bims-cesirm 2025-11-09 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–11–09
27 papers selected by
Tigist Tamir, University of North Carolina

Human Citrate Synthase Post-Translational Modification Mimics and Molecular Dynamic Simulations Demonstrate Attenuation of Acetyl-CoA/CoA Binding.
Regenerating liver uses ammonia to support de novo pyrimidine synthesis and cell proliferation.
Machine learning-driven prediction of substrates for enzymes introducing or removing protein post-translational modifications.
Non-thermal Plasma-Derived Reactive Oxygen Species Induces Cell Death in Radioresistant Head and Neck Cancer via the c-MET/STAT3 Pathway.
Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy.
Cell populations in human breast cancers are molecularly and biologically distinct with age.
Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.
Distinct profiles of mitochondrial bioenergetics and redox balance in left atrial and ventricular myocardium in the healthy rat heart.
Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer.
Phosphoproteomic profiling highlights CDC42 and CDK2 as key players in the regulation of the TGF-β pathway in ALMS1 and BBS1 knockout models.
GADD45β inhibits hepatic lipogenesis through the AMPK/SREBP1 pathway via reducing the ubiquitination-mediated degradation of SIRT1.
IGF-1 regulates cancer cell immune evasion in prostate cancer.
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.
Multi-dimensional Proteomics Reveal Metformin's Impact on Interconnected Regulatory Networks of Protein Turnover, Ubiquitination, DNA Damage, and Cell Cycle.
Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.
Modeling protein-small molecule conformational ensembles with PLACER.
High-fat diet promotes kidney lipid droplet deposition contributing to the pathogenesis of obesity-related glomerulopathy in mice through gut microbial metabolism.
Highly Sensitive Detection of Tyrosine and Neurotransmitters by Stereoselective Biosynthesis and Photochemically Induced Dynamic Nuclear Polarization.
Enhanced prediction of breast cancer patient response to chemotherapy by integrating deconvolved expression patterns of immune, stromal and tumor cells.
Probing omics data via harmonic persistent homology.
Clinical glycoproteomics in cancer: toward tissue-based glycoform profiling and biomarker discovery.
LSR overexpression induces chemoresistance in triple negative breast cancer cells through MDR1 upregulation and apoptosis attenuation.
Effect of phosphate availability on the dynamics of polyphosphate accumulation in microalgae.
Creatine kinase B regulates glycolysis and de novo lipogenesis pathways to control lipid accumulation during adipogenesis.
Homeostatic response of phospholipid pathways to PCYT2 deficiency and impaired de Novo synthesis of phosphatidylethanolamine.
Multi-omics analysis reveals metabolic regulation of phosphatidylcholine, triglycerides, phosphatidylethanolamine, and cardiolipin metabolism in mouse liver with metabolic dysfunction-associated steatotic liver disease.

Proteins. 2025 Nov 03.

Human Citrate Synthase Post-Translational Modification Mimics and Molecular Dynamic Simulations Demonstrate Attenuation of Acetyl-CoA/CoA Binding.

Noah Shackelford, Zach Zavodny, Nathan Fancher, Michael A Moxley.

  Human citrate synthase (hCS) is a mitochondrial enzyme that catalyzes the aldol condensation of acetyl coenzyme A (AcCoA) to oxaloacetate to form citrate in the TCA cycle. CS activity is important for aerobic exercise performance and basic metabolic function as a housekeeping enzyme. It has been shown through several mass spectrometry-based physiological studies that CS is post-translationally modified (PTM) on numerous residues via acetylation, phosphorylation, and methylation reactions. Few follow-up studies have been reported on the impact of PTMs on CS activity. Thus, we kinetically characterized several hCS PTM mimics near and distant from the active site by site-directed mutagenesis coupled with steady-state kinetics. Most modifications had a negative impact on AcCoA kcat/Km but to a much lesser extent on oxaloacetate kcat/Km. Most notably, the K393 acetylation mimic, K393Q displays an increase in Km for AcCoA relative to WT by about 30-fold, with no significant change in kcat. To complement our kinetic analyses, we performed molecular dynamics simulations on 26 PTM and mutant CS-substrate complexes, providing a combined kinetic and MD simulation approach. Among the MD results, CS K393AcK showed the greatest reduction in AcCoA/CoA binding.

Keywords:  enzyme kinetics; molecular dynamics; post‐translational modifications

DOI:  https://doi.org/10.1002/prot.70082
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
Commun Chem. 2025 Nov 07. 8(1): 340

Machine learning-driven prediction of substrates for enzymes introducing or removing protein post-translational modifications.

Nashira H Ridgeway, Anand Chopra, Valentina Lukinović, Michal Feldman, François Charih, Dan Levy, James R Green, Kyle K Biggar.

The exploration of post-translational modifications (PTMs) within the proteome is pivotal for advancing our understanding of disease and the function of cancer therapeutics. However, identifying genuine sites of PTMs introduced or removed by an enzyme of interest amid numerous candidates is challenging. We present a machine learning (ML)-driven search method, which combines ML with enzyme-mediated modification of complex peptide arrays to predict unexplored PTM sites for an enzyme of interest. Experimental validation confirmed that this approach correctly predicted 37-43% of proposed PTM sites, unveiling candidate sites of the methyltransferase SET8 and the deacetylases SIRT1-7. Our approach marks an important performance increase over traditional in vitro methods across separate enzyme classes. Mass spectrometry analysis confirmed the dynamic methylation status of several predicted SET8 substrates, and the deacetylation of 64 unique sites identified for SIRT2. This method has also revealed changes in SET8-regulated substrate network among breast cancer missense mutations, collectively revealing insight into differential enzyme function in disease. By disentangling the substrate features that dictate PTM-inducing enzyme specificity, this approach demonstrates potential in uncovering enzyme-substrate networks within PTM pathways.

