bims-cesirm 2025-07-06 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–07–06
twenty papers selected by
Tigist Tamir, University of North Carolina

SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming.
Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.
Integrated multi‑omics analysis of liver metabolic dysregulation in ACE2 knockout mice.
High-Throughput Post-Translational Modification Analyses by Reverse Phase Protein Array.
Multiomics reveals metformin's dual role in gut microbiome remodeling and hepatic metabolic reprogramming for MAFLD intervention.
Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer.
Ursolic acid suppresses triple-negative breast cancer progression through mediating FABP4/PPARG pathway.
TARG1 affects EGFR signaling through the regulation of RNA metabolism.
Aerobic and resistance exercise-regulated phosphoproteome and acetylproteome modifications in human skeletal muscle.
SREBP-1 in obesity-induced breast cancer: mechanisms and therapeutic perspectives.
Heterogeneous protein dynamics links to mitochondrial activity, glucose transporter, and ALDH cancer stem cell properties.
KDM3A Modulates Trastuzumab Resistance in HER2- Positive Breast Cancer Cells via the PI3K/AKT/ERK Pathway.
Tubulin Acetylation and the Cellular Mechanosensing and Stress Response.
MTX2 facilitates PKM2 tetramerization to promote cardiac glucose metabolism and protects the heart against ischemia/reperfusion injury.
Phosphorylated IRF3 promotes GSDME-mediated pyroptosis through RIPK1/FADD/caspase-8 complex formation during mitotic arrest in ovarian cancer.
Involvement of dysregulated RNA binding protein and alternative splicing regulatory networks in diabetic nephropathy from type 2 albuminuric cohorts.
Novel Data-Driven Mechanistic Modeling of Untargeted Metabolome Data Reveals Feed Component Effects in CHO Cell Bioprocess Using Column Generation-Based EFMs.
The Impact of Iron Homeostasis in Insulin-Sensitive Tissues and Gut Microbiome on Obesity-Driven Metabolic Disorders.
Exogenous H2S reduces oxidative stress induced by lipid mixture in HepG2 cells through USP22/SIRT1 axis.

J Nanobiotechnology. 2025 Jul 04. 23(1): 485

SIRT5-modified human umbilical cord mesenchymal stem cells loaded with antioxidant polydopamine nanozyme enhance parpi resistance in ovarian cancer via fatty acid metabolism reprogramming.

Jin Zhang, Xiuluan Du, Xin Dai, Yanxiang Liu, Kai Guo, Donghua Gu.

  Ovarian cancer remains one of the most aggressive cancers, and resistance to Poly (ADP-ribose) Polymerase inhibitors (PARPi) poses a major therapeutic challenge. SIRT5, a NAD + -dependent desuccinylase, plays a crucial role in regulating fatty acid metabolism, which is often reprogrammed in cancer cells to promote drug resistance. This study aimed to investigate the potential of polydopamine (PDA)-polymerized antioxidant nanozyme-loaded SIRT5-modified human umbilical cord mesenchymal stem cells (hUCMSCs) to overcome PARPi resistance in ovarian cancer. We employed multi-omics approaches, including transcriptomics, metabolomics, and proteomics, to identify key molecular pathways associated with resistance mechanisms. High-throughput sequencing and metabolic profiling revealed that SIRT5 modifies fatty acid β-oxidation and regulates the desuccinylation of Enoyl-CoA Hydratase (ECHA), a key enzyme involved in this process. In vitro and in vivo experiments demonstrated that nanozyme-engineered hUCMSCs effectively enhanced PARPi resistance by promoting fatty acid metabolism and desuccinylation. These findings suggest that SIRT5-modified hUCMSCs loaded with antioxidant nanozymes offer a promising therapeutic strategy to combat PARPi resistance in ovarian cancer. The study provides new insights into overcoming drug resistance through metabolic reprogramming and enhances the potential of engineered stem cells in cancer therapy.

Keywords:  Antioxidant nanozyme-engineered stem cells; Desuccinylation; Enoyl-CoA hydratase; Multi-omics; Ovarian cancer; Poly (ADP-ribose) polymerase inhibitors resistance; SIRT5

DOI:  https://doi.org/10.1186/s12951-025-03516-6
Cell Commun Signal. 2025 Jul 01. 23(1): 311

Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.

Mincong Shu, Yuhan Liu, Jianbin Wang.

  Serine is a non-essential amino acid, serving as a precursor for other amino acids, lipids, and nucleotide synthesis. Its supply is ensured by two main mechanisms: exogenous uptake and endogenous synthesis. The serine synthesis pathway (SSP) connects glycolysis with the one-carbon cycle and plays an important role in cellular homeostasis by regulating substance synthesis, redox homeostasis, and gene expression. The de novo SSP involves three successive enzymatic reactions catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). Post-translational modifications (PTMs), as essential regulatory mechanisms of proteins, play pivotal roles in physiological and pathological processes. This review focuses on the regulatory mode of PTMs on PHGDH, PSAT1, and PSPH, including phosphorylation, ubiquitination, acetylation, methylation, S-palmitoylation, S-nitrosylation, deamidation, SUMOylation, and lactylation. We summarize how these PTMs participate in the metabolic reprogramming of SSP. It helps us better understand the molecular mechanisms and physiological significance of the PTM network in serine synthetic metabolism, providing guidance for subsequent research and development in the future.

