bims-cesirm 2025-09-21 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–09–21
twelve papers selected by
Tigist Tamir, University of North Carolina

Cysteine redoxome landscape in the liver of male mice fed a high-fat high-sucrose diet.
27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling.
Cystathionine γ-Lyase Protects Against Choline-Deficient High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Cysteine-Glutathione Axis in Mice.
mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.
Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment.
Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.
Leveraging learned representations and multitask learning for lysine methylation site discovery.
Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.
Metabolic Tracing of Methyl Donor Utilization in Histone Methylation via Relative Quantification of Isotopomer Distribution Mass Spectrometry.
Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.
α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion.
Tryptophan metabolite atlas uncovers organ, age, and sex-specific variations.

J Biol Chem. 2025 Sep 16. pii: S0021-9258(25)02582-7. [Epub ahead of print] 110730

Cysteine redoxome landscape in the liver of male mice fed a high-fat high-sucrose diet.

Cynthia M Galicia-Medina, Hein Ko Oo, Takumi Nishiuchi, Ryota Tanida, Tuerdiguli Abuduyimiti, Hisanori Goto, Yujiro Nakano, Yumie Takeshita, Kiyo-Aki Ishii, Takashi Toyama, Yoshiro Saito, Hiroaki Takayama, Toshinari Takamura.

  Reversible cysteine post-translational modifications serve as a "switch" for protein structure-function dynamics. Herein, we applied a comprehensive strategy to map the cysteine redoxome by pinpointing over 5,000 oxidized and reduced cysteine residues in the liver of male mice fed either a normal chow diet (NCD) or a high-fat/high-sucrose diet (HFHSD). The global and subcellular distribution of oxidized and reduced cysteine residues remained stable across both diet groups, indicating that HFHSD does not induce widespread shifts in cysteine redox equilibrium. Proteomic analyses revealed that HFHSD upregulates proteins involved in genomic stability, lipid detoxification, and energy regulation, while downregulating those linked to detoxification and metabolic flexibility. Notably, 169 cysteine residues exhibited dynamic redox changes in response to HFHSD, mapping to 35 KEGG pathways central to redox balance and energy homeostasis. Motif and structural analyses demonstrated that the reactivity of cysteine residues sensitive to redox stress is dictated by distinct electrostatic microenvironments and subcellular localization. Cysteine residues sensitive to HFHSD-induced oxidation were enriched in mitochondria and cytosol, and cysteine residues sensitive to HFHSD-induced reduction in extracellular regions. Furthermore, cysteine residues sensitive to HFHSD-induced reduction mainly participate in disulfide bond formation and are exposed to the surface of the protein, suggesting roles as molecular switches in protein function. The current cysteine redoxome strategy broadens the disease-associated proteome landscape and provides potential therapeutic target cysteine residues critical for regulating protein functions and interactions relevant to pathophysiology.

Keywords:  liver metabolism; oxidation-reduction (redox); post-translational modification (PTM); protein motif; proteomics

DOI:  https://doi.org/10.1016/j.jbc.2025.110730
Metabolism. 2025 Sep 15. pii: S0026-0495(25)00261-6. [Epub ahead of print] 156392

27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling.

Jinni Yang, Xue Yang, Yuan Zheng, Anhui Wang, Ziwen Kong, Qinwen Xiao, Yuan Tian, Haijuan Dong, Zunjian Zhang, Min Wang, Rui Song.

   BACKGROUND AND AIMS: Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance.
METHODS: Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity.
RESULTS: Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis.
CONCLUSION: Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.

Keywords:  27-Hydroxycholesterol; Accessible cholesterol; CYP27A1; Insulin receptor; Insulin resistance

DOI:  https://doi.org/10.1016/j.metabol.2025.156392
Antioxid Redox Signal. 2025 Sep 17.

Cystathionine γ-Lyase Protects Against Choline-Deficient High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Cysteine-Glutathione Axis in Mice.

Min Ji Kim, You Ri Park, Gibong Jang, Yong Kwon Han, Isao Ishii, Se Young Jang, Kwon Moo Park.

  Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease, yet its pathogenesis remains incompletely understood. Oxidative stress is thought to play a key role in MASLD progression. This study aimed to investigate the role of cystathionine γ-lyase (CSE), an enzyme essential for cysteine and glutathione (GSH) biosynthesis, in MASLD development. Results: Choline-deficient high-fat diet (CDHFD) feeding led to elevated aspartate aminotransferase, alanine aminotransferase, hepatic triglyceride accumulation, vacuolization, macrophage infiltration, and cell death in both genotypes, with significantly greater changes observed in Cse-/- mice. CDHFD also reduced hepatic CSE expression in Cse+/+ mice and decreased cysteine/GSH levels in both genotypes, with more pronounced reductions in Cse-/- mice. Furthermore, Cse deletion was associated with increased oxidized glutathione/total GSH ratios and elevated levels of 4-hydroxynonenal and malondialdehyde. Expression of glutathione synthetase and γ-glutamyl transpeptidase was increased by CDHFD in Cse+/+ mice but blunted in Cse-/- mice. Furthermore, CSE deficiency exacerbated CDHFD-induced hepatic iron accumulation. Innovation: Our findings suggest that the CSE-cysteine-GSH axis may serve as a potential therapeutic target for MASLD, providing new intervention strategies beyond traditional approaches. This study provides new insights into the molecular mechanisms of MASLD and supports the development of antioxidant-based therapies. Conclusions: CSE deficiency exacerbates CDHFD-induced impairments of cysteine-GSH antioxidant axis, leading to hepatic oxidative stress and cell death. This indicates that CSE plays a protective role against MASLD development and progression. Antioxid. Redox Signal. 00, 000-000.

Keywords:  cystathionine γ-lyase; glutathione; knockout mice; metabolic dysfunction-associated steatotic liver disease; nonalcoholic fatty liver disease; oxidative stress

DOI:  https://doi.org/10.1177/15230864251377735
Mol Cell. 2025 Sep 18. pii: S1097-2765(25)00706-3. [Epub ahead of print]85(18): 3486-3504.e7

mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.

Sejeong Shin, Min-Joon Han, Ishika Patel, Alia M Welsh, Maria Sverdlov, Wonhwa Cho, Stephanie M Cologna, Philippe P Roux, Sang-Oh Yoon.

  The mechanistic target of rapamycin (mTOR) is a key regulator of lipid homeostasis by controlling processes including lipid uptake and biosynthesis. mTOR dysregulation and consequent altered lipid metabolism are common in various diseases, including cancers, making mTOR a promising therapeutic target. Therefore, it is crucial to understand how mTOR activation and inhibition reprogram lipid homeostasis. In human cancer cell lines, mTOR inhibition induces alternative lipid uptake through translation eukaryotic initiation factor 3D (eIF3D)-mediated low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) increase and activates liver X receptor β (LXRβ), promoting cholesterol release from lysosomes and its transport to the plasma membrane via Niemann-Pick disease type C (NPC) intracellular cholesterol transporter 1 (NPC1). This signaling supports tumor cell survival and stress resistance. In mouse xenograft models, combining mTOR inhibition with LRP6 knockdown or NPC1 targeting significantly suppresses tumor growth. Our findings highlight mTOR feedback signaling in reprogramming lipid homeostasis and its therapeutic potential to treat diseases characterized by dysregulated mTOR.

Keywords:  AKT; IGF1R; LRP6; NPC1; cholesterol; mTOR

DOI:  https://doi.org/10.1016/j.molcel.2025.08.021
Cancer Lett. 2025 Sep 11. pii: S0304-3835(25)00586-5. [Epub ahead of print] 218016

Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment.

Shijuan Jiang, Bo Ren, Chen Ding, Changwei Du, Zhe Cao, Gang Yang, Hua Huang, Taiping Zhang.

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, characterized by aggressive malignancy and poor outcomes. Emerging evidence implicates dysregulated polyamine metabolism as a key driver of pancreatic ductal adenocarcinoma immunosuppression, yet the mechanisms underlying this metabolic-immune crosstalk remain poorly defined. This review summarized recent findings demonstrating that pancreatic ductal adenocarcinoma is uniquely dependent on glutamine-derived ornithine for de novo polyamine synthesis, orchestrated by the KRAS-MYC axis. Through metabolic reprogramming of immune cells, polyamines polarize tumor-associated macrophages toward M2-like phenotypes, expand myeloid-derived suppressor cells, and impair T cell activation. Crucially, the immunomodulatory effects of polyamines are source-dependent: tumor-derived spermidine promotes T cell exhaustion, whereas dietary spermidine enhances antitumor immunity through fatty acid oxidation. Preclinical studies have highlighted that polyamine-targeted therapy, which including biosynthesis inhibitors, arginine deprivation agents and polyamine analogue, is a promising strategy to reverse immunosuppression and enhances the efficiency of checkpoint inhibitors. These evidences establish polyamine metabolism as a therapeutic vulnerability in pancreatic ductal adenocarcinoma, offering novel diagnostic tools and combination regimens to overcome therapeutic resistance.

