bims-cesirm 2025-10-12 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–10–12
nineteen papers selected by
Tigist Tamir, University of North Carolina

A Chemical Mechanistic Path Leads the Way to Cellular Argpyrimidine.
Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.
Glycolytic metabolism and biomass production from glucose in human skeletal muscle growth.
Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
Proteogenomic Analysis on RNA m6A Modification-Associated Genes Identifies a Distinct Subgroup with High IGF2BPs Expression Across Cancer Types.
Fueling the fire-a pan-cancer analysis of MYC-regulated lipid metabolism.
Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.
PSMD14-Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression.
Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma.
Decoding replication stress responses through post-translational modifications.
The differential regulation of the urea cycle in tumors goes awry.
Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress.
SAPP: Structure Aware PTM Prediction.
Integrating cross-sample and cross-modal data for spatial transcriptomics and metabolomics with SpatialMETA.
O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth.
Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.
Protein Lysine Crotonylation Analysis Reveals an Important Role in the Regulation of Aeromonas hydrophila Maltose Transport.
Differential Expression of One-Carbon Pathway Enzyme ALDH1L1 Is Linked to Tumorigenicity of Low-Grade Bladder Cancer Cells Through Metabolic Reprogramming.
Aloesin activates Nrf2 signaling to attenuate obesity-associated oxidative stress and hepatic steatosis in high-fat diet-fed rats.

J Am Chem Soc. 2025 Oct 10.

A Chemical Mechanistic Path Leads the Way to Cellular Argpyrimidine.

Vo Tri Tin Pham, Suprama Datta, Amy C Sterling, Stefan M Hansel, Rebecca A Scheck.

Argpyrimidine (APY) is a methylglyoxal-derived advanced glycation end-product (AGE) that has been associated with multiple diseases. As APY forms without an enzyme, it remains exceptionally difficult to pinpoint where APY is likely to be found, both on individual proteins and in cells. In this study, we used a peptide model system and mass spectrometry analysis to investigate the chemical mechanism through which APY arises from methylglyoxal (MGO), a biologically relevant glycating agent. Consistent with other proposed APY formation mechanisms, our results identify AGE species with a mass change of [M + 144], presumably including tetrahydropyrimidine (THP), as a direct precursor to APY. However, our results rule out previously proposed reductone or oxidative decarboxylation mechanisms. Instead, we show that a formal oxidation step is not required, and that formate is released instead of CO2. We further show the potential for a nearby residue such as Tyr to assist in the APY formation mechanism by acting as a general base. These experiments also reveal that phosphorylated Tyr or Ser residues can also promote equivalent levels of APY formation, despite introducing additional negative charges that we previously showed to impede glycation. Guided by these mechanistic insights and a newly defined role for phosphorylated residues on glycation substrates, we performed quantitative bottom-up proteomics analysis for MGO-treated cells. Gene ontology and functional annotation clustering analyses for APY-modified proteins suggested a correlation with phosphorylation-related terms (e.g., kinase activity or protein phosphorylation), which was validated using synthetic phosphopeptide substrates. Collectively, these data define a chemical mechanistic path to APY and suggest significant crosstalk between cellular phosphorylation and glycation events including APY formation.

DOI: https://doi.org/10.1021/jacs.5c09369
Biomark Res. 2025 Oct 10. 13(1): 124

Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma.

Lingbo An, Zongfang Li.

  Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major cause of cancer-related mortality worldwide, with rising incidence and limited treatment options, especially for patients diagnosed at advanced stages. In recent years, metabolic reprogramming has emerged as a hallmark of cancer that enables HCC cells to survive, proliferate, and resist therapy under hostile conditions. HCC cells undergo profound remodeling of glucose, lipid, and amino acid metabolism to adapt to hypoxia and nutrient deprivation. These processes are orchestrated by key signaling cascades, including the PI3K/AKT/mTOR, Ras-Raf-MEK-ERK-cMYC, and LKB1-AMPK pathways, forming a dynamic and integrated metabolic-signaling network. This review comprehensively integrates recent advances in the understanding of metabolic pathways in HCC, with a particular focus on glycolysis, de novo lipogenesis, and glutamine metabolism. We delineate the regulatory mechanisms underlying these pathways and construct an interaction map linking metabolic circuits to clinical phenotypes such as tumor heterogeneity, metastatic potential, and immune modulation. Furthermore, we systematically evaluate the biomarker potential of metabolic intermediates, rate-limiting enzymes, and key regulators in the context of early detection, molecular classification, prognosis prediction, and therapeutic response in HCC. We also highlight cutting-edge technologies, including metabolic imaging, liquid biopsy-based biomarker detection, and metabolism-targeted therapies. The review explores their potential synergy with immunotherapy, chemotherapy, and radiotherapy, aiming to provide a comprehensive framework for individualized HCC management. Our discussion underscores the translational relevance of metabolic biomarkers and offers insights for future research and clinical innovation.