Keywords:  PHGDH; PSAT1; PSPH; Post-translational modification; Serine synthetic pathway

DOI:  https://doi.org/10.1186/s12964-025-02327-4
Cell Commun Signal. 2025 Jul 01. 23(1): 307

Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.

Yiyi Shou, Ruiqi Liu, Hao Xiong, Keke Xu, Xiaoyan Chen, Luanluan Huang, Yitian Zhang, Hailong Sheng, Haibo Zhang, Yanwei Lu.

  Cancer cells experience metabolic reprogramming to enhance the synthesis of nitrogen and carbon, facilitating the production of macromolecules essential for tumor proliferation and growth. A central strategy in this process involves reducing catabolic activities and managing nitrogen, thereby improving the efficiency of nitrogen utilization. The urea cycle (UC), conventionally recognized for its role in detoxifying excess nitrogen in the liver, is pivotal in this metabolic transition. Beyond the hepatic environment, the differential expression of UC enzymes facilitates the utilization of nitrogen for the synthesis of metabolic intermediates, thereby addressing the cellular metabolic requirements, especially under conditions of nutrient scarcity. In oncogenic contexts, the expression and regulation of UC enzymes undergo substantial modification, promoting metabolic reprogramming to optimize nitrogen assimilation into cellular biomass. This reconfigured UC not only enhances tumor cell survival but also plays a pivotal role in the reorganization of the tumor microenvironment (TME), thereby aiding in immune evasion. This review examines the mechanistic underpinnings of urea cycle dysregulation (UCD) in cancer, highlighting its dynamic roles across various tumor types and stages, as well as the therapeutic implications of these alterations. Understanding how UC relaxation promotes metabolic flexibility and immune evasion may help develop novel therapeutic strategies that target tumor metabolism and enhance anti-cancer immunity.

Keywords:  Cancer metabolism; Cancer treatment; Metabolic reprogramming; Tumor immunogenicity; Urea cycle

DOI:  https://doi.org/10.1186/s12964-025-02328-3
Int J Mol Med. 2025 Sep;pii: 134. [Epub ahead of print]56(3):

Integrated multi‑omics analysis of liver metabolic dysregulation in ACE2 knockout mice.

Shuai Xiao, Jinxiu Guo, Bo Yu, Shiyuan Zhao, Yicun Shang, Ni Li, Jiyao Cui, Fangqiang Song, Pei Jiang.

  The present study systematically investigated the impact of angiotensin‑converting enzyme 2‑knockout (ACE2KO) on hepatic metabolic homeostasis and its molecular mechanisms using integrated transcriptomic, proteomic and metabolomic profiling. ACE2KO exacerbated hepatic lipid accumulation, as evidenced by elevated total cholesterol and triglyceride levels, while disrupting the renin‑angiotensin system equilibrium via increased angiotensin II levels and reduced angiotensin‑(1‑7) levels. Histopathological analysis revealed hepatocyte edema, vacuolar degeneration and inflammatory infiltration in the ACE2KO mice. Multi‑omics integration revealed systemic metabolic dysregulation. Transcriptomics identified 1,004 differentially expressed genes, including lipid metabolism regulators (Scd1 and Fabp1) and circadian rhythm modulators (Arntl and Cry1), proteomics identified 191 differentially expressed proteins associated with interferon signaling activation (Oas1a and Rsad2) and lipid synthesis suppression (Scd1 and Fasn), and metabolomics highlighted 193 differentially expressed metabolites indicative of bile acid dysregulation, glutathione redox imbalance and amino acid metabolism anomalies. Cross‑omics analysis indicated that ACE2 is a key regulator of metabolic homeostasis. Its absence causes systematic metabolic disorders, including lipid metabolism disorder, amino acid metabolic imbalance and detoxification dysfunction. These findings comprehensively delineated the multifaceted role of ACE2 in hepatic metabolic homeostasis, and provided mechanistic insights into and therapeutic targets for ACE2‑associated liver diseases.

Keywords:  angiotensin‑converting enzyme 2; gene knockout; liver metabolic dysregulation; metabolomics; proteomics; transcriptomics

DOI:  https://doi.org/10.3892/ijmm.2025.5575
Methods Mol Biol. 2025 ;2929 53-69

High-Throughput Post-Translational Modification Analyses by Reverse Phase Protein Array.

Zhongcheng Shi, Michael Hoang Nguyen, Yuan Yao, Shixia Huang.

  Post-translational modifications play a crucial role in regulating protein functions by chemically modifying amino acids without altering underlying protein sequences. Protein modifications are highly involved in cellular signal transduction pathways that require swift changes between active and inactive states. Various methods, including reverse phase protein array (RPPA), have been developed to comprehensively assess the proteomic profile. RPPA technology, a robust antibody-based platform, can detect not only protein expression but also modifications, such as phosphorylation, methylation, and acetylation. This chapter presents the detailed RPPA protocol for profiling post-translational modifications, including protein phosphorylation using whole cell lysates and histone modifications using purified histones.