Keywords:  immune cell; immunotherapy; pancreatic cancer; polyamine metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218016
Cancer Med. 2025 Sep;14(18): e71244

Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.

Jilsy M J Punnasseril, Abdul Auwal, Vinod Gopalan, Alfred King-Yin Lam, Farhadul Islam.

   BACKGROUND: Cancer metabolism is a field focused on the unique alterations in metabolic pathways that occur in cancer cells, distinguishing them from the metabolic processes in normal cells.
METHODS: An extensive review of the current literature on the metabolic adaptation of cancer cells was carried out in the current study.
RESULTS: The rapidly proliferating cells require high levels of molecules, such as glucose, amino acids, lipids, and nucleotides, along with increased energy demand (ATP). These requirements are met through alterations in the processes involving glucose, amino acid, lipid, and nucleotide metabolism. Modifications in glucose metabolism in cancer cells involve changes in glucose uptake, glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. Similarly, alterations in amino acid metabolism in cancer cells relate to upregulated amino acid transport and glutaminolysis. Cancer cells also have increased lipid intake from the extracellular microenvironment, upregulated lipogenesis, and enhanced lipid storage and mobilization from intracellular lipid droplets. These rapidly proliferating cells also achieve their increased demand for nucleotides by changing the expression of enzymes in the salvage and de novo nucleotide pathways. Consequently, these metabolic processes are targets for developing cancer therapeutics. However, it is important to note that the metabolic changes in cancer cells can also contribute to resistance against various cancer therapies.
CONCLUSION: This review will explore the various ways in which cancer cells reprogram metabolic processes to sustain rapid proliferation and survival. The information presented in this report could help in the therapeutics designed to target them, and the challenges of cancer drug resistance arising from these metabolic adaptations.

Keywords:  Warburg effect; cancer metabolism; drug resistance; glucose metabolism; nucleotide metabolism; therapeutics

DOI:  https://doi.org/10.1002/cam4.71244
bioRxiv. 2025 Sep 01. pii: 2025.08.27.672583. [Epub ahead of print]

Leveraging learned representations and multitask learning for lysine methylation site discovery.

François Charih, Mullen Boulter, Kyle K Biggar, James R Green.

  Lysine methylation is a dynamic and reversible post-translational modification of proteins carried out by lysine methyltransferase enzymes. The role of this modification in epigenetics and gene regulation is relatively well understood, but our understanding of the extent and the role of lysine methylation of non-histone substrates remains fairly limited. Several lysine methyltransferases which methylate non-histone substrates are overexpressed in a number of cancers and are believed to be key drivers of cancer progression. There is great incentive to identify the lysine methylome, as this is a key step in identifying drug targets. While numerous computational models have been developed in the last decade to identify novel lysine methylation sites, the accuracy of these model has been modest, leaving much room for improvement. In this work, we leverage the most recent advancements in deep learning and present a transformer-based model for lysine methylation site prediction which achieves state-of-the-art accuracy. In addition, we show that other post-translational modifications of lysine are informative and that multitask learning is an effective way to integrate this prior knowledge into our lysine methylation site predictor, MethylSight 2.0. Finally, we validate our model by means of mass spectrometry experiments and identify 68 novel lysine methylation sites. This work constitutes another contribution towards the completion of a comprehensive map of the lysine methylome.

Keywords:  Lysine methylation; deep learning; lysine methylome; multitask learning; transformers

DOI:  https://doi.org/10.1101/2025.08.27.672583
Asian Pac J Cancer Prev. 2025 Sep 01. pii: 91865. [Epub ahead of print]26(9): 3157-3174

Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.

Ahmed S Alhallaq, Nadeen S Sultan.