DOI: https://doi.org/10.1038/s42004-025-01717-6
Antioxid Redox Signal. 2025 Nov 05.

Non-thermal Plasma-Derived Reactive Oxygen Species Induces Cell Death in Radioresistant Head and Neck Cancer via the c-MET/STAT3 Pathway.

Chan Oh, Mi Ae Lim, Shengzhe Cui, Yudan Piao, Sicong Zheng, Yan Li Jin, Shan Shen, Quoc Khanh Nguyen, Se-Hee Park, Young Il Kim, Jae Won Chang, Ho-Ryun Won, Ji Won Kim, Seung-Nam Jung, Bon Seok Koo.

  Aims: Radiation therapy is a crucial treatment modality for head and neck squamous cell carcinomas (HNSCCs). However, acquired radiation resistance due to various mechanisms poses a major clinical challenge for therapeutic strategies. Intriguingly, reactive oxygen species (ROS) are versatile signaling molecules that promote various cellular functions at low concentrations but induce cell death at above-critical threshold levels. Results: Here, we found that radioresistant (RR) cancer cells exhibited reduced ROS levels and activation of the mesenchymal-epithelial transition factor/signal transducer and activator of transcription 3 (c-MET/STAT3) pathway. To target common vulnerabilities in RR cancers, we applied ROS enhancement therapy using nonthermal plasma-activated media (NTPAM), a novel approach that effectively inhibits the viability of RR cancer cells and is associated with inactivation of the c-MET/STAT3 pathway. Mechanistically, the downregulation of total c-MET is related to ROS-mediated lysosomal degradation. In addition, NTPAM suppressed tumor growth in a mouse model of RR cancer, concurrently reducing the levels of both the total and activated forms of c-MET and decreasing STAT3 phosphorylation. Innovations and Conclusions: These findings suggest that ROS enhancement therapy can overcome radiation resistance, thereby offering a compelling rationale for considering NTPAM as a stand-alone or complementary therapeutic approach for treating patients with HNSCCs. Antioxid. Redox Signal. 00, 000-000.

Keywords:  c-MET/STAT3; lysosomal degradation; non-thermal plasma activated media; radiation resistance cancer; reactive oxygen species

DOI:  https://doi.org/10.1177/15230864251393938
Cell Death Differ. 2025 Nov 03.

Mitochondria-transliterated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy.

Dan Wu, Xin Zhao, Caiyu Shi, Jing Zhao, Zeyu Yan, Runjiao Zhang, Xianchun Lan, Jiaze An, Qichao Huang, Xianli He, Tingting Ren, Jinliang Xing.

To prevent cell death induced by elevated oxidative stress, cancer cells activate a series of antioxidant defense mechanisms to mitigate cytotoxicity, thereby enhancing the resistance to pro-oxidative therapy. However, the underlying antioxidant mechanisms in cancer cells remain inadequately understood. Through co-immunoprecipitation followed by quantitative mass spectrometry analysis, we for the first time identified that cytoplasmic ALDH1L1 translocates into mitochondria and co-localizes with mitochondrial transcription factor TFAM in cancer cells in a ROS-dependent feedback manner. Mitochondria-translocated ALDH1L1 maintains mitochondrial redox homeostasis by producing NADPH. Moreover, our findings revealed that the ROS-mediated oxidative modification of ALDH1L1 is necessary for its interaction with HSP90β and subsequent translocation into mitochondria via TOM70, where it binds to TFAM to prevent degradation by LONP1. Furthermore, we found that mitochondrial ALDH1L1 antagonized the double-edged role of ROS in cancer cell survival, indicating that disruption of ALDH1L1 expression promoted cancer cell proliferation and autophagy but concurrently diminished cellular capacity to counteract ROS-induced apoptosis. Consistently, ALDH1L1 knockout enhanced the anti-tumor effect of low-dose pro-oxidant Elesclomol, thereby achieving better efficacy and safety of pro-oxidant therapy. Furthermore, our results demonstrated that the combination of Elesclomol with HSP90 inhibitor Ganetespib exhibited synergistic anti-tumor effects. In conclusion, our findings that mitochondria-translocated ALDH1L1 functions as a feedback regulator of redox homeostasis in cancer cells to enhance the resistance to pro-oxidative therapy can provide critical insights into developing effective pro-oxidative therapies against tumors.

DOI: https://doi.org/10.1038/s41418-025-01604-6
Nat Aging. 2025 Nov 04.

Cell populations in human breast cancers are molecularly and biologically distinct with age.

Adrienne Parsons, Esther Sauras Colón, Meghana Manjunath, Hanyun Zhang, Julia Chen, Milos Spasic, Beyza Koca, Busem Binboga Kurt, Rachel A Freedman, Elizabeth A Mittendorf, Alexander Swarbrick, Peter van Galen, Sandra S McAllister.

Aging is associated with increased breast cancer risk, and the oldest and youngest patients have worse outcomes, irrespective of subtype. It is unknown how age affects cells in the breast tumor microenvironment or how they contribute to age-related pathology. Here we discover age-associated differences in cell states in human estrogen receptor-positive and triple-negative breast cancers using analyses of existing bulk and single-cell transcriptomic data. We generate and apply an Age-Specific Program ENrichment (ASPEN) analysis pipeline, revealing age-related changes, including increased tumor cell epithelial-mesenchymal transition and cancer-associated fibroblast inflammatory responses in triple-negative breast cancer. Estrogen receptor-positive breast cancer displays increased ESR1 expression and reduced vascular and immune cell metabolism with age. Cell interactome analysis reveals candidate signaling pathways that drive age-related cell states. Spatial analyses across independent clinical cohorts support the computational findings. This work identifies potential targets for age-adapted therapeutic interventions for breast cancer.

