bims-cesirm 2025-08-03 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–08–03
nineteen papers selected by
Tigist Tamir, University of North Carolina

Multiomics analysis of GSTP1 knockdown pancreatic cancer cells reveals key regulators of redox and metabolic homeostasis.
Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma.
Matrix stiffness boosts PDAC chemoresistance via SCD1-dependent lipid metabolic reprogramming.
DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism.
HBx Drives Liver Cancer Stem Cell Generation Through Stimulating Glucose Metabolic Reprogramming.
Integrating Redox Proteomics and Computational Modeling to Decipher Thiol-Based Oxidative Post-Translational Modifications (oxiPTMs) in Plant Stress Physiology.
Integrating deep learning for post-translational modifications crosstalk on Hsp90 and drug binding.
Response Gene to Complement 32 promotes cell proliferation and tamoxifen resistance in breast cancer via elevated FoxM1 expression.
Proteomic analysis of tumor cell nuclear expulsion reveals significant cell adhesion and RNA binding programs in extracellular chromatin.
Multifaceted role of serine hydroxymethyltransferase in health and disease.
Cell cycle dependence of ERK activation dynamics is regulated by PI3K and PAK1 signaling.
Immune infiltration related PRDX4 facilitates the malignant features and drug resistance of breast cancer.
GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2.
Filamentation of hCTPS1 with CTP.
Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.
High-fat diet may increase the risk of insulin resistance by inducing dysbiosis.
Proteomic analyses identify targets, pathways, and cellular consequences of oncogenic KRAS signaling.
Comprehensive Prediction of Protein Localization and Signal Peptides Using MULocDeep.
Probiotic Potentials and Protective Effects of Ligilactobacillus animalis LA-1 Against High-Fat Diet-Induced Obesity in Mice.

Biol Open. 2025 Jul 28. pii: bio.061986. [Epub ahead of print]

Multiomics analysis of GSTP1 knockdown pancreatic cancer cells reveals key regulators of redox and metabolic homeostasis.

Jenna N Duttenhefner, Rahul R Singh, Katherine Schmidt, Katie M Reindl.

  Glutathione S transferase pi-1 (GSTP1) is a detoxification enzyme essential for oxidative homeostasis. In cancer, GSTP1 has been implicated in tumorigenicity, cell cycle progression, and chemoresistance. While GSTP1 depletion has been associated with decreased cancer growth in various models, the mechanism remains poorly understood. This study investigates GSTP1 as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using inducible knockdown models. We demonstrate that GSTP1 loss disrupts redox balance, impairs cell survival, and induces metabolic adaptations. Multiomics analysis characterized the global impact of inducible GSTP1 knockdown on the transcriptome and proteome of PDAC cells, identifying 550 differentially expressed genes and 62 proteins. Notably, 43 of these showed consistent regulation at both the mRNA and protein levels. We identify dysregulation of key stress response proteins, including dimethylarginine dimethylaminohydrolase 1 (DDAH1), involved in nitric oxide metabolism, and protein disulfide isomerase A6 (PDIA6), which maintains protein homeostasis. The interplay between GSTP1, DDAH1, and PDIA6 highlights the complexity of redox regulation in pancreatic cancer and suggests that targeting GSTP1 may offer a new therapeutic approach for PDAC.

Keywords:  GSTP1; Multiomics analysis; Pancreatic ductal adenocarcinoma; Redox homeostasis; Therapeutic targets

DOI:  https://doi.org/10.1242/bio.061986
Signal Transduct Target Ther. 2025 Aug 01. 10(1): 244

Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma.

