral squamous cell carcinoma.
Glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma by downregulating GLUD1 and promoting ROS-mediated inhibition of Wnt/β-catenin signaling.
Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.
CircRNAs as central regulators of Immunometabolic crosstalk in hepatocellular carcinoma.
Deorphanisation and functional characterisation of OATP5A1 as transport protein for amino acids and vitamins.
Hexosamine Biosynthesis Pathway in Colorectal Cancer: Current Insights and Therapeutic Opportunities.
c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.
Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.
Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
Ion chromatography-ultra-high-resolution mass spectrometry reveals EZH2-driven reprogramming of nucleic acid and protein methylation.
The Multiple Roles and Targeting Strategies of LonP1 in the Occurrence and Development of Cancer.
GLUL pitches in thrombocytopoiesis by restricting ammonia accumulation during megakaryocyte maturation.
The intelectin 1-bestrophin-2-glutamate axis regulates glutamate homeostasis and suppresses colorectal cancer progression.

bioRxiv. 2026 May 22. pii: 2026.05.20.726580. [Epub ahead of print]

Metabolic Reprogramming Coordinates Mannose and Glutamine Metabolism to Maintain Glucose Homeostasis During Glycosuria.

Nadia Rashid, Moses Otunla, Nazmul Hasan, Michael J Hodges, Heba H Qaissi, Tumininu S Faniyan, Pontiana Ritika Clement, Penghui Lin, Mohamed M Y Kaddah, Teresa A Cassel, Donald A Morgan, Kamal Rahmouni, Kavaljit H Chhabra.

Glycosuria, whether genetically induced or triggered by SGLT2 inhibitors, activates compensatory glucose-producing pathways that limit glucose lowering in type 2 diabetes. To define these pathways, we studied renal Glut2 knockout mice, which progressively lose Slc5a2 (encoding SGLT2) expression yet maintain normoglycemia despite marked urinary glucose loss. Metabolic profiling and isotope tracing revealed coordinated adaptations in mannose and glutamine metabolism during glycosuria. Skeletal muscle reduced glucose utilization and instead oxidized mannose, while whole-body glycolysis declined, establishing a systemic glucose-sparing state. Disruption of glutamine transport or mannose utilization caused hypoglycemia in mice treated with an SGLT2 inhibitor, demonstrating dependence on these substrates to maintain glucose homeostasis during glycosuria. Multiomic profiling revealed increased expression and chromatin accessibility of mannose and glutamine transport pathways. These findings identify a kidney-driven metabolic program that preserves systemic glucose homeostasis during glycosuria and may inform strategies to optimize the glucose-lowering efficacy of SGLT2 inhibitors.

DOI: https://doi.org/10.64898/2026.05.20.726580
Indian J Med Res. 2026 May;pii: 10.25259/IJMR_2652_2025. [Epub ahead of print]163(5): 585-592

Immunohistochemical evaluation of glutaminase-1 enzyme in oral squamous cell carcinoma.

Madhuri Shital Chougule, B R Patil, Vijayalakshmi S Kotrashetti, Priya S Joshi, Ashwini Mane Patil, Suraj B Pawar.

  Background and objectives Malignant cells reprogram their metabolism. Glutamine is a major biosynthetic precursor apart from glucose in various cancers. Glutaminase 1 (kidney type) is the rate limiting enzyme in glutamine metabolism, which is increased in cancers of prostate, breast, colorectum, ovary and oral squamous cell. We aimed to evaluate the intensity and extent of immunohistochemical expression of glutaminase1 in various grades of oral squamous cell carcinoma (OSCC) and investigate whether any association exists between the glutaminase 1expression with staging, grading and tumour infiltrating lymphocytes. Methods This retrospective analysis included 98 formalin-fixed, paraffin-embedded tissue blocks of clinically and histopathologically confirmed cases of OSCC. One section was stained with haematoxylin and eosin and the other, immunohistochemically for glutaminase 1(GLS1). Staging, grading, tumour infiltrating lymphocytes were evaluated for their relation with GLS1 immunoscore. Results Statistically significant association was noted between GLS1 immunointensity (P<0.001) immunoextent (P<0.001) and the immunoscore (P=0.007) with the worsening grades of OSCC. There was no significant association between TNM staging P<0.61) and tumour infiltrating lymphocytes with GLS1 immunoscore (P=0.30). Interpretation and conclusions Glutaminase 1 expression increases with worsening grade of OSCC signifying an altered metabolic phenotype as the cancer cells lose differentiation.