DOI: https://doi.org/10.1038/s43587-025-00984-1
NPJ Metab Health Dis. 2025 Nov 07. 3(1): 43

Cysteine S-acetylation is a widespread post-translational modification on metabolic proteins.

E Keith Keenan, Akshay Bareja, Yannie Lam, Paul A Grimsrud, Matthew D Hirschey.

Protein acetylation is a fundamental regulatory mechanism occurring primarily on lysine amino acids. Here we report systematic in vivo characterization of cysteine S-acetylation as a widespread post-translational modification in mammalian tissues. By developing specialized sample preparation methods that preserve the labile thioester bond, we identified over 400 sites of cysteine acetylation in mouse liver, mirroring the abundance of lysine acetylation. Proteomic surveys across nine murine tissues revealed tissue-specific acetylation patterns that are enriched on metabolic enzymes in the cytoplasm. Cold exposure in mice triggers coordinated remodeling of the brown adipose tissue cysteine acetylome. Functional studies demonstrate that the acetylation of GAPDH Cys150 abolishes catalytic activity and correlates with nuclear enrichment, paralleling the known effects of S-nitrosylation on this enzyme. These findings establish cysteine acetylation as a widespread modification of metabolic proteins that responds to changes in cellular acetyl-CoA availability, fundamentally expanding the landscape of protein acetylation beyond lysine.

DOI: https://doi.org/10.1038/s44324-025-00081-2
Exp Physiol. 2025 Nov 04.

Distinct profiles of mitochondrial bioenergetics and redox balance in left atrial and ventricular myocardium in the healthy rat heart.

Tingting Fang, Alex Chan, Janice Chew-Harris, Toan Pham.

  The left ventricle (LV) is the primary pumping chamber of the heart, generating high systolic pressure to sustain systemic circulation. LV contractile dysfunction is a hallmark of various cardiovascular diseases and is associated with mitochondrial dysfunction, characterised by decreased oxidative phosphorylation (OXPHOS) capacity and increased oxidative stress. While our understanding of cardiac mitochondrial physiology has been gained from studies on LV tissues in animal models or atrial tissues in human studies, findings are often generalised across cardiac regions. Given that fundamental differences in anatomical structure, physiological function and metabolic demands exist between the LV and left atrium (LA), this study aimed to compare mitochondrial bioenergetics between LV and LA tissues from healthy rat hearts. Using high-resolution respirometry coupled with fluorimetry, we assessed mitochondrial respiration, ATP production and hydrolysis, and reactive oxygen species (ROS) production rates. Protein expression of mitochondrial respiratory complexes and antioxidant enzymes was quantified using western blotting. Our results showed that per tissue mass, LV tissues exhibited greater mitochondrial OXPHOS respiration, ATP production and hydrolysis rates, ROS production rate, and higher protein levels of mitochondrial complexes and antioxidant enzymes, consistent with higher citrate synthase activity as a marker of mitochondrial content. However, when normalised to mitochondrial content, LV tissues exhibited lower OXPHOS respiration and ATP production, expression of mitochondrial complexes and antioxidant proteins compared to LA. This study provides new insights into chamber-specific differences in mitochondrial function under physiological conditions, suggesting the importance of considering regional mitochondrial profiles in studies of cardiac mitochondrial function in health and disease.

Keywords:  ATP; ROS; SOD; catalase; left atrium; left ventricle; mitochondrial function

DOI:  https://doi.org/10.1113/EP093102
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
Cell Rep. 2025 Nov 05. pii: S2211-1247(25)01301-4. [Epub ahead of print]44(11): 116530

Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer.

Xurui Li, Zhenghui Sun, Ruijiang Zeng, Ruiling Liu, Pingxia Lin, Zhuo Xing, Xin Jin, Tiejun Yang.

  A high-fat diet (HFD) promotes tumor progression and therapeutic resistance, but its mechanistic role in prostate cancer (PCa) remains unclear. In this study, we show that an HFD not only accelerates PCa progression but also significantly reduces sensitivity to CDK4/6 inhibitors. Mechanistically, an HFD activates CDK4, inducing RB1 phosphorylation and facilitating E2F1 release. Meanwhile, phosphorylation of RB1 at the S249/T252 site enhances its interaction with ETS1 and suppresses ETS1's transcriptional activity. Treatment with CDK4/6 inhibitors induces dephosphorylation at this site, relieving ETS1 suppression and promoting PCYT2 expression and phosphatidylcholine metabolic reprogramming. The resulting metabolic products further disrupt RB1-E2F1 binding, leading to additional E2F1 release and increased resistance to CDK4/6 inhibitors. In conclusion, our results identify a diet-metabolism-transcriptional regulatory axis centered on RB1 phosphorylation and ETS1 reactivation, reveal a mechanism of acquired resistance to CDK4/6 inhibitors of castration-resistant PCa, and provide a theoretical basis for combinatorial strategies targeting metabolic and oncogenic signals.

Keywords:  CDK4/6 inhibitors; CP: cancer; CP: metabolism; RB1; high-fat diet; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.116530
Sci Rep. 2025 Nov 05. 15(1): 38710

Phosphoproteomic profiling highlights CDC42 and CDK2 as key players in the regulation of the TGF-β pathway in ALMS1 and BBS1 knockout models.

Brais Bea-Mascato, Girolamo Giudice, Iguaracy Pinheiro-de-Sousa, Carlos Solarat, Pablo Barbeito, Evangelia Petsalaki, Diana Valverde.