Keywords:  Combined diagnosis and treatment; Hepatocellular carcinoma; Metabolic networks; Metabolic reprogramming; Metabolic–signaling interactions; Targeted drugs

DOI:  https://doi.org/10.1186/s40364-025-00844-5
Am J Physiol Cell Physiol. 2025 Oct 10.

Glycolytic metabolism and biomass production from glucose in human skeletal muscle growth.

Sakari Mäntyselkä, Marco Ahvenlammi, Jennika Vartiainen, Eeli J Halonen, Kalle Kolari, Henning Wackerhage, Perttu Permi, Markku Varjosalo, Milla M Kelahaara, Juha P Ahtiainen, Elina Kalenius, Riikka Kivelä, Juha J Hulmi.

  Skeletal muscle is the main consumer of glucose after a mixed meal, and resistance exercise further increases muscle glucose uptake. Emerging evidence suggests that glucose uptake in muscles is not only stored as glycogen or used as a fuel but can also be incorporated into other biomass during growth. We aimed to study the utilization of glucose-derived carbons for protein, RNA, and lipid synthesis during human skeletal muscle (HSkM) cell growth. We also investigated whether muscle growth in vivo by resistance training (RT) affects the abundance of metabolites and enzymes required for these processes in human muscle. We found that differentiated HSkM cells incorporated glucose-derived carbon into proteins, RNA, and lipids, and anabolic stimulation further increased these processes. Liquid chromatography-mass spectrometry metabolomics and proteomics revealed that 10 weeks of RT in humans increased essential metabolites and enzymes for nucleotide, serine, and glycine synthesis, including phosphoglycerate dehydrogenase (PHGDH) in muscle. We also examined whether the PHGDH enzyme, starting the serine synthesis pathway branching from glycolysis, is sufficient and essential for human muscle protein, RNA, and lipid anabolism. We found that PHGDH inhibitors decreased protein synthesis and glucose-derived carbon incorporation into macromolecules, whereas manipulation of PHGDH abundance had mixed effects. Moreover, PHGDH was revealed to be important for myogenesis. The data suggest that glucose is not only used for ATP generation but also as a building block in human muscle cell growth. The results open new avenues for studies investigating the mechanisms of RT and muscle growth in improving muscle glucose metabolism.

Keywords:  Metabolomics; Myogenesis; PHGDH; Proteomics; Resistance training

DOI:  https://doi.org/10.1152/ajpcell.00525.2025
Nat Commun. 2025 Oct 08. 16(1): 8952

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.

Vidhi Pareek, Stephen Benkovic.

Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.

DOI: https://doi.org/10.1038/s41467-025-64013-w
Int J Med Sci. 2025 ;22(15): 3815-3827

Proteogenomic Analysis on RNA m6A Modification-Associated Genes Identifies a Distinct Subgroup with High IGF2BPs Expression Across Cancer Types.

Yebin Ryu, Eunhyong Chang, Hayoon Park, Sung-Yup Cho, Joon-Yong An.

  Background: RNA N6-methyladenosine (m6A) modification is a key epitranscriptomic mechanism that regulates post-transcriptional gene expression. Although m6A-associated regulators have been implicated in cancer, their context-dependent roles and impacts on tumor heterogeneity remain incompletely defined. Methods: We conducted a pan-cancer proteogenomic analysis of m6A-dependent mechanisms using multi-omics datasets from the Clinical Proteomic Tumor Analysis Consortium, utilizing genomic, transcriptomic, proteomic, and phosphoproteomic data. Unsupervised clustering based on expression of m6A regulatory genes identified distinct subgroups. We integrated m6A-seq and RIP-seq data from cancer cell lines and analyzed the immune deconvolution results to define m6A-driven regulatory programs and assess tumor immune infiltration across subgroups. Results: Three molecular subgroups (IGF2BP-H, -M, and-L) were defined based on the expression patterns of m6A readers, with IGF2BP1/2/3 acting as the primary markers distinguishing the subgroups. Their upregulation has been attributed to either copy number amplification or transcription factor activation, depending on the tumor context. The IGF2BP-H subgroup exhibited enhanced cell cycle activity, which was supported by concordant transcriptomic, proteomic, and phosphoproteomic signatures. Mechanistic analyses revealed that IGF2BPs directly bind to and stabilize m6A-modified transcripts, including TOP2A, ANLN, and TFRC, thereby promoting their translation and contributing to cell cycle progression. IGF2BPs also enhanced VEGFA expression in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma, potentially promoting immunosuppressive signaling. Immune deconvolution revealed reduced CD8+ T cell infiltration in IGF2BP-H tumors, suggesting a less inflamed microenvironment and potentially diminished responsiveness to immunotherapy. Conclusion: Our results highlight the pivotal role of IGF2BP in governing m6A-dependent regulatory mechanisms in cancer cells, highlighting their potential link with aggressive tumor behavior and immune evasion. This study provides important insights into the heterogeneity of m6A-related processes across different malignancies and reveals potential avenues for therapeutic interventions.