Qi Wang, Juan Liu, Ming Yang, Jun Zhou, Yaxuan Li, Jingjing Zheng, Hao Jia, Shuhua Yue, Yinpeng Le, Yuxin Su, Wenrui Ma, Ni An, Yunfang Wang, Jiahong Dong.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and resistance to systemic therapies remains a significant clinical challenge. This study investigated the mechanisms by which metabolic reprogramming contributes to systemic treatment resistance in HCC. We established HCC cell lines with multidrug resistance characteristics and observed enhanced metabolic activity in these cells. Integrated multiomics analyses revealed hyperactive glucose‒lipid and glutathione metabolic pathways that play critical roles in supporting tumor cell proliferation and survival. We constructed a metabolic reprogramming atlas for HCC-resistant cells and identified aldo-keto reductase (Aldo-keto reductase family 1 Member B1, AKR1B1) as a key regulator of this reprogramming, which sustains drug resistance by regulating energy metabolism and enhancing stress tolerance. Importantly, AKR1B1 expression levels are closely associated with drug resistance and poor prognosis in HCC patients. The secretory nature of AKR1B1 not only underscores its predictive value but also facilitates the intercellular transmission of drug resistance. In terms of overcoming resistance, the AKR1B1 inhibitor epalrestat significantly mitigated drug resistance when it was used in combination with standard therapies. These findings underscore the importance of metabolic reprogramming in the development of HCC resistance. AKR1B1, a key enzyme that regulates metabolic reprogramming, has been identified as a potential biomarker and therapeutic target, providing new insights into overcoming resistance in HCC treatment.

DOI: https://doi.org/10.1038/s41392-025-02321-9
Regen Biomater. 2025 ;12 rbaf056

Matrix stiffness boosts PDAC chemoresistance via SCD1-dependent lipid metabolic reprogramming.

Xue Zhang, Biwen Zhu, Jiashuai Yan, Xi Chen, Di Wu, Zhen Wang, Xiaoqi Guan, Yan Huang, Yahong Zhao, Yumin Yang, Yibing Guo.

  PDAC cells perceive and respond to mechanical stimuli in their extracellular microenvironments (ECMs), playing a crucial role in chemoresistance, while the underlying mechanisms are not fully understood. The progression of various solid tumors is accompanied by metabolic reprogramming. RNA-seq and untargeted metabolomics analysis indicated that stiff substrate may regulate lipid metabolism. The expression of lipogenesis-related genes, including fatty acid synthase (FASN), ATP citrate lyase (ACLY) and acetyl-CoA carboxylase (ACC) was elevated, also the sum of lipid droplets and the triglyceride content. Herein, whether lipid metabolism is involved in matrix stiffness-mediated PDAC chemoresistance and the in-depth mechanism were further explored. Rescue with C75 (FASN inhibitor) validated that fatty acid synthesis participated in matrix stiffness-regulated chemoresistance. Simultaneously, the SCD1 expression was reinforced, consistent with PDAC tissues. The concurrent restraint SCD1 (with inhibitor CAY10566 or shSCD1) and addition of oleic acid confirmed that SCD1 is involved in matrix stiffness-mediated chemoresistance through fatty acid synthesis. In addition, Piezo1 regulated SCD1 expression through the augmentation of Ca2+ influx, and the PI3K/Akt pathway participated in this process. Taken together, our research sheds light on lipid metabolism exerts an essential role during matrix stiffness-mediated chemoresistance through Piezo1-elicited elevation of SCD1. Our findings delivered a supplement PDAC chemoresistance mechanism mediated by matrix stiffness from the perspective of lipid metabolic reprogramming, and provided a novel strategy for improving clinical therapies.

Keywords:  chemoresistance; lipid metabolism; matrix stiffness; pancreatic ductal adenocarcinoma; stearoyl-CoA desaturase 1

DOI:  https://doi.org/10.1093/rb/rbaf056
Mol Metab. 2025 Jul 30. pii: S2212-8778(25)00132-2. [Epub ahead of print] 102225

DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism.

Dotan Moskovich, Daniel Beilinson, Amit Rosemarin, Aileen Cohen, Itai Fabian, Tzuri Lifschytz, Bernard Lerer, Govindasamy Mugesh, Maya Gottfried, Osnat Ashur-Fabian.