  Metabolic reprogramming induced by the glutamine/glutamate (Gln/Glu) metabolic pathway is a key mechanism in ATP production, precursor biosynthesis, and redox homeostasis, promoting prostate cancer (PCa) growth and proliferation. This evolutionarily acquired hallmark of cancers enables malignant cells to adapt their bioenergetic and biosynthetic pathways in response to microenvironmental stresses. Therefore, Gln/Glu metabolism orchestrates epigenetic regulation, metastatic capacity, and oxidative homeostasis in PCa, supporting the survival of PCa tumors. Fluctuations in Glu metabolite levels and oxygen tension shape the PCa epigenome by facilitating Glu-derived α-ketoglutarate (α-KG) activation of TET and KDM enzymes, which drive histone and DNA demethylation. Furthermore, tumor progression toward metastatic castration-resistant PCa is characterized by heightened Gln/Glu dependency and increased Gln uptake. Within the tumor microenvironment (TME), a dynamic tug-of-war occurs between tumor and immune cells, competing for Gln metabolites. Gln/Glu converges on critical oncogenic signaling axes, including NF-κB/Nrf2, c-Myc/androgen receptor, MAPK/ERK, and PI3K/AKT/mTOR. Additionally, extracellular Glu release via SLC7A11 and PSMA triggers metabotropic glutamate receptor (mGluR) signaling, further potentiating oncogenic programs. Targeting this Gln/Glu metabolic network thus presents a promising therapeutic approach against PCa. In this review, we summarize the role of Gln/Glu in PCa progression based on the compartmentalization of the Gln/Glu metabolic pathway to elucidate why PCa cells manifest dependence on Gln/Glu. Eventually, we highlight potential therapeutic targets that can be exploited for PCa treatment.

Keywords:  Glutamine; Metabolic Reprogramming; Prostate Cancer; Tumor Microenvironment; glutamate

DOI:  https://doi.org/10.31557/APJCP.2025.26.9.3157
ACS Chem Biol. 2025 Sep 16.

Metabolic Tracing of Methyl Donor Utilization in Histone Methylation via Relative Quantification of Isotopomer Distribution Mass Spectrometry.

Hui Tang, Kangling Zhang.

Histone methylation depends on one-carbon metabolism, with methyl groups donated by methionine-, serine-, and glucose-derived intermediates. To dissect the metabolic origins of histone methylation, we developed Relative Quantitative Methyl Isotopomer Distribution Mass Spectrometry (RQMID-MS), a high-resolution mass spectrometry-based method that uses diagnostic low-mass fragment ions to quantify methyl group transfer from isotope-labeled precursors. Using this method, we mapped methylation sources to histone lysines in glioblastoma cells under nutrient and oxygen stress. Methionine was the dominant methyl donor under replete condition. Under combined serine and methionine depletion or prolonged methionine depletion alone, glucose emerged as a key compensatory source, particularly in U87 cells with elevated 3-phosphoglycerate dehydrogenase (PHGDH) expression. In contrast, U251 cells favored exogenous serine and glycine, correlating with higher levels of serine hydroxymethyltransferase 2 (SHMT2) expression. Hypoxia initially enhanced glucose-derived methylation but later suppressed it, likely due to impaired vitamin B12-dependent remethylation of homocysteine. RQMID-MS enables precise tracking of methyl donor routing to histones and offers a robust platform for studying metabolic and epigenetic crosstalk in cancer and beyond.

DOI: https://doi.org/10.1021/acschembio.5c00528
bioRxiv. 2025 Sep 08. pii: 2025.09.04.673818. [Epub ahead of print]

Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.

Colin Sheehan, Lyndon Hu, Guillaume Cognet, Grace Croley, Thao Trang Nguyen, Anika Thomas-Toth, Darby Agovino, Patrick B Jonker, Mumina Sadullozoda, Leah M Ziolkowski, James K Martin, Alica K Beutel, Ranya Dano, Mohammed A Khan, Christopher J Halbrook, Kay F Macleod, Christopher R Weber, James L LaBelle, Alexander Muir.