Keywords:  Cell cycle; IGF2BP; Immune infiltration; Multi-omics; Pan-cancer; Precision medicine; m6A

DOI:  https://doi.org/10.7150/ijms.115609
Front Cell Dev Biol. 2025 ;13 1669544

Fueling the fire-a pan-cancer analysis of MYC-regulated lipid metabolism.

Tilottama Chatterjee, Ethan Beffert, Daniel Liefwalker.

  The oncogene MYC and its product c-Myc are responsible for a multitude of changes in cancerous cells that trigger cell growth, proliferation and metastasis. The efforts to understand the multifaceted role of MYC in malignancies have highlighted metabolic reprogramming as a prominent function of this transcription factor, with effects across glycolysis, protein and lipid metabolism, mitochondrial respiration and energy storage. In particular, the role of MYC in lipid metabolism has been the focus of several studies in the past two decades, elucidating how the balance of lipid production and breakdown aids in tumor proliferation. Here, we provide a comprehensive summary of how modulation of MYC alters fatty acid synthesis and degradation, the metabolism of compound lipids, and the consequences for other metabolic pathways. The observed effects are highly cell type-specific, highlighting the MYC network's ability to harness the existing cellular signaling pathways and specific tumor microenvironment to promote tumor growth and metastasis.

Keywords:  MYC; fatty acid synthesis; lipid synthesis; lipids; metabolic reprogramming; metabolism

DOI:  https://doi.org/10.3389/fcell.2025.1669544
Gene. 2025 Oct 06. pii: S0378-1119(25)00608-0. [Epub ahead of print] 149819

Suppressor of cytokine signaling 6 (SOCS6) mediates ubiquitination degradation of SLC7A11 to drive ferroptosis and block lipid metabolism in ovarian cancer cells.

Yuelian Fan, Yuping Suo.

  Ovarian cancer (OVCA) is a highly malignant gynecological tumor characterized by a dismal 5-year survival rate that is closely linked to aberrant ferroptosis regulation and lipid metabolic reprogramming. This study integrated bioinformatics analyses of TCGA and The Human Protein Atlas datasets, clinical validation in 30 pairs of OVCA tissues, in vitro functional assays using HO8910 and HEYT30 cell lines, and nude mouse xenograft models to explore the role of suppressor of cytokine signaling 6 (SOCS6) in OVCA prognosis. The results revealed that SOCS6 was significantly downregulated in OVCA tissues and cell lines, and low expression was strongly correlated with poor patient prognosis. Mechanistically, SOCS6 overexpression inhibited cellular proliferation, migration, and invasion and enhanced sensitivity to the ferroptosis inducer erastin. This effect occurs by promoting the ubiquitin-proteasomal degradation of the ferroptosis antagonist SLC7A11, reducing intracellular glutathione (GSH) levels, and augmenting reactive oxygen species (ROS) and Fe2+ accumulation. Additionally, SOCS6 suppressed de novo fatty acid synthesis by downregulating the key enzymes FASN and ACC, leading to decreased triglyceride and phospholipid production. In vivo xenograft experiments confirmed that SOCS6 overexpression inhibited tumor growth and reduced the expression of SLC7A11 and lipid metabolism-related molecules. Collectively, these results establish SOCS6 as a critical molecular hub linking ferroptosis and lipid metabolism in OVCA, highlighting its potential as both a prognostic biomarker and a therapeutic target for improving clinical outcomes in OVCA.