  Metabolic reprogramming emerges as a central driver of therapy resistance and survival disadvantage in ovarian cancer. We recently demonstrated that inhibiting the enzyme Deiodinase type 3 (DIO3) reduces ovarian cancer growth, although the underlying mechanism remains unclear. Here, we studied DIO3 role in metabolism in genetically manipulated ovarian cancer cells using protein expression analysis, integrative proteomics, endogenous and extracellular metabolomics, metabolic assays including lactate and glutamate secretion, reactive oxygen species (ROS) production and the Seahorse Cell Mito Stress test. We reveled that inhibiting DIO3 suppresses glycolysis while enhancing ATP production through oxidative phosphorylation (OXPHOS). We corroborated these findings using two models of ovarian cancer xenografts, demonstrating a marked reduction in glycolytic proteins upon silencing or inhibiting DIO3 using our first in class small molecule. Moreover, altered glutamine metabolism was also documented, favoring urea cycle and TCA cycle engagement over antioxidant production, accompanied by elevated ROS. Intriguingly, DIO3 depletion in fallopian tube cells, the precursor of HGSOC, displayed distinct metabolic adaptations, including enhanced glycolysis and lipid metabolism, suggesting tissue-specific roles for DIO3. These collective findings position DIO3 as a potential regulator of ovarian cancer metabolism, with implications for targeting this enzyme to disrupt tumor energetics as a novel therapeutic approach.

Keywords:  Deiodinase type 3; Thyroid hormones; gynecological malignancy; metabolism; ovarian cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102225
J Cell Mol Med. 2025 Jul;29(14): e70722

HBx Drives Liver Cancer Stem Cell Generation Through Stimulating Glucose Metabolic Reprogramming.

Jinchen Liu, Xueqin Wu, Qiushi Yin, Luying Zhang, Kun Liu, Kailin Huang, Junnv Xu, Xiaowei Li, Bo Lin, Mingyue Zhu, Mengsen Li.

  Recurrence of hepatocellular carcinoma (HCC) is closely related to the infection of hepatitis B virus (HBV). The HBV x protein (HBx) plays a key role in promoting the malignant transformation of hepatocytes and cancer heterogeneity, but the role of HBx in metabolism influencing the generation of cancer stem cells (CSCs) is still unclear. This study explores HBx-induced glucose metabolic reprogramming of HCC cells to promote the generation of CSCs. Immunohistochemical analysis of the expression of glucose metabolic reprogramming-related enzymes and stemness markers in HCC tissues and corresponding paracancer tissues of 30 patients; Western blotting, laser confocal microscopy, and metabolism-detection kits were applied to analyse the expression of glucose metabolism-related enzymes and cancer stemness markers and glucose metabolic products; the generation of CSCs was observed by stem cell pellet and soft agar colony formation experiments. Results indicated that the expression of PKM2, HK2, LDHA, CSC-related proteins, and CD133 and CD44 in HCC tissues was significantly higher than that in the corresponding paracancerous tissues. HBx stimulated the expression of the key enzyme of the Warburg effect and CSC-related proteins, and these proteins were significantly reduced after interference with the expression of the PKM2 protein. PKM2 and OCT4 interact in HCC cells, and PKM2 has a regulatory effect on OCT4 function. This study found that HBx stimulated the Warburg effect and induced HCC stemness reprogramming by activating the PI3K/AKT signalling pathway; PKM2 played a key role in promoting the initiation of HCC stem cells. Targeting HBx and PKM2 is a new strategy for the treatment of HCC.

Keywords:   HBx ; Warburg effect; cancer stem cells; glucose metabolism reprogramming; hepatocellular carcinoma

DOI:  https://doi.org/10.1111/jcmm.70722
Int J Mol Sci. 2025 Jul 18. pii: 6925. [Epub ahead of print]26(14):

Integrating Redox Proteomics and Computational Modeling to Decipher Thiol-Based Oxidative Post-Translational Modifications (oxiPTMs) in Plant Stress Physiology.

Cengiz Kaya, Francisco J Corpas.