  The primary cilium is a sensory organelle that extends from the plasma membrane. It plays a vital role in physiological and developmental processes by controlling different signalling pathways such as WNT, Sonic hedgehog (SHh), and transforming growth factor β (TGF-β). Ciliary dysfunction has been related to different pathologies such as Alström (ALMS) or Bardet-Biedl (BBS) syndrome. The leading cause of death in adults with these syndromes is chronic kidney disease (CKD), which is characterised by fibrotic and inflammatory processes often involving the TGF-β pathway. Using genomic editing with CRISPR-CAS9 and phosphoproteomics we have studied the TGF-β signalling pathway in knockout (KO) models for ALMS1 and BBS1 genes. We have developed a network diffusion-based analysis pipeline to expand the data initially obtained and to be able to determine which processes were deregulated in TGF-β pathway. Finally, we have analysed protein-protein and kinase-substrate interactions to prioritise candidate genes in the regulation of the TGF-β pathway in ALMS and BBS. Analysis of differentially phosphorylated proteins identified 10 candidate proteins in the ALMS1 KO model and 41 in the BBS1 KO model. After network expansion using a random walk with a restart algorithm, we were able to identify the TGF-β signalling pathway together with other related processes such as endocytosis in the case of ALMS1 or the regulation of the extracellular matrix in BBS1. Protein interaction analyses demonstrated the involvement of CDC42 as a central protein in the interactome in ALMS1 and CDK2 in the case of BBS1. In conclusion, the depletion of ALMS1 and BBS1 affects the TGF-β signalling pathway, conditioning the phosphorylation and activation of several proteins, including CDC42 in the case of ALMS1 and CDK2 in the case of BBS1.

Keywords:  ALMS1; Alström syndrome; BBS1; Bardet–Biedl syndrome; Ciliopathies; Phosphoproteomics; TGF-β

DOI:  https://doi.org/10.1038/s41598-025-22584-0
Sci Rep. 2025 Nov 07. 15(1): 39026

GADD45β inhibits hepatic lipogenesis through the AMPK/SREBP1 pathway via reducing the ubiquitination-mediated degradation of SIRT1.

Yuanyuan Xiao, Renjie Wang, Chaoyu Zhu, Qianqian Wang, Xinyi Wang, Wenjing Song, Shouxia Li, Fusong Jiang, Jun Yin, Li Wei.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally increasing metabolic disorder associated with serious health complications. The molecular mechanisms linking stress-response proteins to hepatic lipogenesis in MASLD remain poorly understood. Here, we identified GADD45β as a key suppressor of de novo lipogenesis through SIRT1 stabilization. In both methionine-choline-deficient (MCD) diet-fed mice and palmitic acid (PA)-treated hepatocytes, GADD45β deficiency exacerbated lipid accumulation and upregulated lipogenic genes (SREBP1, FASN, ACC). Mechanistically, GADD45β directly bound to SIRT1 and inhibited its ubiquitination, thereby prolonging SIRT1 protein stability. Enhanced SIRT1 stability increased AMPK phosphorylation, which suppressed SREBP1-mediated transcription of lipogenic targets. Crucially, hepatic overexpression of GADD45β reversed PA-induced steatosis in vitro. Our study uncovered a GADD45β/SIRT1-/AMPK axis as a central regulator of hepatic lipogenesis, proposing GADD45β as a therapeutic target for MASLD.

Keywords:  GADD45β; Lipogenesis; MASLD; SIRT1; Ubiquitination

DOI:  https://doi.org/10.1038/s41598-025-24864-1
Sci Rep. 2025 Nov 03. 15(1): 38422

IGF-1 regulates cancer cell immune evasion in prostate cancer.

Ashwin M Nandakumar, Alessandro Barberis, Jinseon Kim, Cameron R Lang, Jack V Mills, Guillaume Rieunier, Dimitrios Doultsinos, Avigail Taylor, Ashwin Jainarayanan, Su M Phyu, Leticia Campo, Alistair Easton, Eileen E Parkes, Timothy James, Freddie C Hamdy, Clare Verrill, Ian G Mills, Valentine M Macaulay.

Insulin-like growth factor-1 (IGF-1) is associated with prostate cancer (PCa) development and lethality and exhibits immunosuppressive properties in other models. We investigated IGF-1's tumor-intrinsic immune effects in PCa to understand mechanisms underlying its poor immunotherapy response. Transcriptional profiling of human (DU145, 22Rv1) and murine (Myc-CaP) PCa cells revealed that IGF-1 suppresses cytokine signalling, antigen processing and presentation, and additional immune regulatory pathways. We further examined the expression of components involved in cancer cell recognition and immune evasion: the antigen processing machinery and PD-L1 checkpoint. IGF-1 downregulated key elements such as transporters associated with antigen processing (TAPs), endoplasmic reticulum aminopeptidase-1 (ERAP-1), and Class I β2-microglobulin, without significantly altering Class I allele expression. These changes were associated with reduced surface presentation of Class I complexes on Myc-CaP cells, suggesting disrupted peptide transport, processing, and/or presentation. In contrast, IGF-1 upregulated the immune checkpoint CD274 (PD-L1) via IGF receptor/AKT/ERK-dependent signalling. Analysis of TCGA Firehose Legacy PCa data showed higher CD274 expression in tumors with elevated IGF1 and IGFBP5. Multiplex immunofluorescence in primary PCa confirmed increased PD-L1 in patients with high serum IGF-1, supporting its role in immune evasion. Overall, these findings reveal a novel IGF-1-driven immunosuppressive mechanism that may underlie PCa's resistance to immunotherapy.

DOI: https://doi.org/10.1038/s41598-025-22288-5
Science. 2025 Nov 06. eadx9717

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.

Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis.

Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT's enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.

DOI: https://doi.org/10.1126/science.adx9717
Mol Cell Proteomics. 2025 Oct 30. pii: S1535-9476(25)00539-0. [Epub ahead of print] 101440

Multi-dimensional Proteomics Reveal Metformin's Impact on Interconnected Regulatory Networks of Protein Turnover, Ubiquitination, DNA Damage, and Cell Cycle.