Keywords:  Ferroptosis; Lipid metabolism; OVCA; SLC7A11; SOCS6

DOI:  https://doi.org/10.1016/j.gene.2025.149819
Adv Sci (Weinh). 2025 Oct 06. e05762

PSMD14-Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression.

Ri-Shang Lu, Li-Kun Ren, Xiao-Bin Fei, Song-Bai Liu, Yong-Jia Gao, Jun-Yi Hou, Chi Wang, Peng Liu, Chang-Hao Zhu, Xing Wang, Yao-Zhen Pan.

  Aberrant lipid metabolism is intimately linked to tumor progression. As a pivotal post-translational modification, ubiquitination regulates diverse oncogenic processes. However, the interplay between ubiquitination and lipid metabolic dysregulation in pancreatic cancer (PC), along with its underlying molecular mechanisms, remains poorly understood. Here, it is demonstrated that glycolytic enzyme lactate dehydrogenase A (LDHA) potentiates lipid biosynthesis under the regulation of deubiquitinases. Specifically, PSMD14 directly binds and stabilizes LDHA through its deubiquitinase activity, resulting in intracellular lactate accumulation. Elevated lactate levels enhance histone lactylation marks, which transcriptionally activate ATP citrate lyase (ACLY) to promote malignant progression via fatty acid synthesis pathway activation. This study reveals a previously unrecognized role of PSMD14-derived lactate in mediating histone lactylation-coupled lipid deposition and tumor progression. Therapeutic co-targeting of PSMD14 and glycolytic lactylation significantly suppresses tumor growth in patient-derived xenograft models, suggesting a promising combinatorial strategy for pancreatic cancer treatment.

Keywords:  Deubiquitination; LDHA; histone lactylation; lipid metabolism; pancreatic cancer

DOI:  https://doi.org/10.1002/advs.202505762
Cell Discov. 2025 Oct 07. 11(1): 81

Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma.

Guangyao Shan, Yunyi Bian, Qihai Sui, Jiaqi Liang, Shencheng Ren, Binyang Pan, Haochun Shi, Zhaolin Zheng, Dejun Zeng, Junkan Zhu, Zhencong Chen, Guoshu Bi, Hong Fan, Cheng Zhan.

Lactylation, a lactate-mediated post-translational modification, has garnered significant attention for its pivotal role in epigenetic modulation. However, the intricate interplay between lactylation and ferroptosis in lung adenocarcinoma (LUAD) remains to be fully elucidated. Utilizing metabolomic profiling and comprehensive metabolic library screening, our study uncovers that ferroptosis markedly enhances lactic acid accumulation and subsequent protein lactylation, which in turn confers resistance to ferroptosis in LUAD cells. Functional assays, comprising cell viability tests, lipid peroxidation detection, as well as malondialdehyde and glutathione measurements, collectively reveal that SUMO2-K11 lactylation (SUMO2-K11la), the most prominently elevated lactylation in response to ferroptosis induction, serves as a pivotal factor in determining ferroptosis resistance. Sumoylation proteomics and co-immunoprecipitation assays reveal that SUMO2-K11la impairs the interaction between SUMO2 and ACSL4. Consequently, this disruption facilitates the degradation of ACSL4, thereby disrupting lipid metabolism and effectively mitigating ferroptosis. Furthermore, AARS1 is identified as the lactyltransferase and HDAC1 as the delactylase for SUMO2-K11la. Based on these findings, we develop a cell-penetrating peptide that competitively and specifically inhibits SUMO2-K11la. This peptide significantly potentiates ferroptosis and sensitizes LUAD to cisplatin in xenograft models, while enhancing chemoimmunotherapy responses in spontaneous lung cancer models. Overall, our findings imply that SUMO2-K11la is a pivotal regulator of ferroptosis resistance in LUAD, and suggest a promising strategy to potentiate ferroptosis-based cancer therapies via targeting SUMO2-K11la by the cell-penetrating peptide.

DOI: https://doi.org/10.1038/s41421-025-00829-6
Nat Chem Biol. 2025 Oct 07.

Decoding replication stress responses through post-translational modifications.

Jinhua Han, Mengjie Wu, Ting Liu, Jun Huang.

DNA replication is a fundamental cellular process that ensures the faithful duplication of the genome during cell division. However, this process is frequently challenged by various intrinsic and extrinsic factors that can impede replication fork progression and jeopardize genomic integrity. To safeguard against these challenges, cells have evolved intricate stress response mechanisms, including replication checkpoint activation, translesion DNA synthesis, repriming and fork reversal, all of which are vital for preserving genomic stability. Central to the orchestration of these pathways are post-translational modifications (PTMs), which dynamically regulate the stability, localization, and activity of key proteins involved in the replication stress responses. In this Review, we summarize the primary mechanisms that orchestrate cellular responses to replication stress and highlight emerging insights into the roles of both histone and nonhistone PTMs in the precise and coordinated regulation of replication fork dynamics under genotoxic conditions.