Cytotoxic chemotherapy remains the standard-of-care treatment for patients with pancreatic ductal adenocarcinoma (PDAC). However, chemotherapy only has modest effects at improving patient survival due to primary or rapidly acquired chemoresistance. The biological underpinnings of PDAC therapy resistance are incompletely defined, but the tumor microenvironment is known to be a major contributor to chemoresistance. We have found chemoresistance is imprinted on PDAC cells by the tumor microenvironment and persists for a period of days after PDAC cells are removed from tumors. However, PDAC chemoresistance is lost upon long term culture in standard laboratory conditions. Interestingly, culture of PDAC cells in Tumor Interstitial Fluid Medium (TIFM), a culture medium we developed to recapitulate the nutrient availability of the tumor microenvironment, maintains PDAC cells in a chemo- and targeted therapy resistant state even after long term culture ex vivo . These findings suggest that microenvironmental metabolic stress keeps PDAC cells in a physiologically relevant, therapy resistant cell state that standard culture models fail to maintain. Using TIFM culture, we sought to understand how PDAC cells in this state resist therapeutic challenge. We found that chemo- and targeted therapies largely retain on-target activity within TIFM medium but fail to activate cell death, enabling a "chemotolerant" cell state, which is also observed in PDAC tumors. This chemotolerant state is driven by suppression of apoptotic priming and can be overcome by targeting the anti-apoptotic regulator BCL-XL. Taken together, these findings suggest that reprogramming of cell death mechanisms by the PDAC nutrient microenvironment is a key contributor to therapy resistance in this disease.

DOI: https://doi.org/10.1101/2025.09.04.673818
Sci Adv. 2025 Sep 19. 11(38): eady8048

α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion.

Canqi Cui, Danielle C Leander, Sarah M Gray, Kimberley El, Alex Chen, Paul A Grimsrud, Jessica O Becker, Austin Taylor, Guo-Fang Zhang, Kyle W Sloop, C Bruce Verchere, Andrew N Hoofnagle, David A D'Alessio, Jonathan E Campbell.

α cells secrete proglucagon peptides to regulate nutrient metabolism. Recent findings support an α cell-to-β cell axis that is mediated by paracrine signaling through the glucagon receptor and glucagon-like peptide 1 (GLP-1) receptor in β cells. To address which proglucagon peptides stimulate insulin secretion, we developed an assay to quantify levels of GLP-1(7-36)NH2. We also generated three transgenic mouse lines that allow α cell-specific, inducible deletion of the genes for the two prohormone convertase enzymes that process proglucagon . Our studies reveal that both mouse and human islets contain GLP-1(7-36)NH2, but glucagon mediates α cell-to-β cell communication in mice. However, in the absence of normal production of glucagon, α cells up-regulate prohormone convertase 1 (PC1/3) to generate GLP-1 and enhance glucose tolerance. Human islets have substantially higher levels of GLP-1 than mice, which positively correlate with rates of insulin secretion. These studies show plasticity in proglucagon processing to support α cell-to-β cell communication.

DOI: https://doi.org/10.1126/sciadv.ady8048
FEBS Open Bio. 2025 Sep 19.

Tryptophan metabolite atlas uncovers organ, age, and sex-specific variations.

Lizbeth Perez-Castro, Afshan F Nawas, Jessica A Kilgore, Pedro A S Nogueira, M Carmen Lafita-Navarro, Paul H Acosta, Roy Garcia, Noelle S Williams, Maralice Conacci-Sorrell.

  Tryptophan (Trp) is the largest and most structurally complex amino acid, yet it is the least abundant in the proteome. Its distinct indole ring and high carbon content allow it to give rise to several biologically active metabolites, including serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P). Dysregulation of Trp metabolism has been implicated in a range of diseases, from depression to cancer. Investigating Trp and its metabolites in healthy tissues provides insight into how disease-associated disruptions may be targeted selectively while preserving essential physiological functions. Whereas previous studies have typically focused on individual organs or single metabolic branches, our analysis spans 12 peripheral organs, the central nervous system, and serum in male and female (C57BL/6) mice across three life stages: young (3 weeks), adult (54 weeks), and aged (74 weeks). We identified striking tissue-, sex-, and age-specific differences in Trp metabolism, including elevated levels of I3P and Kyn, both linked to tumor growth, in aging males. We also compared Trp metabolite profiles in tissues from mice fed a control defined diet versus a Trp-deficient diet for three weeks. This intervention led to a marked reduction in circulating Trp and its metabolites, with more modest effects observed in the liver and central nervous system. These findings underscore the importance of organ-specific and diet-sensitive analyses of Trp metabolism for understanding its role in both normal physiology and disease. Establishing baseline levels of Trp metabolites across tissues may also provide a foundation for identifying organ-specific metabolic reprogramming in cancer and other illnesses.

Keywords:  atlas; indole‐3‐pyruvate; kynurenine; metabolism; serotonin; tryptophan

DOI:  https://doi.org/10.1002/2211-5463.70123