Zhiyuan Wang, Jianlong Li, Jinyan Duan, Bing Shan, Yaoyang Zhang.

  Metformin, a first-line therapy for type 2 diabetes, has also been implicated in regulating diverse physiological and pathological processes, including lifespan extension, cancer, and other disease-related conditions. However, its mechanisms of action remain incompletely understood, with many effects still unexplained. In this study, we investigated the impact of metformin on the cellular ubiquitinome and associated protein turnover. Through an integrated analysis combining ubiquitinome profiling with pulsed metabolic labeling, we found that metformin markedly suppresses global protein ubiquitination, including various types of ubiquitin chain linkages, and concurrently inhibits both protein synthesis and degradation. Notably, metformin induces a marked reduction in the ubiquitination of histone H4, a modification closely associated with DNA damage repair. We further establish a mechanistic link whereby metformin regulates DNA damage repair and cell cycle progression through downregulating ubiquitination. Together, our findings demonstrate that metformin modulates ubiquitination and proteostasis, central processes that regulate numerous cellular functions. By identifying histone H4 ubiquitination as a key target, we elucidate a potential mechanism through which metformin influences DNA repair and cell cycle progression. This comprehensive dataset advances understanding of the drug's multifaceted pharmacological activities and provides a valuable resource for future drug development.

Keywords:  Cell cycle; DNA damage repair; Metformin; Proteostasis; Ubiquitinome

DOI:  https://doi.org/10.1016/j.mcpro.2025.101440
FASEB Bioadv. 2025 Nov;7(11): e70071

Emerging Roles of De Novo Proline Biosynthesis in Human Diseases.

Ethan Pei, Junfeng Ma.

  De novo proline synthesis is a highly conserved and essential biochemical pathway in mammals. Beyond serving as a fundamental building block for proteins, proline also plays key roles in diverse cellular functions and maintaining tissue homeostasis. Over the past decade, accumulating evidence has underscored the significance of this pathway in regulating critical cellular processes, including redox balance, cell growth, signal transduction, and the synthesis of nucleotides and proteins, as well as overall cellular metabolism. The biosynthesis of proline is tightly controlled by multiple evolutionarily conserved mechanisms to ensure proper cellular function. Importantly, disruptions in proline metabolism-particularly changes in the activity or expression of enzymes involved in its synthesis and degradation-have been implicated in the onset and progression of several diseases, notably cancer and fibrosis. In this review, we highlight recent advances in understanding the regulation of de novo proline synthesis. We also examine how dysregulation of this pathway contributes to disease development and influences therapeutic outcomes. Finally, we explore the therapeutic potential of targeting proline metabolism in disease treatment.

Keywords:  biochemistry; de novo synthesis; metabolism; proline

DOI:  https://doi.org/10.1096/fba.2025-00147
Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2427161122

Modeling protein-small molecule conformational ensembles with PLACER.

Ivan Anishchenko, Yakov Kipnis, Indrek Kalvet, Guangfeng Zhou, Rohith Krishna, Samuel J Pellock, Anna Lauko, Gyu Rie Lee, Linna An, Justas Dauparas, Frank DiMaio, David Baker.

  Modeling the conformational heterogeneity of protein-small molecule interactions is important for understanding natural systems and evaluating designed systems but remains an outstanding challenge. We reasoned that while residue-level descriptions of biomolecules are efficient for de novo structure prediction, for probing heterogeneity of interactions with small molecules in the folded state, an entirely atomic-level description could have advantages in speed and generality. We developed a graph neural network called PLACER (protein-ligand atomistic conformational ensemble resolver) trained to recapitulate correct atomic positions from partially corrupted input structures from the Cambridge Structural Database and the Protein Data Bank; the nodes of the graph are the atoms in the system. PLACER accurately generates structures of diverse organic small molecules given knowledge of their atom composition and bonding. When given a description of the larger protein context, it builds up structures of small molecules and protein side chains for protein-small molecule docking. Because PLACER is rapid and stochastic, ensembles of predictions can be readily generated to map conformational heterogeneity. In enzyme design efforts described here and elsewhere, we find that using PLACER to assess the accuracy and preorganization of the designed active sites results in higher success rates and higher activities; we obtain a preorganized retroaldolase with a kcat/KM of 11,000 M-1min-1, considerably higher than any pre-deep learning design for this reaction. We anticipate that PLACER will be widely useful for rapidly generating conformational ensembles of small molecule and small molecule-protein systems and for designing higher activity preorganized enzymes.

Keywords:  enzyme design; ligand docking; machine learning

DOI:  https://doi.org/10.1073/pnas.2427161122
Genomics. 2025 Nov 03. pii: S0888-7543(25)00167-3. [Epub ahead of print] 111151

High-fat diet promotes kidney lipid droplet deposition contributing to the pathogenesis of obesity-related glomerulopathy in mice through gut microbial metabolism.

Kai-Wen Cai, Ying-Ying Xie, Zi-Yan Deng, Zong-Chao Yu, Hong-Wei Wu, Zhuang-Feng Weng, Zhen-Chuan Lin, Bin Xia, Xiao-Hua Wang, Zhi-Hua Zheng, Chun Tang, Ting Zhu, Yong-Ping Lu.