Keywords:  Antibody-based proteomics; High throughput; Histone; Phosphorylation; Post-translational modification; Reverse phase protein array

DOI:  https://doi.org/10.1007/978-1-0716-4595-6_5
Sci Rep. 2025 Jul 02. 15(1): 22699

Multiomics reveals metformin's dual role in gut microbiome remodeling and hepatic metabolic reprogramming for MAFLD intervention.

Yuan-Dong Sun, Hao Zhang, Xiao-Long Gong, Yuan-Min Li, Ruiqin Han, Chun-Xiao Zhou, Jian-Jun Han.

  Metabolic Associated Fatty Liver Disease (MAFLD), previously known as Non-Alcoholic Fatty Liver Disease, is a growing global health issue associated with obesity, type 2 diabetes, and metabolic syndrome. This study investigates the potential of metformin, a common anti-diabetic drug, to slow the progression of MAFLD using a multi-omics approach. Male Wistar rats were fed a choline-deficient diet to induce MAFLD and treated with metformin through their drinking water for 48 weeks. We conducted a comprehensive analysis including liver histology, untargeted metabolomics, lipidomics, and gut microbiome profiling to assess the effects of metformin on liver and gut metabolic patterns. Metformin administration led to significant changes in gut microbiome diversity and the abundance of specific microbial species in MAFLD rats. Histological analysis showed that metformin-treated rats had reduced lipid accumulation and fibrosis in the liver compared to untreated MAFLD rats. Metabolomic and lipidomic analyses revealed that metformin corrected abnormal lipid metabolism patterns, reduced hepatic fat deposition, and influenced key metabolic pathways associated with MAFLD progression. Our findings suggest that metformin has a protective role against MAFLD by modulating gut microbiota and liver metabolism, thereby slowing the progression of hepatic fibrosis. This study provides insights into the therapeutic potential of metformin for MAFLD by addressing metabolic pattern disorders and abnormal changes in gut microbial diversity, highlighting its impact on lipid metabolism and gut-liver axis interactions.

Keywords:  Liver cirrhosis; Liver metabolism; Metabolic associated fatty liver disease; Metformin; Multi-omics

DOI:  https://doi.org/10.1038/s41598-025-07557-7
Cancer Lett. 2025 Jun 27. pii: S0304-3835(25)00455-0. [Epub ahead of print]630 217887

Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer.

Enkui Zhang, Xinjia Ding, Jixin Zhang, Weikang Liu, Guangnian Liu, Mingzhe Li, Xinxin Liu, Yingjin Wang, Fusheng Zhang, Baoyi Li, Yu Zhu, Yupeng Yan, Jiayu Liu, Yuxin Wang, Xiaodong Tian, Yongsu Ma, Yinmo Yang.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic reprogramming, with polyamine metabolism emerging as a key driver of tumor progression and immune evasion. However, its comprehensive role and clinical significance in PDAC remain largely unexplored. We performed an integrative analysis using bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and functional assays to systematically characterize polyamine metabolism in PDAC. A polyamine metabolism-based prognostic model (PMscore) was developed via principal component analysis, and key regulatory genes were identified using a random forest algorithm. Functional studies in vitro and in vivo assessed the role of NT5E (CD73), a core gene involved in polyamine metabolism, in tumor biology and the tumor microenvironment (TME). Polyamine metabolism was markedly upregulated in PDAC and associated with poor prognosis. The PMscore effectively stratified patients into three prognostic subgroups and was predictive of metabolic and immune features. NT5E was identified as a critical regulator, highly expressed in epithelial and mesenchymal cells. Its knockdown impaired polyamine metabolism, reduced tumor cell proliferation and migration, and altered TME composition. Notably, CD73+ cancer-associated fibroblasts (CAFs) were enriched near tumor cells, suggesting their involvement in metabolic crosstalk and immunosuppression. Our study provides a comprehensive multi-omics characterization of polyamine metabolism in PDAC. NT5E serves as a key metabolic and immunoregulatory gene, representing a promising biomarker and therapeutic target. Combined inhibition of NT5E and polyamine metabolism may offer a novel strategy to suppress tumor progression and modulate the immunosuppressive TME in PDAC.

Keywords:  NT5E; Pancreatic cancer; Polyamine metabolism; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217887
Eur J Med Res. 2025 Jul 02. 30(1): 550

Ursolic acid suppresses triple-negative breast cancer progression through mediating FABP4/PPARG pathway.

Ying Deng, Junyi Wu, Di Pan, Wan Su, Songpo Wang.