DOI: https://doi.org/10.1038/s41589-025-02023-x
Biochem Pharmacol. 2025 Oct 07. pii: S0006-2952(25)00630-6. [Epub ahead of print] 117365

The differential regulation of the urea cycle in tumors goes awry.

Ahmed M Abou-Shanab, Mennatallah A Khedr, Sandro Matosevic.

  Cancer cells exhibit significant metabolic reprogramming to support their rapid proliferation and survival. Most of the normal and cancer cells are glucose avid, which is metabolized, producing lactate (the Warburg effect). The urea cycle (UC) is traditionally associated with nitrogen detoxification in the liver. UC is boosted in normally proliferating cells; however, disruptions in UC activity are frequently observed in various cancers, leading to altered nitrogen metabolism and the accumulation of ammonia. This review covers the intricate relationship between the UC and cancer progression. We discuss how UC dysregulation contributes to tumorigenesis by promoting pyrimidine synthesis, altering amino acid metabolism, and modulating the tumor microenvironment. Additionally, we explore the impact of ammonia accumulation on cancer cell proliferation, stemness, and immune evasion. Understanding the metabolic rewiring of the UC in cancer offers novel therapeutic opportunities. Targeting UC enzymes or ammonia detoxification pathways may provide effective strategies to inhibit tumor growth and enhance the efficacy of immunotherapeutics.

Keywords:  Ammonia; Cancer; Metabolism; Tumor microenvironment; Urea cycle

DOI:  https://doi.org/10.1016/j.bcp.2025.117365
Cell Death Discov. 2025 Oct 07. 11(1): 451

Targeting ESR1 restores SQSTM1-dependent autophagy and sensitizes ER-positive breast cancer to oxidative and radiation stress.

Yi-Fang Yang, Zhao-Jing He, Han-Hsi Kuo, Yu-Yu Lin, Cheorl-Ho Kim, Huei-Yu Cai, Chi-Long Chen, Michael Hsiao, Ying-Chung Chen, Peter Mu-Hsin Chang, Yu-Chan Chang.

Estrogen receptor-positive (ER⁺) breast cancer is commonly treated with hormone therapy; however, these tumors frequently develop drug resistance and exhibit poor responses to radiotherapy. To investigate the molecular basis of therapy resistance, we explored the role of estrogen receptor alpha (ESR1) in modulating sensitivity to oxidative and radiation stress. Through integrative analysis of publicly available datasets, we identified ESR1 as a key molecular marker associated not only with breast cancer classification but also with radiosensitivity. In ER⁺ breast cancer cell lines, higher endogenous ESR1 expression correlated with increased resistance to ionizing radiation. Functional studies using ESR1 overexpression and knockdown models revealed that depletion of ESR1 sensitized cells to radiation-induced DNA damage, impaired DNA repair efficiency, and reduced clonogenic survival. Notably, we found that the ESR1-SQSTM1 (p62) interaction impairs autophagic flux, contributing to treatment resistance. Mechanistically, ESR1 translocates to the cytoplasm and binds to SQSTM1, thereby disrupting autophagosome maturation. Furthermore, estradiol enhances ESR1 phosphorylation and its affinity for SQSTM1, reinforcing this inhibitory effect on autophagy and promoting resistance to radiation. Our findings uncover a previously unrecognized ESR1-SQSTM1 axis that governs autophagy and redox response in ER⁺ breast cancer. Targeting this pathway may restore sensitivity to radiotherapy and offer a new therapeutic strategy. Assessment of ESR1 expression and autophagy activity may serve as predictive biomarkers for treatment response in ER⁺ breast cancer patients.

DOI: https://doi.org/10.1038/s41420-025-02755-8
Comput Biol Med. 2025 Oct 08. pii: S0010-4825(25)01522-7. [Epub ahead of print]198(Pt A): 111169

SAPP: Structure Aware PTM Prediction.

Yujin Choo, Seungjin Na, Eunok Paek.