Keywords:  Cancer metabolism; Glutaminase 1 expression; Oral squamous cell carcinoma; TNM staging; Tumour grade; Tumour infiltrating lymphocytes

DOI:  https://doi.org/10.25259/IJMR_2652_2025
Pathol Res Pract. 2026 May 18. pii: S0344-0338(26)00197-4. [Epub ahead of print]286 156544

Glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma by downregulating GLUD1 and promoting ROS-mediated inhibition of Wnt/β-catenin signaling.

Liyong Bai, Keying Wang, Lu Liu, Yuan Liu.

  Osteosarcoma is a highly malignant primary bone tumor that predominantly affects children and adolescents. Although chemotherapy has significantly improved overall survival, drug resistance remains a major cause of poor prognosis. Current studies largely focus on isolated signaling events and still lack a systematic understanding of the coordinated interplay among metabolic reprogramming, redox homeostasis, and cell death, thereby limiting translational relevance and the identification of effective therapeutic targets. The present study aimed to investigate how glutamine regulates reactive oxygen species (ROS) levels in osteosarcoma cells and to clarify the mechanism by which the Wnt/β-catenin pathway influences doxorubicin sensitivity. The effects of glutamine metabolism on osteosarcoma chemosensitivity were systematically evaluated using both in vitro and in vivo models. Integrated transcriptomic analysis was further performed to identify key metabolic and signaling regulators associated with redox balance and chemosensitivity. The results showed that glutamine deprivation or L-asparaginase treatment significantly enhanced the sensitivity of HOS, MNNG, and their doxorubicin-resistant derivatives to doxorubicin, as evidenced by reduced cell proliferation and increased expression of the apoptosis-related proteins Bax and cleaved caspase-3. Glutamine depletion also increased intracellular ROS levels, decreased glutathione content and mitochondrial membrane potential, altered cellular glycolytic status, and downregulated GLUD1 expression. Similarly, GLUD1 silencing recapitulated these effects, whereas NAC treatment partially reversed them. Moreover, both glutamine deprivation and ROS accumulation suppressed activation of Wnt/β-catenin signaling. In vivo, the combination of L-asparaginase and doxorubicin, as well as treatment with XAV-939, significantly inhibited tumor growth, whereas NAC attenuated these effects. In conclusion, glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma. Mechanistically, this chemosensitizing effect is mediated by downregulation of GLUD1, which promotes intracellular ROS accumulation and subsequently suppresses Wnt/β-catenin signaling.

Keywords:  Chemosensitivity; Glutamine; Osteosarcoma; ROS; Wnt/β-catenin signaling

DOI:  https://doi.org/10.1016/j.prp.2026.156544
Free Radic Biol Med. 2026 May 30. pii: S0891-5849(26)00827-0. [Epub ahead of print]253 463-477

Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.

Kai Li, Chenggong Luo, Heng Zhang, Ting Yue, Tengda Wang, Yong Ban, Zhaoxuan Li, Xuan Liu, Lingyue An, Guangheng Luo, Zehua Ma.

  Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate cancer (CRPC) remains largely elusive. Here, we demonstrate that mitochondrial oxidative phosphorylation (OXPHOS) is critical for development of androgen receptor signaling inhibitors (ARSI) resistance. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment. Notably, there is no significant change in glycolytic activity. Importantly, this metabolic remodeling relies on glucose and glutamine utilization. Mechanistically, ARSI treatment activates reactive oxygen species/AMPK/SIRT1/PGC-1α signaling axis, leading to nuclear accumulation of PGC-1α and enhancement of mitochondrial OXHPOS and tricarboxylic acid cycle. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Inhibitors of PGC-1α and mitochondrial OXPHOS restore drug sensitivity and synergize with ARSI to inhibit CRPC growth. Our findings demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying PGC-1α/mitochondrial OXPHOS axis as a potential metabolic target for CRPC treatment.

Keywords:  Androgen receptor signaling inhibitors; Castration-resistant prostate cancer; Metabolic remodeling; Mitochondria; Oxidative phosphorylation; PGC-1α

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.323
Clin Chim Acta. 2026 May 30. pii: S0009-8981(26)00304-9. [Epub ahead of print]591 121122

CircRNAs as central regulators of Immunometabolic crosstalk in hepatocellular carcinoma.