  Redox signaling is central to plant adaptation, influencing metabolic regulation, stress responses, and developmental processes through thiol-based oxidative post-translational modifications (oxiPTMs) of redox-sensitive proteins. These modifications, particularly those involving cysteine (Cys) residues, act as molecular switches that alter protein function, structure, and interactions. Advances in mass spectrometry-based redox proteomics have greatly enhanced the identification and quantification of oxiPTMs, enabling a more refined understanding of redox dynamics in plant cells. In parallel, the emergence of computational modeling, artificial intelligence (AI), and machine learning (ML) has revolutionized the ability to predict redox-sensitive residues and characterize redox-dependent signaling networks. This review provides a comprehensive synthesis of methodological advancements in redox proteomics, including enrichment strategies, quantification techniques, and real-time redox sensing technologies. It also explores the integration of computational tools for predicting S-nitrosation, sulfenylation, S-glutathionylation, persulfidation, and disulfide bond formation, highlighting key models such as CysQuant, BiGRUD-SA, DLF-Sul, and Plant PTM Viewer. Furthermore, the functional significance of redox modifications is examined in plant development, seed germination, fruit ripening, and pathogen responses. By bridging experimental proteomics with AI-driven prediction platforms, this review underscores the future potential of integrated redox systems biology and emphasizes the importance of validating computational predictions, through experimental proteomics, for enhancing crop resilience, metabolic efficiency, and precision agriculture under climate variability.

Keywords:  computational modeling; machine learning; nitric oxide; redox proteomics; redox signaling networks; thiol-based oxidative post-translational modifications (oxiPTMs)

DOI:  https://doi.org/10.3390/ijms26146925
J Biol Chem. 2025 Jul 25. pii: S0021-9258(25)02370-1. [Epub ahead of print] 110519

Integrating deep learning for post-translational modifications crosstalk on Hsp90 and drug binding.

Jennifer A Heritz, Katherine A Meluni, Sarah J Backe, Sara J Cayaban, Laura A Wengert, Meik Kunz, Mark R Woodford, Dimitra Bourboulia, Mehdi Mollapour.

  Post-translational modification (PTM) of proteins regulates cellular proteostasis by expanding protein functional diversity. This naturally leads to increased proteome complexity as the result of PTM crosstalk. Here, we used the molecular chaperone protein, Heat shock protein-90 (Hsp90), which is subject to a plethora of PTMs, to investigate this concept. Hsp90 is at the hub of proteostasis and cellular signaling networks in cancer and is, therefore, an attractive therapeutic target in cancer. We demonstrated that deletion of histone deacetylase 3 (HDAC3) and histone deacetylase 8 (HDAC8) in human cells led to increased binding of Hsp90 to both ATP and its ATP-competitive inhibitor, Ganetespib. When bound this inhibitor, Hsp90 from both HDAC3 and HDAC8 knock out human cells exhibited similar PTMs, mainly phosphorylation and acetylation, and created a common proteomic network signature. We used both a deep-learning artificial intelligence (AI) prediction model and data based on mass-spectrometry analysis of Hsp90 isolated from the mammalian cells bound to its drugs to decipher PTM crosstalk. The alignment of data from both methods demonstrates that the deep-learning prediction model offers a highly efficient and rapid approach for deciphering PTM crosstalk on complex proteins such as Hsp90.

Keywords:  Hsp90; acetylation; artificial intelligence; chaperone; cochaperone; deep learning; histone deacetylase; phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2025.110519
PLoS One. 2025 ;20(7): e0328698

Response Gene to Complement 32 promotes cell proliferation and tamoxifen resistance in breast cancer via elevated FoxM1 expression.

Xinlei Li, Yan Liu, Zhiqian Wang, Xiaocui Bu, Yu Wang, Wei Zhang, Peng Zhao.

Despite the high sensitivity of estrogen receptor positive (ER+) breast cancer to endocrine therapy, many patients have primary resistance or develop resistance to endocrine therapies. Acquired resistance to endocrine therapy is a great challenge in the treatment of ER+ breast cancer patient. Here we showed that Response Gene to Complement (RGC)-32 expression is higher in breast cancer than paired normal tissues, which was a poor predictive factor. RGC-32 overexpression resulted in tamoxifen resistance, whereas knockdown of RGC-32 in tamoxifen-resistant cells restored tamoxifen sensitivity. Tamoxifen resistance mediated by RGC-32 was shown to be partially dependent on FoxM1 expression. Mechanistically, RGC-32 could activated PI3K signaling pathway, and then enhanced estrogen receptor alpha (ERα) activity. ERα activation is essential for RGC-32-mediated the expression of FoxM1. These data support that targeting RGC-32 could effectively mitigate cancer progression and tamoxifen resistance, offering a complementary therapeutic approach to reduce acquired endocrine resistance.