  Post-translational modifications (PTMs) play critical roles in regulating cellular processes such as signal transduction, cell growth, and differentiation. Accurate identification of PTM sites is fundamental to understanding cellular mechanisms and developing therapeutic interventions. However, traditional computational models have predominantly relied on sequence data alone, neglecting important structural contexts such as intrinsically disordered regions and solvent accessibility. To address this gap, we introduce SAPP (Structure-Aware PTM Prediction), a pioneering model that integrates structural features derived from AlphaFold2 predictions with sequence information using a unified Transformer-based framework. Utilizing self-attention and cross-attention mechanisms, SAPP effectively captures complex interactions between sequences and their structural states, improving prediction accuracy and biological relevance over sequence-based models. Notably, SAPP is among the first structure-based PTM prediction frameworks, which allows for fine-tuning from a phosphorylation-pretrained model to other PTM types, achieving generalization performance in PTM types with limited training data. This supports the critical role of structural information in PTM prediction, deepening our understanding of their biological significance.

Keywords:  Deep learning; Post-translational modification; Protein structure; Transfer learning; Transformer

DOI:  https://doi.org/10.1016/j.compbiomed.2025.111169
Nat Commun. 2025 Oct 06. 16(1): 8855

Integrating cross-sample and cross-modal data for spatial transcriptomics and metabolomics with SpatialMETA.

Ruonan Tian, Ziwei Xue, Yiru Chen, Yicheng Qi, Jian Zhang, Jie Yuan, Dengfeng Ruan, Junxin Lin, Jia Liu, Di Wang, Youqiong Ye, Wanlu Liu.

Simultaneous profiling of spatial transcriptomics (ST) and spatial metabolomics (SM) on the same or adjacent tissue sections offers a revolutionary approach to decode tissue microenvironment and identify potential therapeutic targets for cancer immunotherapy. Unlike other spatial omics, cross-modal integration of ST and SM data is challenging due to differences in feature distributions of transcript counts and metabolite intensities, and inherent disparities in spatial morphology and resolution. Furthermore, cross-sample integration is essential for capturing spatial consensus and heterogeneous patterns but is often complicated by batch effects. Here, we introduce SpatialMETA, a conditional variational autoencoder (CVAE)-based framework for cross-modal and cross-sample integration of ST and SM data. SpatialMETA employs tailored decoders and loss functions to enhance modality fusion, batch effect correction and biological conservation, enabling interpretable integration of spatially correlated ST-SM patterns and downstream analysis. SpatialMETA identifies immune spatial clusters with distinct metabolic features in cancer, revealing insights that extend beyond the original study. Compared to existing tools, SpatialMETA demonstrates superior reconstruction capability and fused modality representation, accurately capturing ST and SM feature distributions. In summary, SpatialMETA offers a powerful platform for advancing spatial multi-omics research and refining the understanding of metabolic heterogeneity within the tissue microenvironment.

DOI: https://doi.org/10.1038/s41467-025-63915-z
Cell Death Differ. 2025 Oct 06.

O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth.

Bingyi Lin, Junjie Zhou, Didi Geng, Siyuan Chai, Xuanming Zhang, Zengle Zhang, Jiating Hu, Qin Tang, Xiaoming Chen, Wen Yi, Liming Wu.

The tumor microenvironment is an immunosuppressive niche that contributes to tumor growth by downregulating immune cell functions or restraining immune cell infiltration. The underlying mechanisms are not still poorly understood. Here, we demonstrate that O-linked N-acetylglucosamine (O-GlcNAcylation), a prevalent form of protein glycosylation, contributes to establishing the immunosuppressive niche through regulating the metabolic and non-metabolic functions of uridine diphosphate glucose dehydrogenase (UGDH). Tumor cells carrying O-GlcNAcylation-deficient UGDH showed reduced xenograft tumor growth and improved survival in mice. Cytometry by time-of-flight (CyTOF) analysis suggests UGDH O-GlcNAcylation negatively correlates with cytotoxic CD8+ T cell infiltration. O-GlcNAcylation on serine 350 of UGDH is located within the UDP-binding domain, and the subsequent extensive all-atom molecular dynamics simulations reveal that O-GlcNAcylation reinforces hydrogen-bonding interaction and enzymatic activity of UGDH, leading to enhanced hyaluronic acid (HA) synthesis in the extracellular matrix. Moreover, O-GlcNAcylation of UGDH reduces CD8+ T cell infiltration by decreasing the chemokine CXCL10 expression. Specifically, O-GlcNAcylation enhances UGDH interaction with KPNA2 to compete with STAT1, and suppresses translocation of STAT1 into the nucleus, thereby transcriptionally downregulating CXCL10 expression. Thus, our study identifies UGDH O-GlcNAcylation as a key regulator of tumor immunity and further suggests a potential strategy for enhancing immunotherapy.