Seerwan Hamadameen Sulaiman, Rebaz Anwar Omer, Hemn A H Barzani, Hunar Yasin Muhammad, Avan Bazid Qader, Evan Hashm Muhammad, Darya Kaife Muhammad, Sara Wezhawan Ahmad, Hoshyar Saadi Ali.

  Hepatocellular carcinoma (HCC) is distinguished by profound metabolic reprogramming and a highly immunosuppressive tumor microenvironment, two hallmarks that cooperatively drive tumor progression and therapeutic resistance. While metabolic rewiring and immune escape have traditionally been studied as parallel processes, the molecular regulators that integrate these pathways remain incompletely defined. Circular RNAs (circRNAs) are a type of covalently closed non-coding RNAs with exceptionally stable and regulatory versatility, and have recently emerged as critical modulators of both cancer metabolism and immune signaling. However, their coordinated role at the intersection of metabolism and immunology in HCC has not been systematically synthesized. This review provides a comprehensive, mechanistic framework that positions circRNAs as central regulators of immunometabolic crosstalk in HCC. We summarize how circRNAs modulate glycolysis, lipid remodeling, glutamine metabolism, and redox balance while simultaneously regulating immune checkpoint pathways, macrophage polarization, T-cell depletion, and NK-cell dysfunction. We further discuss exosomal circRNAs as mediators of tumor-immune communication and remodeling of the tumor microenvironment, linking metabolic stress responses to adaptive immune suppression. Importantly, we highlight circRNA-driven immunometabolic circuits as contributors to resistance against immune checkpoint inhibitors and metabolic therapies. By integrating metabolic, immune, and translational perspectives, this review identifies key knowledge gaps, including context-dependent circRNA functions, challenges in detection standardization, and the need for multi-omic stratification strategies. We propose that targeting circRNA-mediated immunometabolic networks represents a promising frontier for precision therapy in HCC.

Keywords:  CircRNAs; Hepatocellular carcinoma; Immunometabolic reprogramming; Metabolism–immunity axis; Therapeutic resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cca.2026.121122
Cell Mol Biol Lett. 2026 Jun 02. pii: 75. [Epub ahead of print]31(1):

Deorphanisation and functional characterisation of OATP5A1 as transport protein for amino acids and vitamins.

Elena Kohlmann, Nikola K Schmid, Arne Gessner, Martin F Fromm, Jörg König.

   BACKGROUND: Transport proteins are important for the uptake, distribution and elimination of endogenous substances and drugs, and therefore essential for, e.g., cellular metabolism or drug effects. While the export of substrates out of cells is mediated by ATP-binding cassette (ABC) transporters, SLC (solute carrier) transporters are mainly responsible for the uptake into cells. In contrast to most well-characterised ABC transporters, many SLC transporters have been studied insufficiently. Such transporters are called orphan transporters. Despite the fact that the SLC21/SLCO family contains several important transporters for widely prescribed drugs, one of its family members, OATP5A1 (SLCO5A1), is such an orphan transporter. OATP5A1 is ubiquitously expressed throughout the body, including expression in the brain, heart, intestine and various cancerous tissues. However, no substrates have been characterised for this transporter to date.
METHODS: Using stably-transfected HEK293 cells overexpressing human OATP5A1 (HEK-OATP5A1) and the respective control cells (HEK-VC), we investigated known substrates of other OATP family members as potential OATP5A1 substrates. Furthermore, an untargeted metabolomics analysis of both cell lines was performed after incubation with human plasma. Candidate substances were further characterised as substrates of OATP5A1.
RESULTS: After characterisation of the stably-transfected HEK-OATP5A1 cells, uptake assays and untargeted metabolomics analysis identified the hormone conjugate estrone-3-sulfate, the amino acids glutamine, glycine and tyrosine, the vitamins pantothenic acid (vitamin B5) and thiamine (vitamin B1) and the nucleotide thymine as potential OATP5A1 substrates. While estrone-3-sulfate, tyrosine and thiamine were further characterised as uptake substrates, glutamine and glycine were exported by OATP5A1. Moreover, pantothenic acid and thymine inhibited OATP5A1-mediated tyrosine uptake. For estrone-3-sulfate, tyrosine and thiamine, kinetic transport parameters (Km values) of 102.2 µM, 169.9 µM and 15.6 µM were calculated, respectively.
CONCLUSIONS: In the present study, OATP5A1 was deorphanised by characterising amino acids and vitamins as substrates of this transport protein. Estrone-3-sulfate, tyrosine and thiamine were taken up by OATP5A1. Moreover, OATP5A1 mediated the efflux of the amino acids glutamine and glycine, which play essential roles in brain function.