DOI: https://doi.org/10.1371/journal.pone.0328698
Sci Rep. 2025 Aug 01. 15(1): 28054

Proteomic analysis of tumor cell nuclear expulsion reveals significant cell adhesion and RNA binding programs in extracellular chromatin.

Justin M Gray, Woo Yong Park, Ronald J Holewinski, Thorkell Andresson, Carmelo Carmona-Rivera, Mariana J Kaplan, Li Yang.

  Understanding mechanisms of cancer cell death and the resulting effect on disease progression is crucial in cancer biology and the insight will likely offer better options for therapeutic treatment. Nuclear expulsion occurs in apoptotic cancer cells in a peptidylarginine deiminase 4 (Padi4) dependent manner. The resulting tumor cell nuclear expulsion product (TuNEP) promotes the outgrowth of neighboring cancer cells through chromatin-bound protein complexes. It is not clear what the protein compositions and functionalities are in these TuNEPs. In this study, we performed extensive proteomic profiling and identified key TuNEP protein components from mouse and human breast cancer cells as well as human lung cancer cells (4T1, MDA-MB-231, and PC9). We further compared TuNEP- specific proteins with those from apoptotic bodies or NETs from neutrophils. We found an enrichment of cellular adhesion molecules as well as increased citrullination of proteins associated with RNA binding. We showed that cellular adhesion molecules integrin and basigin (BSG) promote the growth of tumor spheroids. Our work revealed the unique TuNEP protein components distinct from neutrophil-derived NETs and shed light on potential mechanisms by which these cancer cell-derived TuNEPs promote tumor progression.

Keywords:  Apoptosis; Cancer; Chromatin; Nuclear expulsion; Proteomics

DOI:  https://doi.org/10.1038/s41598-025-11807-z
Mol Cells. 2025 Jul 28. pii: S1016-8478(25)00086-X. [Epub ahead of print] 100262

Multifaceted role of serine hydroxymethyltransferase in health and disease.

Jing Zhang, Seong Eun Lee, Ji Yeon Yoon, Bon Jeong Ku, Junyoung O Park, Da Hyun Kang, Jun Yeong Heo, Yea Eun Kang.

  Serine hydroxymethyltransferase (SHMT) is a key enzyme in one-carbon metabolism (OCM), a biochemical pathway critical for cellular growth, proliferation, and survival. OCM integrates the folate and methionine cycles to produce essential intermediates necessary for nucleotide synthesis, methylation reactions, and redox homeostasis. SHMT exists in two isoforms, SHMT1, which is localized in the cytoplasm, and SHMT2, which is localized in the mitochondria. SHMT1 and SHMT2 have distinct yet complementary functions. Both are involved in serine and glycine metabolism, ensuring a continuous supply of the one-carbon units required for biosynthetic and epigenetic processes. SHMT dysregulation has been implicated in cancer progression and metabolic disorders, including cardiovascular diseases, diabetes, and neurological abnormalities. In cancer, the abnormal expression of SHMT has been associated with tumor growth, metabolic reprogramming, and treatment resistance, and has also been shown to correlate with poor patient outcomes. Considering its critical role in both cancer and metabolic diseases, SHMT has emerged as a potential therapeutic target in cancer. Recent studies have shown that SHMT inhibitors can reduce tumor proliferation and restore metabolic homeostasis. This review provides a comprehensive overview of the role of SHMT in the regulation of metabolic pathways and its role in tumor progression and metabolic diseases. In this review, we aimed to highlight the therapeutic potential of targeting SHMT and offer insights into the development of innovative treatment strategies in oncology and metabolic medicine. These insights support the hypothesis that targeting SHMT, particularly isoform-specific inhibition, may provide novel therapeutic avenues in both oncology and metabolic medicine.

Keywords:  One-carbon metabolism; SHMT1; SHMT2; cancer; metabolic disease; neurological disorders

DOI:  https://doi.org/10.1016/j.mocell.2025.100262
Sci Rep. 2025 Jul 29. 15(1): 27688

Cell cycle dependence of ERK activation dynamics is regulated by PI3K and PAK1 signaling.