   BACKGROUND: Obesity-related glomerulopathy (ORG) is a kidney disorder associated with obesity, where dysbiosis of the gut microbiota and disturbances in lipid metabolism play crucial roles in its development. However, the exact mechanisms by which imbalances in gut microbiota influence lipid metabolism and contribute to the pathogenesis of ORG are still not fully understood.
METHODS: A high-fat diet (HFD)-induced ORG model was established using 6-week-old male C57BL/6 J mice to investigate the role of gut microbiota and gut-derived metabolites in ORG progression. 16S rRNA sequencing was employed to profile the gut microbiota, while liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied for metabolite analysis in fecal, serum, and kidney samples.
RESULTS: Compared to age-matched normal diet (ND) mice, ORG mice exhibited significant increases in triglycerides (TG), cholesterol (CHO), and urinary albumin-to-creatinine ratio (UACR), alongside enhanced lipid droplet accumulation in renal tubules and glomerular hypertrophy. Metabolomic analysis revealed altered metabolic profiles in ORG mice, particularly the reprogramming of glycerophospholipid metabolism. Additionally, 16S rRNA sequencing demonstrated reduced gut microbiota diversity in ORG mice relative to the ND group. Further investigation revealed that the shift in renal glycerophospholipid metabolism and elevated blood lipid levels in ORG mice were closely linked to gut microbiota dysbiosis, specifically increased abundance of Lachnospiraceae and decreased abundance of Muribaculaceae.
CONCLUSION: The dysbiosis of gut microbiota induced by a HFD leads to glycerophospholipid metabolic reprogramming, promoting lipid droplet deposition in the kidneys and contributing to ORG progression. Our study highlights the contribution of gut microbial metabolism to the development of ORG, offering new perspectives for potential therapeutic strategies targeting the gut in ORG treatment.

Keywords:  Glycerophospholipid metabolism; Gut microbiota; High-fat diet; Lipid droplet deposition; Obesity-related glomerulopathy

DOI:  https://doi.org/10.1016/j.ygeno.2025.111151
J Am Chem Soc. 2025 Nov 05.

Highly Sensitive Detection of Tyrosine and Neurotransmitters by Stereoselective Biosynthesis and Photochemically Induced Dynamic Nuclear Polarization.

Ummay Mahfuza Shapla, Jamorious L Smith, Anubhab Halder, Lillian Thompson, Andrew R Buller, Silvia Cavagnero.

Tyrosine (Tyr) is a building block of proteins and a precursor of key neurotransmitters including dopamine and epinephrine. Investigations on the metabolic fate of Tyr are hampered by poor sensitivity and resolution, hindering the diagnosis of debilitating diseases including phenylketonuria, tyrosine-hydroxylase deficiency and progressive infantile encephalopathy. Here, we show that Tyr constructs bearing either a quasi-isolated 1Hα-13Cα spin pair (QISP Tyr) or natural-abundance nuclides are detected at high sensitivity and resolution in biologically relevant media by optically enhanced NMR. QISP Tyr, generated via a chemoenzymatic strategy starting from achiral materials, was quantified at 200 nM and 10 μM levels in aqueous buffer and cell extracts, respectively, via low-concentration photochemically induced dynamic nuclear polarization (LC-photo-CIDNP). Further, natural-abundance epinephrine was revealed at unprecedented 10 nM levels (1.3 nanograms), while Tyr and L-DOPA required 500 nM concentrations. In all, this study establishes the ultrasensitive atomic-resolution detection of Tyr and Tyr-related neurotransmitters by optically enhanced NMR.

DOI: https://doi.org/10.1021/jacs.5c11334
Cancer Lett. 2025 Oct 30. pii: S0304-3835(25)00673-1. [Epub ahead of print] 218101

Enhanced prediction of breast cancer patient response to chemotherapy by integrating deconvolved expression patterns of immune, stromal and tumor cells.

Saugato Rahman Dhruba, Sahil Sahni, Binbin Wang, Di Wu, Padma Sheila Rajagopal, Yael Schmidt, Eldad D Shulman, Sanju Sinha, Stephen-John Sammut, Carlos Caldas, Kun Wang, Eytan Ruppin.

The tumor microenvironment (TME) is a complex ecosystem of diverse cell types whose interactions govern tumor growth and clinical outcome. While multiple studies have extensively charted the TME's impact on immunotherapy, its role in chemotherapy response remains less explored. To address this, we developed DECODEM (DEcoupling Cell-type-specific Outcomes using DEconvolution and Machine learning), a generic computational framework leveraging cellular deconvolution of bulk transcriptomics to associate gene expression of individual cell types in the TME with clinical response. Employing DECODEM to analyze gene expression of breast cancer patients treated with neoadjuvant chemotherapy across three bulk cohorts, we find that the expression of specific immune cells (myeloid, plasmablasts, B-cells) and stromal cells (endothelial, normal epithelial, CAFs) are highly predictive of chemotherapy response, achieving the same performance levels as the expression of malignant cells. Notably, ensemble models integrating the estimated expression of different cell types perform the best and outperform models built on the original tumor bulk expression. These findings and model generalizability are further tested and validated using two single-cell (SC) cohorts of triple negative breast cancer. To investigate the possible role of immune cell-cell interactions (CCIs) in mediating chemotherapy response, we extended DECODEM to DECODEMi to identify such key functionally important CCIs, validated in SC data. Our findings highlight the importance of active pre-treatment immune infiltration for chemotherapy success. DECODEM and DECODEMi are made publicly available to facilitate studying the role of the TME in mediating response in a wide range of cancer indications and treatments.

DOI: https://doi.org/10.1016/j.canlet.2025.218101
Sci Rep. 2025 Nov 06. 15(1): 38836

Probing omics data via harmonic persistent homology.

Davide Gurnari, Aldo Guzmán-Sáenz, Filippo Utro, Aritra Bose, Saugata Basu, Laxmi Parida.

  Identifying molecular signatures from complex disease patients with underlying symptomatic similarities is a significant challenge in the analysis of high-dimensional multi-omics data. Topological data analysis (TDA) provides a way of extracting such information from the geometric structure of the data and identifying multi-way higher-order relationships. Here, we propose an application of harmonic persistent homology, which overcomes the limitation of the ambiguity of the choice of a cycle representing a specific homology class. When applied to multi-omics data, this leads to the discovery of hidden patterns highlighting the relationships between different omic profiles, while allowing for common tasks in multi-omics analyses, such as disease subtyping, and most importantly biomarker identification for similar latent biological pathways that are associated with complex diseases. Our experiments on multiple cancer data show that harmonic persistent homology effectively dissects multi-omics data to identify biomarkers by detecting representative cycles predictive of disease subtypes.