   BACKGROUND: Triple-negative breast cancer (TNBC) remains the deadliest subtype of breast cancer owing to high metastatic potential and poor prognosis. Herein, we examined the antitumor effects of ursolic acid (UA), a pentacyclic triterpene compound, against TNBC and the underlying mechanisms.
METHODS: TNBC cells were exposed to a graded concentration of UA, and cell proliferation and migration were examined through CCK-8 and wound healing assays. Transcriptome data of 116 TNBC and 290 normal tissues were acquired for determining differentially expressed genes. Using the PubChem and the SwissTargetPrediction, potential UA targets were inferred. 10 pairs of human TNBC and normal tissues were gathered for examining the expression of UA targets FABP4 and PPARG. The influence of FABP4/PPARG knockdown and overexpression on the therapeutic effects of UA was then observed.
RESULTS: UA treatment hampered proliferation and migration of TNBC cells in a concentration-based fashion. FABP4 and PPARG were determined as targets of UA. Their expression levels were gradually elevated as the increase of UA concentration. Clinically, TNBC tumor tissues displayed notable down-regulation of FABP4 and PPARG in comparison with normal tissues. UA treatment increased PPARG expression and promoted its activation, which could be effectively attenuated by FABP4 knockdown. In addition, the efficacy of UA on suppressing TNBC cell growth and migration was notably reversed and enhanced by FABP4/PPARG knockdown and overexpression, respectively.
CONCLUSIONS: This study suggests that UA treatment increases PPARG expression through modulating FABP4, thus preventing TNBC progression, expanding the clinical application of UA and providing a theoretical basis for its usage in TNBC treatment.

Keywords:  FABP4/PPARG pathway; Migration; Proliferation; Triple-negative breast cancer; Ursolic acid

DOI:  https://doi.org/10.1186/s40001-025-02794-y
Sci Rep. 2025 Jul 02. 15(1): 23651

TARG1 affects EGFR signaling through the regulation of RNA metabolism.

Mihály Mérey, Roberta Fajka-Boja, Gergely Imre, Péter Gudmann, Zsolt Török, Lajos Mátés, Ágnes Czibula, Gyula Timinszky.

Epidermal Growth Factor Receptor (EGFR) signaling plays a central role in cell proliferation, migration, and survival. Emerging evidence suggests a connection between ADP-ribosylation and EGFR regulation. Previous studies implicated PARP's role in EGFR signaling, but the participation of ADP(ribosyl)hydrolases in it, that can revert their enzymatic modifications, still remained elusive. The role of TARG1, a macrodomain-containing hydrolase, that has been implicated in RNA metabolism, and cellular stress response, but was not studied in EGFR signaling before. Here, we investigate the impact of TARG1 depletion in U2-OS osteosarcoma cells using knockout (KO) and knockdown (KD) models. We find that TARG1 loss reduces both EGFR protein and mRNA levels. Our results show increased mRNA turnover and altered RNA distribution and translation in TARG1 KO cells, suggesting that TARG1 influences RNA metabolism and translational regulation. Notably, TARG1-deficient cells exhibit heightened sensitivity to MEK1/2 inhibition, indicating potential crosstalk between TARG1 and the Ras/MEK/ERK pathway. These findings suggest that TARG1, and possibly ADP-ribosylation, regulate EGFR expression and translation through RNA biogenesis-mediated mechanisms, highlighting its potential role in cancer cell signaling and survival.

DOI: https://doi.org/10.1038/s41598-025-08010-5
Nat Commun. 2025 Jul 01. 16(1): 5700

Aerobic and resistance exercise-regulated phosphoproteome and acetylproteome modifications in human skeletal muscle.

Mark W Pataky, Carrie J Heppelmann, Kyle J Sevits, Aneesh K Asokan, Arathi Prabha Kumar, Katherine A Klaus, Surendra Dasari, Hawley E Kunz, Matthew D Strub, Matthew M Robinson, Joshua J Coon, Ian R Lanza, Christopher M Adams, K Sreekumaran Nair.

Despite indisputable benefits of different exercise modes, the molecular underpinnings of their divergent responses remain unclear. We investigate post-translational modifications in human skeletal muscle following 12 weeks of high-intensity aerobic interval or resistance exercise training. High-intensity aerobic training induces acetylproteome modifications including several mitochondrial proteins, indicating post-translational regulation of energetics machinery, whereas resistance exercise training regulates phosphoproteomic modifications of contractile/cytoskeletal machinery, consistent with greater strength. Furthermore, despite similar transcriptional responses to a single acute bout of aerobic and resistance exercise, more robust phosphoproteomic and metabolomic responses occur with acute aerobic exercise, including phosphorylation of structural/contractile and membrane transport machinery, and the nascent polypeptide-associated complex-α, a regulator of protein translation. Together, our findings provide new insight on the intricate phosphoproteomic and acetylproteomic modifications in muscle that potentially explain physiological responses to different modes of chronic and acute exercise. This study is registered with ClinicalTrials.gov, numbers NCT01477164 and NCT04158375.

DOI: https://doi.org/10.1038/s41467-025-60049-0
Mol Biol Rep. 2025 Jul 01. 52(1): 663

SREBP-1 in obesity-induced breast cancer: mechanisms and therapeutic perspectives.

Urvashi Tiwari, Salman Akhtar, Snober S Mir, Mohammad Kalim Ahmad Khan.