Ryo Yoshizawa, Yasushi Sako.

Growth factor-induced RTK/RAS/MAPK signaling is crucial for cell cycle progression, including G1 to S and G2 to M phase transitions. However, the regulatory mechanism of MAPK (ERK) in the S-G2M phase remains unclear. In this study, we analyzed the nuclear translocation dynamics of fluorescently labeled ERK induced by EGF during cell cycle progression and simultaneously analyzed the membrane translocation dynamics of GRB2 and PI3K. The transient ERK dynamics in a population of cells with a high frequency of G0/G1 cells became sustained with the increase in S-G2M cells. The sustained localization of PI3K, rather than GRB2, showed a stronger correlation with nuclear ERK localization. PI3K-mediated PAK1 activation was essential for ERK translocation. EGFR/PI3K clusters frequently formed on the plasma membrane and were rapidly endocytosed in the high G0/G1 cell population, resulting in transient PI3K localization, whereas dispersed PI3K predominated in the high S-G2M cells, resulting in sustained PI3K localization. On the other hand, PAK1 remained on the plasma membrane. Our results suggest that the sustained spatial colocalization of PI3K and PAK1, particularly in the S-G2M phase, prolonged the PAK1 signaling for ERK activation. Sustained ERK activation was also correlated with a shorter time to cell division.

DOI: https://doi.org/10.1038/s41598-025-13686-w
Sci Rep. 2025 Jul 28. 15(1): 27507

Immune infiltration related PRDX4 facilitates the malignant features and drug resistance of breast cancer.

Wenying Jiang, Maonan Wang, Qingning Chen, Xiaoqian Yu, Guoqian Liu, Xiaoyun He, Cheng Mei, Chunlin Ou.

  The incidence of breast cancer continues to increase annually, posing a significant challenge for countries worldwide in terms of its prevention and treatment. Therefore, identifying novel therapeutic targets for breast cancer is urgently needed. The peroxiredoxin (PRDX) family is regarded as a good diagnostic marker for various tumors. However, the expression and prognostic significance of PRDX family members in breast cancer remain unclear and require systematic investigation. By using bioinformatic tools such as UALCAN, TIMER2.0, Human Protein Atlas Project (HPA), Gene Set Cancer Analysis (GSCA), and the cBioportal database, we systematically analyzed the expression pattern, prognostic value, methylation status and immune infiltrating association of PRDX gene family members in breast cancer. Through comprehensive analysis, we found that PRDX4 has good prognostic value and is closely related to immune infiltration, and further exploration of its oncogenic function in breast cancer is warranted. Subsequently, we performed a series of cellular assays to explore the potential role of PRDX4 in the progression of breast cancer. We demonstrated that PRDX4 promoted the proliferation, invasion, metastasis, and inhibited the apoptosis of breast cancer cells. In addition, PRDX4 expression was associated with the half maximal inhibitory concentration (IC50) of neratinib which primarily targets human epidermal growth factor receptor 2 (HER2) and showed good binding in molecular docking. Our subsequent experiments showed that the PRDX4-HER2 axis may serve as a potential combined target for neratinib therapy. Our findings suggest that PRDX4 may be a potential diagnostic and prognostic marker for breast cancer, and targeting PRDX4 could represent a novel strategy to improve the efficacy of targeted therapy for patients with HER2-positive breast cancer.

Keywords:  Breast cancer; Drug resistance; Immune infiltration; PRDX4; Prognosis; Therapeutic target

DOI:  https://doi.org/10.1038/s41598-025-13361-0
Cell Commun Signal. 2025 Jul 25. 23(1): 355

GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2.

Qingyi Hu, Qianzhi Chen, Wen Yang, Anwen Ren, Jie Tan, Tao Huang.