Keywords:  Amino acids; Glutamine; Glycine; OATP; OATP5A1; Orphan transporter; Solute carrier; Thiamine; Transport; Tyrosine

DOI:  https://doi.org/10.1186/s11658-026-00943-7
Comb Chem High Throughput Screen. 2026 May 20.

Hexosamine Biosynthesis Pathway in Colorectal Cancer: Current Insights and Therapeutic Opportunities.

Yi Zou, Xin Chen, Xinwen Ma, Yanbo Zhang, Haoyue Wang, Haotian Cui, Junkai Wen, Xueqing Hu, Wanli Deng.

  Colorectal Cancer (CRC) is a prevalent malignancy characterized by significant metabolic alterations that drive tumor progression and therapy resistance. The Hexosamine Biosynthetic Pathway (HBP) functions as a critical nutrient-sensing hub by integrating fluxes from glucose, glutamine, fatty acids, and uridine to control protein O-GlcNAcylation. Dysregulation of this pathway contributes to CRC oncogenesis through the modulation of oncogenic signaling cascades and metabolic plasticity. This review elucidates the distinct roles of key enzymes, including GFAT, PGM3, UAP1, and the O-GlcNAc cycling enzymes OGT and OGA, in exerting oncogenic roles. We detail how aberrant pathway flux and downstream O-GlcNAcylation orchestrate critical malignant phenotypes such as epithelial-to-mesenchymal transition, maintenance of cancer stemness, and DNA repair mechanisms that confer chemoresistance. Furthermore, we highlight emerging evidence linking dysregulation of the HBP to Tumor Microenvironment (TME) remodeling, specifically its role in promoting immune evasion via macrophage polarization and immune checkpoint stabilization. Beyond mechanistic insights, this article critically evaluates current therapeutic strategies targeting the pathway, ranging from novel inhibitors and interventions guided by biomarkers to combination therapies that synergize with conventional chemotherapy or immunotherapy. We also analyze the major hurdles hindering clinical translation. By framing both the biological complexity and therapeutic opportunities of this metabolic nexus, this work aims to provide a translational roadmap for developing precise and effective metabolic interventions to improve the clinical management of refractory CRC.

Keywords:  Colorectal cancer; O-GlcNAcylation; hexosamine biosynthesis pathway; metabolic alterations; therapeutic intervention.; tumor microenvironment

DOI:  https://doi.org/10.2174/0113862073443622260330054300
Cell Death Dis. 2026 May 31.

c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.

Liyan Ao, Zhiqiang Chen, Jingliang Zhang, Qi Wang, Jin Luo, Zhuoran Li, Qilong Jiao, Bobin Ning, Shiyuan Peng, Wenhao Hu, Yuqi Jia, Weimin Ci, Baojun Wang, Zhouhuan Dong, Xu Zhang, Shaoxi Niu.

Prostate cancer is a highly heterogeneous malignancy, with distinct subtypes displaying unique molecular and metabolic profiles. This study identifies a compensatory shift in α-ketoglutarate (α-KG) metabolism in prostate cancer, where the tumor relies on IDH1 to incorporate citrate into the TCA cycle. IDH1 inhibition, leads to lower α-KG levels. Since α-KG is required for HIF-1α hydroxylation, IDH1 inhibition stabilizes HIF-1α, which subsequently upregulates c-Fos. C-Fos enhances GLUD1 transcription, promoting the conversion of glutamate to α-KG as a compensatory mechanism. Additionally, c-Fos upregulates downstream effectors, including FOXC1 and SOX2, driving neuroendocrine differentiation in prostate cancer. Targeting α-KG-metabolizing enzymes, such as IDH1 or GLUD1, presents promising therapeutic strategies for prostate cancer subtypes by inhibiting tumor proliferation and inducing oxidative stress, thus sensitizing tumors to ferroptosis. Overall, these findings uncover a metabolic adaptation in response to IDH1 inhibition and highlight the pivotal role of c-Fos in mediating this compensatory pathway, offering new insights into potential metabolic targets for prostate cancer treatment and ferroptosis-based therapies.