DOI: https://doi.org/10.1038/s41418-025-01591-8
Nat Commun. 2025 Oct 08. 16(1): 8932

Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling.

Jung Seok Hwang, JiHoon Kang, Jaehyun Kim, Kiyoung Eun, Sophia West, Hannah E Bacho, Vanessa Avalos, Sydney Shuff, Dong M Shin, Nabil F Saba, Kelly R Magliocca, Cheng-Kui Qu, Haian Fu, Suresh S Ramalingam, Andrey A Ivanov, Taro Hitosugi, Sumin Kang.

Chemotherapy is often a primary treatment for cancer. However, resistance leads to therapeutic failure. Acetylation dynamics play important regulatory roles in cancer cells, but the mechanisms by which acetylation mediates therapy resistance remain poorly understood. Here, using acetylome-focused RNA interference (RNAi) screening, we find that acetylation induced by mitochondrial dihydrolipoyl transacetylase (DLAT), independent of the pyruvate dehydrogenase complex, is pivotal in promoting resistance to chemotherapeutics, such as cisplatin. Mechanistically, DLAT acetylates methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) at lysine 44 and promotes 10-formyl-tetrahydrofolate (10-formyl-THF) and consequent mitochondrially encoded cytochrome c oxidase II (MT-CO2) induction. DLAT signaling is elevated in cancer patients refractory to chemotherapy or chemoimmunotherapy. A decoy peptide DMp39, designed to target DLAT signaling, effectively sensitizes cancer cells to cisplatin in patient-derived xenograft models. Collectively, our study reveals the crucial role of DLAT in shaping chemotherapy resistance, which involves an interplay between acetylation signaling and metabolic reprogramming, and offers a unique decoy peptide technology to overcome chemotherapy resistance.

DOI: https://doi.org/10.1038/s41467-025-63892-3
J Proteome Res. 2025 Oct 10.

Protein Lysine Crotonylation Analysis Reveals an Important Role in the Regulation of Aeromonas hydrophila Maltose Transport.

Yuying Fu, Xiaowei Zhang, Meizhen Lin, Qian Hou, Wenjia Jiang, Xiaoyun Wu, Farman Ali, Xiangmin Lin.

  Protein lysine crotonylation (Kcr) has been reported to play a role in the regulation of prokaryotic cell metabolism. However, its distribution and functional significance remain largely unexplored. In this study, a global proteomic landscape of Kcr in Aeromonas hydrophila was mapped, identifying 4424 Kcr sites on 1248 proteins using LC-MS/MS. Gene ontology analysis revealed that Kcr-modified proteins are primarily enriched in cellular and primary metabolic processes, stress responses, macromolecule biosynthesis, and transmembrane transport. Moreover, Kcr proteins are involved in diverse metabolic pathways, such as the pentose phosphate pathway, TCA cycle, and methane metabolism. Functional validation assays revealed that the maltodextrin-binding protein (MalE) at the K57 site, as well as the maltose/maltodextrin import ATP-binding protein (MalK) at the K11 and K181 sites, positively regulated maltose transport, whereas the K223 site on MalE had a negative regulatory effect. Bioinformatics analysis further demonstrated that the different Kcr status at the K11 site of MalK may positively regulate the cavity volume within the MalFGK2 complex, which may be involved in the regulation of bacterial maltose transport. Overall, our findings indicate the important role of Kcr modification in the nutrient transport system, providing insights into the regulatory roles of bacterial protein post-translational modifications.

Keywords:  Aeromonas hydrophila; MalFGK2 maltose transporter; lysine crotonylation modification

DOI:  https://doi.org/10.1021/acs.jproteome.5c00502
Cancer Med. 2025 Oct;14(19): e71291

Differential Expression of One-Carbon Pathway Enzyme ALDH1L1 Is Linked to Tumorigenicity of Low-Grade Bladder Cancer Cells Through Metabolic Reprogramming.

Halle M Meyers, Jaspreet Sharma, Amira A Abdellatef, Mikyoung You, David Raines, Kyle C Strickland, Susan Sumner, Blake R Rushing, Natalia I Krupenko, Sergey A Krupenko.