  Breast cancer is the most prevalent form of malignant cancer among women worldwide, and obesity is a significant risk factor. Sterol regulatory element-binding protein 1 (SREBP-1) is a crucial transcription factor that governs lipid synthesis and is aberrantly activated in obesity-induced breast cancer. This review examines the intricate relationship between SREBP-1, obesity, and breast cancer, emphasizing the mechanisms by which obesity-induced activation of SREBP-1 facilitates tumor growth, metastasis, and therapeutic resistance. Obesity disrupts the PI3K/AKT/mTOR and AMPK pathways, resulting in hyperactivation of SREBP-1 and excessive lipid accumulation in breast cancer cells. This metabolic reprogramming fosters a tumor-supportive microenvironment, thereby enhancing cancer cell proliferation, survival, and epithelial-mesenchymal transition. Moreover, obesity adversely affects various breast cancer therapies, including surgery, radiotherapy, chemotherapy, endocrine therapy, and immunotherapy by inducing drug resistance and exacerbating side effects. Targeting SREBP-1 and its regulatory pathways is a promising therapeutic strategy for obesity-induced breast cancer. Natural compounds and small molecules such as fatostatin, mollugin, xanthohumol, and docosahexaenoic acid have demonstrated potential in inhibiting SREBP-1 activation and reducing lipid synthesis in breast cancer cells. Integrating these targeted therapies with conventional treatments may enhance the outcomes of obese patients with breast cancer. Further research is warranted to elucidate the complex mechanisms linking metabolic imbalance and breast cancer, and to develop innovative strategies that effectively combine metabolic and oncological approaches.

Keywords:  Breast cancer; Lipid synthesis; Metastasis; Obesity; SREBP-1; Therapeutic resistance

DOI:  https://doi.org/10.1007/s11033-025-10775-x
BMC Cancer. 2025 Jul 01. 25(1): 1085

Heterogeneous protein dynamics links to mitochondrial activity, glucose transporter, and ALDH cancer stem cell properties.

Martin Krkoška, Zuzana Tylichová, Pavlína Zatloukalová, Petr Müller, Bořivoj Vojtěšek, Philip John Coates.

   BACKGROUND: Cancer stem-like cells (CSCs) represent a subset of tumor cells that have the ability to self-renew, a long lifespan and a relatively quiescent phenotype, and show resistance to conventional therapies. Various markers are used to identify CSCs, and have shown that different CSC subtypes may be present within a tumor. One functional property of CSCs is their relative lack of proteasomal activity compared to the tumor bulk.
METHODS: We introduced an unstable fluorescent molecule into FaDu oropharyngeal squamous cell carcinoma cells and analyzed the association of proteasome activity with aldehydehyde dehydrogenase (ALDH) activity as another common CSC marker, and with other stem-cell related properties of glucose metabolism. We also analyzed publicly available gene expression profiling data of ALDH+ CSCs for alterations in mRNAs associated with proteostasis.
RESULTS: We show that FaDu CSCs identified by low proteasome activity are associated with the population identified by high ALDH activity. Futher characterization shows that these CSCs have a relatively high mitochondrial membrane potential and low levels of glucose transporter, indicating a non-Warburg metabolic phenotype. We also show that proteasome-low FaDu CSCs exhibit decreased rates of protein synthesis. Gene expression profiling of other cancer cell lines reveal common statistically significant differences in proteostasis in ALDH+ CSCs compared to the bulk of the tumor cells, including reduced levels of Hsp70 and/or Hsp90 in CSCs defined by ALDH, together with reduced levels of UCHL5 mRNA.
CONCLUSIONS: These data provide additional insights into the functional characteristics of proteasome-low/ALDH-high CSCs, indicating a metabolic phenotype of reduced reliance on aerobic glycolysis and a decreased protein synthesis rate. We also identify specific chaperone and ubiquitin ligase activities that can be used to identify CSCs, with corresponding implications for therapeutic strategies that target CSCs through their altered metabolic properties.

Keywords:  Cancer stem cells; Glucose transporter; Mitochondrial membrane potential; Protein degradation; Proteosynthesis; Squamous cell carcinoma

DOI:  https://doi.org/10.1186/s12885-025-14460-x
Biochem Genet. 2025 Jul 02.

KDM3A Modulates Trastuzumab Resistance in HER2- Positive Breast Cancer Cells via the PI3K/AKT/ERK Pathway.

Yuanxing Han, Jiayi Guo, Ting Yang, Xuewen Liu, Honghuo Yan, Yuanzhang Li, Juan Yao.

  Trastuzumab (TRA) is a key therapeutic agent for HER2-positive breast cancer (HER2+BC), effectively suppressing tumor progression. However, its prolonged use has led to the development of TRA resistance in many patients, worsening their clinical outcomes. Lysine-specific histone demethylase 3A (KDM3A) is known to be overexpressed in BC cells, contributing to enhanced proliferation, invasion, and migration. However, its involvement in TRA resistance in HER2+BC remains poorly understood. This study demonstrated TRA-resistant HER2+BC cell models and knocked down the expression of KDM3A to investigate its role and underlying mechanisms. The findings revealed that KDM3A expression was markedly upregulated in TRA-resistant cells and was associated with increased levels of AKT, ERK1/2, HER2, and their phosphorylated forms (p-AKT, p-ERK1/2, and p-HER2). KDM3A silencing suppressed cell survival, invasion, and migration, induced apoptosis, and arrested the cell cycle in the G0/G1 phase. Further analysis revealed that KDM3A silencing decreased mRNA and protein levels of PI3K, AKT, ERK1/2, HER2, and BCL-2 while increasing BAX expression. Protein phosphorylation levels of AKT, ERK1/2, and HER2 were also reduced. These results indicate that KDM3A contributes to TRA resistance in HER2+BC cells via the PI3K/AKT/ERK pathway, suggesting its potential as a therapeutic target for overcoming TRA resistance in HER2+BC.