DOI: https://doi.org/10.1038/s41419-026-08918-4
Redox Biol. 2026 Jun 02. pii: S2213-2317(26)00243-0. [Epub ahead of print]95 104245

Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.

Leandro L Coutinho, Erika M Palmieri, Lisa A Ridnour, Robert Y S Cheng, William F Heinz, Stephen K Anderson, Timothy R Billiar, Jenny Chang, Stephen J Lockett, M Cristina Rangel, Douglas D Thomas, Daniel W McVicar, David A Wink.

  Nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX2) lie at a critical intersection between inflammation, metabolism, and oncogenic signaling, where they cooperatively promote and establish a Nitric Oxide (NO)-driven Warburg phenotype in advanced cancers. Early work in macrophages established NOS2-derived NO as both a signaling molecule and metabolic stressor that inhibits oxidative phosphorylation (OXPHOS) by targeting iron-sulfur enzymes and respiratory complexes, forcing neighboring cells to rewire metabolism. In human tumors, sustained NOS2 expression in cancer cells and tumor-associated macrophages (TAMs) enforces a Warburg-like state characterized by high glycolytic flux, glutamine dependence, and enhanced NADPH production, supporting proliferation, biosynthesis, and resistance to oxidative stress. At nitrosative-signaling concentrations (≈100-500 nM), NO breaks carbon entry into the TCA cycle at aconitase and pyruvate dehydrogenase, progressively disables dehydrogenase complexes containing dihydrolipoamide dehydrogenase (DLD) and electron-transport complexes (ETCs), and activates hypoxia-inducible factor 1-alpha (HIF-1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated kinase (ERK)/pyruvate kinase M2 (PKM2)/c-Myc signaling axis, nuclear factor erythroid 2-related factor 2 (Nrf2), and transforming growth factor Beta (TGF-β)/SMAD pathways. These biochemical and signaling effects convert transient glycolytic adaptation into chemically enforced dependency, further stabilized by metabolite-driven inhibition of ten-eleven translocation (TET) and Jumonji demethylases, creating an "epigenetic lock" that maintains oncogenic transcriptional programs. NOS2 and COX2 form a reciprocal feed-forward circuit in which NO, prostaglandin E2 (PGE2), interleukin (IL)-6, and IL-8 reinforce one another, driving tumor-promoting inflammation, immunosuppression, angiogenesis, and metastasis while depleting nutrients and acidifying the tumor interstitial fluid. Spatially, NOS2/COX2 niches at the tumor-stroma interface and within immune deserts generate gradients of NO, PGE2, oxygen, and metabolites that partition tumors into microdomains with distinct metabolic states, immune composition, and therapeutic vulnerabilities. Integrating these insights with Hanahan's updated hallmarks of cancer, we propose that NOS2-derived NO functions as a node synchronizing deregulated energetics, inflammation, immune evasion, plasticity, and therapy resistance within the tumor microenvironment (TME). Targeting the NOS2-COX2 axis and its downstream NO-iron-epigenetic circuitry may therefore disrupt multiple hallmarks and reveal combinatorial strategies to exploit NO-induced metabolic liabilities in cancer.

Keywords:  COX2-PGE(2) signaling; Metabolic reprogramming; Nitric oxide synthase 2 (NOS2); Tumor microenvironment (TME); Warburg effect

DOI:  https://doi.org/10.1016/j.redox.2026.104245
bioRxiv. 2026 May 26. pii: 2026.05.25.727505. [Epub ahead of print]

Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.

Melis Kose, Elizabeth M McCormick, Kelsey Keith, Cristina Remes, Suraiya Haroon, Eiko Nakamaru-Ogiso, Marni J Falk.

Background: Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear.
Methods: We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygous ERCC6 pathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux.
Results: Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ∼20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including N -acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine).
Conclusions: ERCC6 -based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients.