   BACKGROUND: Due to the lack of effective targeted therapies and the high likelihood of acquired resistance, triple-negative breast cancer (TNBC) remains one of the deadliest cancers affecting women globally. Investigating the mechanism underlying TNBC's resistance to platinum-based chemotherapy and identifying new therapeutic targets are urgent priorities.
METHODS: The expression level of GPX3, cisplatin sensitivity, and ROS production were compared across three TNBC cell lines to elucidate the relationship between GPX3 and platinum resistance. RNA sequencing and bioinformatics analyses of GPX3 knockdown cells revealed its regulation of stress-related signaling pathways and TGFB1. The regulation of TGFB1 by GPX3 was further investigated using Western blotting, RNA interference, confocal microscopy, and inhibitor treatments. The correlation between the expression level of GPX3, TGFB1, and ZEB2 was analyzed using breast cancer microarrays and the TCGA database. The effect of GPX3 on platinum sensitivity in TNBC was studied using a mouse xenograft model.
RESULTS: GPX3 expression was upregulated in more invasive TNBC cells, promoting resistance to cisplatin-based chemotherapy. RNA sequencing revealed that the deletion of GPX3 resulted in a decrease in gene expression patterns associated with pro-tumor signaling pathways. Validation experiments confirmed that the upregulation of TGFB1 in acquired cisplatin resistance is highly dependent on GPX3. Further investigation revealed that the TGFB1-ZEB2 axis mediated platinum resistance and metastasis through epithelial-mesenchymal transition (EMT). Additionally, platinum treatment increased GPX3 and TGFB1 expression and secretion, and their depletion enhanced platinum sensitivity in TNBC cells. We identified the GPX3-TGFB1-ZEB2 regulatory axis and found a positive correlation in the expression of all three in clinical samples. Our study also demonstrated that GPX3 knockdown inhibited TNBC tumor growth in platinum-treated mouse models.
CONCLUSIONS: This study reveals the signaling pathway mediated by GPX3-TGFB1-ZEB2 and its role in acquired platinum resistance and EMT in TNBC. Our findings suggest that GPX3 is a promising biomarker and potential therapeutic target for the diagnosis, treatment, and prognosis of high-risk TNBC patients.

Keywords:  Chemoresistance; Cisplatin; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s12964-025-02356-z
Cell Biosci. 2025 Jul 30. 15(1): 112

Filamentation of hCTPS1 with CTP.

Chen-Jun Guo, Xiaojie Bao, Ji-Long Liu.

  CTP synthase (CTPS) is a key enzyme in de novo CTP synthesis, playing a critical role in nucleotide metabolism and cellular proliferation. Human CTPS1 (hCTPS1), one of the two CTPS isoforms, is essential for immune responses and is highly expressed in proliferating cells, making it a promising therapeutic target for immune-related diseases and cancer. Despite its importance, the regulatory mechanisms governing hCTPS1 activity remain poorly understood. Here, we reveal that CTP, the product of CTPS, acts as a key regulator for hCTPS1 filamentation. Using cryo-electron microscopy (cryo-EM), we resolve the high-resolution structure of CTP-bound hCTPS1 filaments, uncovering the molecular details of CTP binding and its role in filament assembly. Importantly, we demonstrate that CTP generated from the enzymatic reaction does not trigger filament disassembly, suggesting a conserved regulatory pattern. Furthermore, by analyzing the binding modes of two distinct CTP-binding pockets, we provide evidence that this filamentation mechanism is evolutionarily conserved across species, particularly in eukaryotic CTPS. Our findings not only elucidate a novel regulatory mechanism of hCTPS1 activity but also deepen the understanding of how metabolic enzymes utilize filamentation as a conserved strategy for functional regulation. This study opens new avenues for targeting hCTPS1 in therapeutic interventions.

Keywords:  CTP synthase; Cryo-EM; Cytoophidium; Metabolic filament; Product feedback regulation

DOI:  https://doi.org/10.1186/s13578-025-01450-6
Cancer Res. 2025 Jul 31.

Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.

Rui-Zhe Li, Guo-Qiang Pan, Chen Xiong, Zi-Niu Ding, Tuan-Song Zhang, Lun-Jie Yan, Dongxu Wang, Xiaolu Zhang, Xiao-Feng Dong, Yu-Chuan Yan, Yu Zhou, Rui Dong, Zhao-Ru Dong, Tao Li.