Keywords:  HER2-positive breast cancer; KDM3A; Signal pathway; Trastuzumab resistance

DOI:  https://doi.org/10.1007/s10528-025-11170-8
Results Probl Cell Differ. 2025 ;75 141-162

Tubulin Acetylation and the Cellular Mechanosensing and Stress Response.

Bruno Carmona, Inês L S Delgado, Sofia Nolasco, Rita Marques, João Gonçalves, Helena Soares.

  Microtubule (MT) acetylation has emerged as a critical regulator of cellular stress responses, integrating mechanical and oxidative stimuli to support cellular adaptability and survival. This post-translational modification (PTM) enhances MT flexibility and resilience, enabling cells to withstand mechanical challenges such as changes in extracellular matrix stiffness and applied forces. Through its impact on MT physical properties, acetylation minimizes cytoskeletal breakage, reducing the need for constant remodeling and supporting cellular integrity under mechanical stress. Furthermore, tubulin acetylation regulates intracellular trafficking by modulating interactions with molecular motors, allowing for efficient cargo transport and precise spatial organization without disrupting the MT network. In the context of oxidative stress, tubulin acetylation responds to redox imbalances by stabilizing MTs and influencing cellular pathways that regulate reactive oxygen species (ROS). This modification is linked to enhanced antioxidant responses, autophagy regulation, and mitochondrial dynamics, highlighting its role in maintaining cellular homeostasis under oxidative conditions. The dual function of tubulin acetylation, responding to and integrating signals from mechanical and oxidative stress, acts as a bridging mechanism between physical and chemical signaling pathways. Consequently, it has the potential to be a therapeutic target in diseases characterized by dysregulated stress responses, including neurodegenerative disorders, cancer, and cardiovascular conditions. Despite significant progress has been made, unanswered questions persist, particularly regarding the molecular mechanisms by which acetylated MTs encode spatial and functional information and their interplay with other tubulin PTMs.

Keywords:  Mechanical stress; Microtubule; Oxidative stress; Tubulin acetylation; Tubulin post-translational modifications

DOI:  https://doi.org/10.1007/978-3-031-91459-1_5
Theranostics. 2025 ;15(14): 6737-6752

MTX2 facilitates PKM2 tetramerization to promote cardiac glucose metabolism and protects the heart against ischemia/reperfusion injury.

Yueyang Li, Yu Li, Yang Li, Yufan Jiang, Miao Wang, Mingyi Wang, Jie Liu, Mingrui Ma, Xiaofeng Zhai, Li Yi, Tao Chen, Zhenyu Xiong, Yundai Chen.

  Rationale: Myocardial ischemia reperfusion (I/R) injury is a major cause of adverse outcomes following revascularization therapy. Although alterations in metabolic activities during reperfusion have been implicated, the molecular mechanisms underlying the pathogenesis of I/R injury remain elusive. Metaxin 2 (MTX2), initially identified as a core component of protein import complexes, has recently been characterized in diverse cellular functions. Nevertheless, its involvement in myocardial I/R injury has yet to be fully elucidated. In this study, we aim to evaluate the role and the underlying mechanism of MTX2 in I/R injury. Methods: The myocardial I/R model was established, and the protein levels of MTX2 were determined at different time points following coronary occlusion. Loss-of-function and gain-of-function strategies were applied via genetic ablation or intra-myocardial adenovirus injection to ascertain the role of MTX2 in myocardial I/R injury. RNA sequencing, seahorse metabolic analysis, and mass spectrometry were conducted to uncover the underlying molecular mechanisms. Results: We observed that the expression of MTX2 was significantly decreased in I/R hearts. Tamoxifen-induced cardiomyocyte-specific deletion of Mtx2 led to aggravated myocardial I/R injury, resulting in impaired cardiac oxidative phosphorylation and glycolysis. Mechanistically, dimeric PKM2, a less active pyruvate kinase form compared with tetrameric PKM2, was found to be dramatically accumulated in Mtx2 deficiency mice after myocardial I/R surgery. The TOM37 domain of MTX2 interacted directly with PKM2 to promote PKM2 tetramerization, thereby modulating glucose metabolic flux. Pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, rescued the metabolic and functional outcomes of I/R in Mtx2 deficiency mice. Conclusions: Our results identified, for the first time, a cardioprotective role of MTX2 in modulating cardiac glucose metabolism by facilitating PKM2 tetramerization. Targeting metabolic homeostasis by restoring MTX2 might be a promising therapeutic strategy to mitigate myocardial I/R injury.