   BACKGROUND: RT4 bladder cancer cell line, derived from a nonmuscle-invasive low-grade subtype, is one of the few neoplastic cell lineages that maintain high expression of the candidate tumor suppressor ALDH1L1. Here, we investigated how differential ALDH1L1 expression affects cellular characteristics and tumorigenicity of RT4 cells as well as tumor metabotypes.
METHODS: We characterized RT4 cells and two shRNA clones (sh506/low ALDH1L1 expression; sh572/ALDH1L1 is lost) for proliferation, migration, clonogenic capacity, and mitochondrial respiration. We have further evaluated the tumorigenic potential of RT4 cells and the two clones in nude mice and compared metabotypes of derived tumors using untargeted metabolomics.
RESULTS: Both clones with diminished ALDH1L1 expression exhibited increased proliferation rates with doubling times of 19.4 h (sh506) and 23.2 h (sh572) versus 36.3 h for RT4 cells. Downregulation of ALDH1L1 expression also enhanced motility and clonogenic capacity. Proliferation and clonogenic capacity were highest for the sh506 clone (low ALDH1L1 expression), while motility was strongest for the sh572 clone (complete ALDH1L1 loss). Both clones showed altered energy metabolism, as indicated by a reduced basal oxygen consumption rate and enhanced maximal respiration rate following oligomycin treatment. Mouse xenograft tumors derived from ALDH1L1-deficient RT4 clones were significantly larger than RT4 cell-derived tumors. Of note, complete ALDH1L1 loss (sh572 clone) was less advantageous for tumor growth than the partial loss of the protein (sh506 clone). Untargeted metabolomics has shown that tumors with downregulated ALDH1L1 have altered the metabolism of fatty acids, amino acids, CoA, and acylcarnitines. Alterations in several key pathways, including glutathione metabolism (sh506), and TCA cycle (sh572), depend on the extent of ALDH1L1 downregulation.
CONCLUSIONS: Our study underscores ALDH1L1 as a key metabolic regulator of proliferation, migration, and tumorigenicity in RT4 bladder cancer cells, suggesting that retaining low ALDH1L1 expression can provide a metabolic advantage for growth of aggressive tumors.

Keywords:   ALDH1L1 ; RT4 bladder cancer cells; one‐carbon metabolism; untargeted metabolomics; xenograft tumors

DOI:  https://doi.org/10.1002/cam4.71291
Sci Rep. 2025 Oct 07. 15(1): 34888

Aloesin activates Nrf2 signaling to attenuate obesity-associated oxidative stress and hepatic steatosis in high-fat diet-fed rats.

Sarah M Alamri, Laila Naif Al-Harbi, Ghedeir M Alshammari, Nawal A Albadr, Ali Saleh, Mohammed Abdo Yahya.

  Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder characterized by hepatic steatosis, oxidative stress, and chronic inflammation. With limited therapeutic options available, there is growing interest in safe bioactive compounds that target underlying mechanisms. Aloesin, a chromone isolated from Aloe vera, possesses potent antioxidants and hypoglycemic properties; however, its protective effect against NAFLD has not been previously examined. This study investigated the hepatoprotective potential of aloesin in rats with high-fat diet (HFD)-induced NAFLD, focusing on the role of Nrf2 signaling. Adult male Wistar rats were divided into seven groups (n = 8/group): control, control + aloesin (200 mg/kg), HFD alone, HFD + aloesin (50, 100, or 200 mg/kg), and HFD + aloesin (200 mg/kg) + brusatol (0.2 mg/kg, i.p.). Treatments were administered twice weekly for 12 weeks. Aloesin dose-dependently improved metabolic and hepatic profiles, reducing body and liver weights, fasting glucose, insulin, HbA1c, HOMA-IR, and serum and hepatic levels of triglycerides, cholesterol, and LDL-c, with 200 mg/kg showing the greatest efficacy. It increased hepatic glucokinase and decreased G6Pase activity. Liver histology revealed restored architecture and reduced inflammation. Serum ALT, AST, and GGT were significantly lowered. Molecular analyses showed increased nuclear Nrf2 and antioxidant markers (GSH, SOD, HO-1), with suppressed NF-κB, TNF-α, IL-6, Bax, and caspase-3, and upregulated Bcl-2. Aloesin also modulated lipid metabolism by decreasing SREBP1 and increasing PPARα expression. These effects were reversed by brusatol, confirming Nrf2 pathway involvement. In conclusion, aloesin confers potent Nrf2-mediated protection against NAFLD, with 200 mg/kg as the optimal therapeutic dose.

Keywords:  Aloe vera; Aloesin; HFD; Inflammation; NAFLD; Oxidative stress

DOI:  https://doi.org/10.1038/s41598-025-18477-x