Keywords:  Data analysis; Multi-omics; Pattern discovery; Topological data analysis

DOI:  https://doi.org/10.1038/s41598-025-12189-y
J Biochem. 2025 Nov 03. pii: mvaf063. [Epub ahead of print]

Clinical glycoproteomics in cancer: toward tissue-based glycoform profiling and biomarker discovery.

Yoshimi Haga.

  Recent advances in mass spectrometry-based proteomics have enabled increasingly precise characterization of protein modifications in clinical specimens. Among these, glycosylation is one of the most structurally complex and biologically informative post-translational modifications, reflecting cellular differentiation and disease states. Ohashi et al. (J. Biochem. 2024; 175: 561-572) performed a site-specific N-glycosylation analysis of LAMP1 in breast cancer tissue samples, demonstrating the feasibility of targeted glycoproteomics in patient-derived specimens and revealing tumor-associated glycoform heterogeneity. Their study exemplifies how focusing on a single glycoprotein target can provide detailed insight into disease-specific glycan remodeling within the tumor microenvironment. In this commentary, I discuss the significance of such targeted approaches in the broader context of clinical glycoproteomics and highlight their potential contribution to cancer biomarker discovery and precision medicine. Continued integration of glycoproteomic data with genomic and clinical information is expected to further advance our understanding of tumor biology and therapeutic response.

Keywords:  biomarker; cancer-associated glycans; clinical proteomics; glycoproteomics; mass spectrometry

DOI:  https://doi.org/10.1093/jb/mvaf063
PLoS One. 2025 ;20(11): e0336124

LSR overexpression induces chemoresistance in triple negative breast cancer cells through MDR1 upregulation and apoptosis attenuation.

Ming Zhao, Zhikun Ma, Amanda B Parris, Xiaohe Yang.

Chemoresistance in breast cancer therapy, especially for triple negative breast cancer (TNBC) remains a significant challenge. Recent studies showed that overexpression of lipolysis-stimulated lipoprotein receptor (LSR), known as a tricellular tight-junction protein, was detected in TNBC and MDR1 was among LSR upregulated genes in a screening assay but its functional impact has not been studied. This study aimed to characterize LSR overexpression-induced regulation of MDR1 in TNBC cells focusing on chemoresistance. LSR was overexpressed in MDA-MB-231 cells and knocked-out via CRISPR/Cas9 in MDA-MB-468 cells for functional studies. Chemoresistance of individual cell lines was evaluated with doxorubicin treatment, followed by cell proliferation, invasion, colony formation and apoptosis assays. Modulated protein and mRNA levels of specific genes were assessed with Western blotting and RT-qPCR. MDR1 inhibitor verapamil and MDR1-targeted siRNA were used to evaluate the functional impact of LSR-induced MDR1. Overexpression of LSR not only promotes cell proliferation and invasion in MDA-MB-231 cells, but also renders the cells resistant to doxorubicin. LSR induces MDR1 expression at both mRNA and protein levels. Moreover, inhibition of MDR1 with specific inhibitor verapamil or MDR1 knockdown reversed cellular resistance to doxorubicin in LSR-overexpressing MDA-MB-231 cells. In contrast, knockout of LSR expression in MDA-MB-468 cells, which express higher levels of LSR, significantly sensitized the cells to doxorubicin-induced growth inhibition and apoptosis. Our data demonstrated that LSR overexpression promotes TNBC cell proliferation and invasion, and upregulation of MDR1 in these cells renders them resistant to doxorubicin, suggesting that targeting LSR could be a useful strategy to overcome chemoresistance in TNBC.

DOI: https://doi.org/10.1371/journal.pone.0336124
Sci Rep. 2025 Nov 07. 15(1): 39069

Effect of phosphate availability on the dynamics of polyphosphate accumulation in microalgae.

Subhisha Raj, Arathi Sreenikethanam, M Gobi, Deepak Sakate, Tharunkumar Jayakumar, Suchitra Rakesh, J Rajesh Banu, Amit K Bajhaiya.

  Phosphorus is one of the crucial elements required for the proper functioning of metabolic processes in microalgae. Despite the crucial role of phosphate (P), the dynamics of polyphosphate accumulation with respect to nutrient availability remain unknown in freshwater microalgae. We have investigated three freshwater microalgal strains - Chlorella pyrenoidosa, Scenedesmus obliquus, and Chlamydomonas reinhardtii under varied phosphate treatments to understand the phosphate metabolic responses and polyphosphate dynamics. Our results show that the accumulation of polyP in microalgae is very dynamic and mainly depends on the availability of extracellular phosphate. Reduced P availability showed algal species-specific reduction in the polyphosphate storage with a decline in growth and total chlorophyll content. Further, an increase in lipid and carbohydrate content with a substantial decrease in protein was observed under P stress, suggesting preferential utilization of stored polyP to support cell survival. Species-specific differences in the fatty acid profiles were also observed in the GC analysis among all three algal strains, indicating varied mechanisms happening among the species to adapt and protect themselves against cellular damage under P stress. Our results suggest the existence of natural variability among the selected algal strains in their ability to accumulate polyP and metabolites with respect to P-varied conditions. Among the three microalgal species, Scenedesmus obliquus showed notably enhanced accumulation of polyphosphate, highlighting its potential application as P-rich biofertilizer.