Keywords:  metabolic homeostasis.; metaxin 2; mitochondria; myocardial ischemia/reperfusion injury; pyruvate kinase M2

DOI:  https://doi.org/10.7150/thno.110162
Cell Commun Signal. 2025 Jul 01. 23(1): 306

Phosphorylated IRF3 promotes GSDME-mediated pyroptosis through RIPK1/FADD/caspase-8 complex formation during mitotic arrest in ovarian cancer.

Wenjian Gong, Dongchen Zhou, Qiuyang Xu, Linghui Wang, Mengshi Luo, Yuewen Zhang, Zhiqi Liao, Fan Xiong, Guangnian Zhao, Bingbing Zhao, Qinglei Gao, Yong Fang.

  Inducing mitotic arrest with anti-mitotic drugs is an effective strategy for cancer therapy. However, the ultimate fate of cells that undergo prolonged mitotic arrest remains largely uncertain. In this study, paclitaxel and nocodazole were used to induce prolonged mitotic arrest in ovarian cancer cells, triggering mitotic catastrophe, during which these cells exhibited hallmarks of pyroptosis. Subsequently, small interfering RNA (siRNA)-mediated downregulation of Gasdermin E (GSDME) inhibited pyroptosis, suggesting that GSDME plays an essential role in this process. The upstream signaling pathway was further investigated through caspase-3 inhibition and caspase-8 knockdown, which demonstrated that pyroptosis induced by paclitaxel and nocodazole was mediated by the caspase-8/caspase-3/GSDME pathway. Moreover, during mitotic arrest, phosphorylation of IRF3, mediated by cGAS/TBK1, led to the formation of the RIPK1/FADD/caspase-8 complex, which subsequently activated caspase-8 and initiated downstream GSDME-mediated pyroptosis. Knockdown of components of this complex or mutation of the IRF3 phosphorylation site inhibited pyroptosis. Furthermore, in vivo experiments also demonstrated that paclitaxel inhibited tumor growth by inducing GSDME-mediated pyroptosis and activating the anti-tumor immune infiltration. TCGA data further suggested that ovarian cancer cases treated with paclitaxel, showing high expression of GSDME and caspase-3, exhibited a more favorable tumor immune microenvironment. This study not only elucidated the specific mechanism of pyroptosis mediated by phosphorylated IRF3 during prolonged mitotic arrest but also revealed that mitotic arrest-induced pyroptosis could enhance immune infiltration in ovarian cancer, providing valuable insights for clinical treatment strategies.

Keywords:  IRF3; Mitotic arrest; Ovarian cancer; Pyroptosis

DOI:  https://doi.org/10.1186/s12964-025-02322-9
BMC Nephrol. 2025 Jul 01. 26(1): 326

Involvement of dysregulated RNA binding protein and alternative splicing regulatory networks in diabetic nephropathy from type 2 albuminuric cohorts.

Yu Wang, Jingjing Zhang, Qian Tang.

   BACKGROUND: Diabetic nephropathy (DN) is a primary contributor to end-stage renal disease, yet the underlying molecular mechanisms remain incompletely understood. This study aims to elucidate the role of RNA-binding proteins (RBPs) and RBP-alternative splicing (AS) regulatory networks in the pathogenesis of DN.
METHODS: Two RNA-seq datasets (GSE117085 and GSE142025) were retrieved from the Sequence Read Archive (SRA) database. Regulated alternative splicing events (RASEs) and genes (RASGs) of RASEs, along with differentiated RBPs, were identified. Validated differentiated RBPs were correlated with clinical features using the Nephroseq v5 online platform. Using the DN mouse model and RT-qPCR, validated the alternative splicing of RNA.
RESULTS: Our analysis revealed 15 differentiated RBP genes and 423 RASEs in the kidney cortex of DN rats compared to controls. Enrichment analysis highlighted lipid metabolism pathways for RASGs. Seven of the identified RBPs were validated in kidney biopsy samples from DN patients versus controls. A co-deregulatory network was constructed based on dysregulated RBPs and RASEs, with select RASGs identified. In vivo experiments, compared to normal mice, the mRNA levels of RPS19 were significantly elevated in the renal tissues of DN mice, while the levels of CPEB4 and CRYZ were markedly decreased.
CONCLUSION: In conclusion, this study provides evidence implicating dysregulated RBPs and RBP-AS regulatory networks in the development of diabetic nephropathy. The validated RBPs exhibited close associations with clinical biomarkers, reinforcing their potential as therapeutic targets for DN. These findings enhance our understanding of the molecular basis of DN and offer new insights for future research and intervention strategies.
CLINICAL TRIAL: Not applicable.

Keywords:  Alternative splicing; Co-expression; Diabetic nephropathy; RNA binding protein; Transcriptome

DOI:  https://doi.org/10.1186/s12882-025-04237-6
Biotechnol J. 2025 Jul;20(7): e70008

Novel Data-Driven Mechanistic Modeling of Untargeted Metabolome Data Reveals Feed Component Effects in CHO Cell Bioprocess Using Column Generation-Based EFMs.