DOI: https://doi.org/10.64898/2026.05.25.727505
Anal Chim Acta. 2026 Aug 22. pii: S0003-2670(26)00603-3. [Epub ahead of print]1412 345653

Ion chromatography-ultra-high-resolution mass spectrometry reveals EZH2-driven reprogramming of nucleic acid and protein methylation.

Mohamed M Y Kaddah, Teresa W-M Fan, Jahid M M Islam, Penghui Lin, Teresa A Cassel, Richard Cunningham, Tom Brown, Richard M Higashi, Andrew N Lane.

  ENHANCER OF ZESTE: homolog 2 (EZH2), a histone H3K27 trimethyltransferase, is a key epigenetic regulator frequently dysregulated in cancer. To determine its impact on nucleotide biosynthesis and nucleic acid methylation in intact cells requires highly sensitive, isomer-resolving analytical workflows. We developed a targeted ion chromatography-ultra-high-resolution Fourier transform mass spectrometry (IC-UHR-FTMS) workflow with lower limits of quantification down to 9 fmol on-column to determine changes in methylation of DNA, total RNA, and mRNA in A549 cells following EZH2 knockdown (KD). Using dual stable isotope tracers, l-methionine-(methyl-13C) and l-glutamine-(15N2), in a multiplexed stable isotope-resolved metabolomics (SIRM) design, we quantified positionally-resolved 13C/15N labeling of methylated nucleotides and their precursors. EZH2 KD reduced 15N incorporation into deoxynucleotides, indicating impaired de novo synthesis from glutamine. It also attenuated 15N and/or 13C labeling of nucleotides and methylated nucleotides in total RNA and mRNA at various atomic positions, reflecting global losses in biosynthesis and S-adenosylmethionine (SAM)-dependent methylation. Notably, AMP methylation at N6 and 2'-O positions was most responsive to EZH2 KD, implicating reduced capped-RNA translation. Some of the EZH2 KD-induced changes in RNA methylation corresponded with the altered expression of their writer or eraser enzymes. This study demonstrates multiplex stable isotope tracers-coupled IC-UHR-MS as a powerful tool for comprehensive tracing of methylation dynamics in mammalian cells and reveals EZH2's role in metabolic-epitranscriptomic regulation by modulating SAM availability via glutamine-fueled de novo purine biosynthesis and RNA methylation.

Keywords:  EZH2; Ion chromatography (IC); Isotopologue analysis; Methylated nucleotides; RNA methylation; Stable isotope-resolved metabolomics (SIRM); Ultra-high-resolution mass spectrometry (UHR-MS)

DOI:  https://doi.org/10.1016/j.aca.2026.345653
Biofactors. 2026 May-Jun;52(3):52(3): e70121

The Multiple Roles and Targeting Strategies of LonP1 in the Occurrence and Development of Cancer.

Qun Zeng, Shitian Huang, Tingting Jiang.

  LonP1, a mitochondrial AAA+ protease, serves as a pivotal integrator of mitochondrial quality control (MQC) and metabolic reprogramming in cancer progression. Alternative splicing generates three functionally distinct isoforms: full-length ISO1 maintains mitochondrial homeostasis by degrading oxidized proteins and stabilizing mitochondrial transcription factor A (TFAM) for mtDNA integrity; truncated ISO2 (Δ42-105 AA) drives glycolytic reprogramming and epithelial-mesenchymal transition (EMT) by upregulating Snail/vimentin; and cytoplasmic ISO3 (Δ1-196 AA) lacks protease activity and is tumor-irrelevant. Tumor microenvironment (TME) cues (hypoxia, H. pylori infection, PFOA exposure, glutamine depletion) regulate LonP1 via Akt phosphorylation/Sirt3 deacetylation, coordinating MQC and metabolic adaptation to support cancer cell survival and metastasis. Functional data confirm its pro-tumor role: LonP1 upregulation enhances cervical cancer mitophagy and gastric cancer glycolysis, while knockdown induces mitochondrial dysfunction and apoptosis. This review summarizes current advances by (1) systematically integrating the isoform-specific functions of LonP1; (2) constructing a "LonP1-MQC-metabolism" regulatory network based on published evidence; and (3) proposing isoform-specific targeted strategies for precision oncology. These insights position LonP1 as a promising candidate for precision oncology, offering a cohesive understanding of mitochondrial regulation in cancer.