Keywords:  FTIR; Gas chromatography; Lead sulfide microscopy; Microalgae; Polyphosphate; Primary metabolites

DOI:  https://doi.org/10.1038/s41598-025-24985-7
Cell Rep. 2025 Nov 05. pii: S2211-1247(25)01260-4. [Epub ahead of print]44(11): 116489

Creatine kinase B regulates glycolysis and de novo lipogenesis pathways to control lipid accumulation during adipogenesis.

Gianluca Renzi, Romane Higos, Ivan Vlassakev, Abdoul Akim Bello, Muhmmad Omar-Hmeadi, Mattias Hansen, Fatiha Merabtene, Christine Rouault, Ondrej Hodek, Lucas Massier, Bruno Antonny, Geneviève Marcelin, Janane F Rahbani, Simon Lecoutre, Salwan Maqdasy.

  White adipocyte differentiation or adipogenesis requires coordination of metabolic sensing and transcriptional modifications to orchestrate lipid storage. Creatine and its kinases are implicated in adipose energy buffering, but the roles of cytosolic (CKB) and mitochondrial (CKMT2) creatine kinases in adipogenesis are unclear. We find that both CKB and CKMT2 are progressively upregulated during differentiation. Functional studies show that CKB restrains de novo lipogenesis (DNL) by limiting activation of carbohydrate-responsive element-binding protein (ChREBP), a key regulator of lipogenic genes. Mechanistically, CKB interacts with AKT and regulates its activation in response to insulin. Loss of CKB causes persistent AKT-mTORC1 signaling, increases glycolytic flux, and enhances ChREBP activation, thereby promoting glucose-derived lipid synthesis. Thus, CKB acts as a metabolic rheostat linking creatine-kinase activity to insulin signaling and nutrient-responsive transcription. We propose a CKB-AKT-ChREBP regulatory axis that contributes to metabolic remodeling and lipid homeostasis during adipocyte differentiation.

Keywords:  AKT-mTORC; CKB; CP: metabolism; ChREBP; adipogenesis; creatine kinase; de novo lipogenesis; white adipocyte

DOI:  https://doi.org/10.1016/j.celrep.2025.116489
Sci Rep. 2025 Nov 05. 15(1): 38747

Homeostatic response of phospholipid pathways to PCYT2 deficiency and impaired de Novo synthesis of phosphatidylethanolamine.

Roya Iraji, Michaela St Germain, Sophie Grapentine, Leanne Perreira, Laila Schenkel, Sara Al-Douri, Lyn M Hillyer, Clara E Cho, David W L Ma, Marica Bakovic.

  PCYT2 is the key regulatory enzyme in the biosynthesis of phosphatidylethanolamine (PE) via the CDP-ethanolamine Kennedy pathway. Deficiencies in this gene have been linked to metabolic, neurological, and cardiac disorders; however, most studies report that PE levels remain unchanged. This study aimed to identify the metabolic mechanisms that preserve PE levels when its synthesis is impaired in PCYT2-knockdown human fibroblasts. We investigated alternative pathways that could compensate for reduced PE synthesis, including phosphatidylcholine (PC) and PE base-exchange to phosphatidylserine (PS), followed by PE resynthesis via PS decarboxylation. These pathways were individually assessed using [14 C]-ethanolamine, [3 H]-choline, and [3 H]-serine, and correlated with the expression and activity of the base-exchange genes PTSS1, PTSS2, and the PS decarboxylase PISD. The base-exchange activity was not significantly altered and mitochondrial PS decarboxylation was inhibited, indicating that these routes do not compensate for reduced PE synthesis in PCYT2-deficient cells. Chronic choline treatment increased ethanolamine and choline transport and upregulated the choline/ethanolamine transporter CTL1, yet PC synthesis and base-exchange activity remained unchanged, demonstrating that choline supplementation does not affect PE sythesis. Instead, PE homeostasis was maintained through reduced degradation and extensive phospholipid remodeling via the Lands' cycle, as evidenced by broad changes in fatty acid composition and increased phospholipid unsaturation. Remodeling extended beyond PC, PE, and PS to include phosphatidylinositol and sphingomyelin. These metabolic adaptations led to elevated reactive oxygen species production and enhanced mitochondrial fusion without significantly affecting autophagy or cell viability. Our findings suggest that in the absence of PCYT2 activity, PE levels are preserved primarily through reduced degradation and remodeling, rather than through alternative biosynthetic pathways.

Keywords:  CDP-ethanolamine kennedy pathway; Fatty acids; PCYT2; Phosphatidylethanolamine; Phospholipids

DOI:  https://doi.org/10.1038/s41598-025-22601-2
PLoS One. 2025 ;20(11): e0332177

Multi-omics analysis reveals metabolic regulation of phosphatidylcholine, triglycerides, phosphatidylethanolamine, and cardiolipin metabolism in mouse liver with metabolic dysfunction-associated steatotic liver disease.

Hong Liang, Kang Song.

The dysregulation of phosphatidylcholine (PC), triglycerides (TG), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism is believed to contribute to the development of MASLD. However, little is known about the mechanisms underlying the onset of this condition. To establish a mouse model of MASLD, C57BL/6J mice were fed a high-fat diet (HFD). Lipidomics was applied to identify differences in liver lipids. RNA-sequencing and bioinformatics analyses were conducted to investigate changes in the expression of genes and pathways associated with these metabolic processes. 49 lipid classes and 3221 lipid species were identified using positive- and negative-ion pattern identification. A total of 678 differentially expressed genes were identified, of which 364 were upregulated and 314 were downregulated in the MASLD group. KEGG enrichment pathway analysis highlighted the downregulation of four genes such as Gpat4, Gpcpd1, Chkb, and Etnppl. These findings contribute to our understanding of the metabolic changes associated with MASLD.

DOI: https://doi.org/10.1371/journal.pone.0332177