Meeri E-L Mäkinen, Markella Zacharouli, Sigrid Särnlund, Yun Jiang, Veronique Chotteau.

  This study presents a novel approach for applying mechanistic metabolic modeling to untargeted metabolomics data. The approach was applied to the production process of a difficult-to-express enzyme by CHO cells, to identify key feed medium component candidates responsible for improved productivity through feed modification. The exploitation of untargeted metabolomics implies no prior decision of the metabolites or pathways and thus allows screening of metabolic phenomena and bringing an objective perspective. However, such exploitation is challenging due to the high-dimensionality, complexity, relative quantitative information, and high analysis cost of the data, leading to data scarcity. A combination of untargeted metabolomics data exploration and mechanistic modeling was developed to leverage metabolomics data. The study analyzed LC/MS/MS metabolomics data (563 cellular and 386 supernatant metabolites) to determine the key metabolites involved in the productivity increase associated with a feeding modification. The metabolome data was utilized to expand the original stoichiometric reaction network of 127 reactions to 370 reactions. Mechanistic modeling using elementary flux modes-based column generation identified and simulated the underlying metabolic pathways. Twenty-one key metabolites significant for productivity improvement were revealed. This included several unexpected metabolites, such as citraconate and 5-aminovaleric acid, in addition to well-known components, as well as their underlying metabolic pathways. This study offers a novel approach for investigating nutrient supplementation in terms of metabolic fluxes and process performance, paving the way for rational process optimization supported by mechanistic understanding.

Keywords:  Chinese hamster ovary cells; bioprocessing; column generation; elementary flux mode; mechanistic metabolic model; metabolomics

DOI:  https://doi.org/10.1002/biot.70008
Adv Exp Med Biol. 2025 ;1480 253-269

The Impact of Iron Homeostasis in Insulin-Sensitive Tissues and Gut Microbiome on Obesity-Driven Metabolic Disorders.

José María Moreno-Navarrete, Isa Galvao Rodrigues, José Manuel Fernández-Real.

  Iron is a crucial element for vital biological processes in both prokaryotic and eukaryotic cells, requiring precise regulation to maintain homeostasis. In humans and animal models, dysregulation of iron homeostasis is often linked to obesity-associated metabolic disturbances, which are characterized by elevated serum ferritin levels and excessive iron accumulation in insulin-dependent tissues like the liver, adipose tissue, and skeletal muscle. Prolonged iron overload in tissues induces oxidative stress, which impairs insulin sensitivity and promotes systemic insulin resistance and hyperglycemia. This creates a vicious cycle in which decreased serum hepcidin levels enhance intestinal iron absorption, further exacerbating iron accumulation. While the impact of iron on gut microbiota is well established, the role of gut microbiota in regulating body iron homeostasis is less studied. Recent studies have uncovered new mechanisms by which gut microbiota influence intestinal iron absorption and the regulation of body iron stores. In this chapter, we summarize recent findings on iron homeostasis in insulin-sensitive metabolic tissues and explore how gut microbiota can modulate body iron regulation in the context of obesity.

Keywords:  Gut microbiota; Hepcidin regulation; Insulin resistance; Iron homeostasis; Obesity-related metabolic disorders

DOI:  https://doi.org/10.1007/978-3-031-92033-2_17
Sci Rep. 2025 Jul 02. 15(1): 23129

Exogenous H2S reduces oxidative stress induced by lipid mixture in HepG2 cells through USP22/SIRT1 axis.

Xiaomeng Cui, Chengjun Li, Shuixiang He, Yarui Li.

  H2S signal transduction involves various physiological processes, including promoting vasodilation, regulating lipid metabolism, inducing angiogenesis, improving oxidative stress and inflammatory response, and avoiding cell apoptosis. Oxidative stress is an important mechanism that causes the pathological progression of NAFLD. However, the effect and specific mechanism of exogenous H2S on oxidative stress in NAFLD are still unclear. Here, we investigated the specific regulatory mechanism of exogenous H2S on oxidative stress and inflammation induced by LM in HepG2 cells. HepG2 cells were stimulated with LM with or without GYY4137 (200 µM) treatment for 24 h. The levels of MDA, SOD, ROS, TNF-α, IL-6, and antioxidant related proteins of cells were detected. We found exogenous H2S remarkably reduced the levels of MDA, ROS, TNF-α and IL-6 and elevated SOD contents as well as the expression of antioxidant-related proteins in LM-induced HepG2 cells. Moreover, exogenous H2S improved the expression of USP22 protein in LM-induced HepG2 cells and inhibited the ubiquitination degradation of SIRT1 through USP22. After USP22 was knocked down, the efficacy of exogenous H2S on mitigating LM-induced oxidative damage and inflammatory reaction in HepG2 cells had been weakened. In conclusion, exogenous H2S inhibited SIRT1 ubiquitination degradation through USP22, thereby alleviating LM-induced oxidative stress and inflammatory responses in HepG2 cells.

Keywords:  Exogenous H2S; GYY4137; Lipid mixture; Oxidative stress; SIRT1; USP22

DOI:  https://doi.org/10.1038/s41598-025-04924-2