Keywords:  LonP1; cancer; isoform‐specific function; metabolic reprogramming; mitochondrial quality control

DOI:  https://doi.org/10.1002/biof.70121
Blood. 2026 Jun 03. pii: blood.2025032496. [Epub ahead of print]

GLUL pitches in thrombocytopoiesis by restricting ammonia accumulation during megakaryocyte maturation.

Jun Chen, Zijiao Li, Yimin Zhang, Baichuan Xu, Fang Chen, Mo Chen, Mingqiang Shen, Mengjia Hu, Xi Ran, Song Wang, Ronghua Diao, Jinghong Zhao, Qian Zhang, Yahan Fan, Yang Xu, Junping Wang.

Polyploidization resulted from massive DNA synthesis is crucial for megakaryocyte maturation, while the regulatory mechanisms of cell fitness upon this special cellular process remain poorly understood. Here, we reveal that glutamine synthetase (GLUL) facilitates thrombocytopoiesis by restricting ammonia accumulation during polyploidization. GLUL is found to be distinctly expressed in platelet-producing megakaryocytes and increasingly elevated with the progression of polyploidization, and GLUL deficiency impairs megakaryocyte maturation and platelet production. Mechanistically, GLUL detoxifies ammonia derived from adenosine deaminase acting on RNA 1 (ADAR1)-mediated double-stranded RNA (dsRNA) editing in megakaryocytes undergoing polyploidization. Ammonia accumulation is observed in megakaryocytes defective in GLUL, leading to lysosomal and mitochondrial damage and even cell death. Fulvotomentoside A (FtA) is identified as a potential GLUL agonist with the capacity to promote thrombocytopoiesis in mice after radiation and chemotherapy injury. Our findings uncover the biological significance of GLUL in megakaryocyte maturation and provide a new avenue for regulating thrombocytopoiesis.

DOI: https://doi.org/10.1182/blood.2025032496
J Pharmacol Exp Ther. 2026 May 12. pii: S0022-3565(26)01140-7. [Epub ahead of print]393(7): 104941

The intelectin 1-bestrophin-2-glutamate axis regulates glutamate homeostasis and suppresses colorectal cancer progression.

Di Lu, Yang Zhou, Han Zhang, Jiannan Wang, Kai Lu, Yaonan Li, Cheng Guo, Yuanzeng Zhu.

  Colorectal cancer (CRC) is a highly prevalent malignancy with a poor prognosis, and metabolic reprogramming (eg, glutamic acid metabolism) drives its progression. However, the key regulators of glutamic acid homeostasis in CRC remain undefined. We analyzed the expression and prognostic significance of bestrophin-2 (BEST2) and intelectin 1 (ITLN1) using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Stable cell lines with BEST2/ITLN1/glutamine synthetase (GS) overexpression or knockdown were constructed, and functional assays including Cell Counting Kit-8, flow cytometry, and ELISA were performed to explore their roles in cell proliferation, apoptosis, and glutamic acid metabolism. Coimmunoprecipitation/immunofluorescence were used to validated BEST2-GS interaction. A nude mouse xenograft model was used to confirm the in vivo effects of the ITLN1-BEST2-GS axis. BEST2 and ITLN1 were downregulated in CRC tissues, and their expression correlated with a favorable prognosis in patients with CRC. BEST2 suppressed CRC cell proliferation and promoted apoptosis by reducing intracellular glutamic acid levels, which was mediated by its membrane-localized interaction with GS to modulate GS activity. ITLN1 acted as an upstream positive regulator of BEST2 by enhancing its promoter activity and exerted tumor-suppressive effects in a BEST2-dependent manner. The ITLN1-BEST2-GS axis orchestrated glutamic acid homeostasis, and ITLN1 overexpression significantly inhibited xenograft tumor growth in nude mice. The ITLN1-BEST2-GS axis regulates glutamic acid metabolism to suppress CRC progression, thus identifying novel potential therapeutic targets for this malignancy. SIGNIFICANCE STATEMENT: The intelectin 1-bestrophin-2-glutamine synthetase axis modulates glutamic acid metabolism and exerts a tumor-suppressive effect in colorectal cancer.

Keywords:  Colorectal cancer; Glutamic acid metabolism; Intelectin 1–bestrophin-2–glutamine synthetase axis; Metabolic reprogramming; Tumor-suppressive mechanism

DOI:  https://doi.org/10.1016/j.jpet.2026.104941