Recently, a PARP1-dependent cell-death process termed "parthanatos" that is driven by DNA damage has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. Here, we investigated the crosstalk between parthanatos and hypoxia. Despite causing DNA damage, hypoxia failed to induce parthanatos in hepatocellular carcinoma (HCC). The creatine transporter SLC6A8 promoted parthanatos antagonism and malignant phenotypes in hypoxic HCC cells. Hypoxia-induced creatine accumulation drove metabolic reprogramming and antagonized parthanatos. Mechanistically, creatine elevated SERPINE1 expression through MPS1-mediated Smad2/3 phosphorylation and formed a creatine/SERPINE1/HIF-1α positive feedback loop. SERPINE1 facilitated USP10-mediated deubiquitination and stabilization of PKLR by forming a SERPINE1-USP10-PKLR complex. USP10 contained a strong PAR-binding motif, and SERPINE1 reversed the attenuated deubiquitination activity of USP10 caused by the direct binding of PAR under hypoxia. The SLC6A8 inhibitor RGX-202 exerted potent antitumor activity alone and in combination with lenvatinib in patient-derived xenografts and primary HCC mouse models. Overall, this study identified intracellular creatine accumulation as a mechanism that allows hypoxic cancer cells to circumvent parthanatos and as a therapeutic target in HCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0301
Metabol Open. 2025 Sep;27 100381

High-fat diet may increase the risk of insulin resistance by inducing dysbiosis.

Ebrahim Abbasi, Iraj Khodadadi.

  High-fat diet (HFD) poses various health risks, such as obesity, insulin resistance (IR), fatty liver, gut microbiota dysbiosis, cognitive impairment, inflammation, and oxidative stress. HFD can alter gastrointestinal function and structure, resulting in changes of the intestinal mucosa, gastric secretions, intestinal connective tissue, intestinal motility, intestinal metabolomics profiles, and intestinal microbiota. The intestine and its microbiota process nutrients and produce molecules that can regulate insulin action and secretion. Changes in the gut microbiome (dysbiosis) and their products may have long-term effects that are not fully understood. Gut microbiota have long been documented to induce metabolic endotoxemia by releasing lipopolysaccharide, which causes systemic inflammation and insulin resistance (IR). HFD may has direct roles in the development of insulin resistance (IR). HFD can induce dysbiosis by reducing SCFAs and decreasing the activation of free fatty acid receptors (FFARs). Furthermore, HFD can increase the activation of the toll-like receptor (TLR) pathway. Hence, HFD by inducing inflammation, oxidative stress, endotoxemia, and hyperglycemia can increase the risk of IR. Therefore, this review aims to delineate the role of gut microbiota directly or indirectly involved in HFD-induced IR. These findings may clarify valuable preventive and therapeutic targets for countermeasures to IR in people who use the Western diet.

Keywords:  Diabetes mellitus; Gut microbiome; High fat diet; Insulin resistance

DOI:  https://doi.org/10.1016/j.metop.2025.100381
Sci Signal. 2025 Jul 29. 18(897): eadt6552

Proteomic analyses identify targets, pathways, and cellular consequences of oncogenic KRAS signaling.

Nicole Kabella, Florian P Bayer, Konstantinos Stamatiou, Miriam Abele, Amirhossein Sakhteman, Yun-Chien Chang, Vinona Wagner, Antje Gabriel, Johannes Krumm, Maria Reinecke, Melanie Holzner, Michael Aigner, Matthew The, Hannes Hahne, Florian Bassermann, Christina Ludwig, Paola Vagnarelli, Bernhard Kuster.

Mutations that activate the small GTPase KRAS are a frequent genetic alteration in cancer, and drug discovery efforts have led to inhibitors that block KRAS activity. We sought to better understand oncogenic KRAS signaling and the cytostatic effects of drugs that target this system. We performed proteomic analyses to investigate changes in protein abundance and posttranslational modifications in inhibitor-treated human KRAS-mutant pancreatic (KRAS G12C and G12D) and lung cancer (KRAS G12C) cells. The inhibitors used target these mutant forms of KRAS, the downstream effectors MEK and ERK, and the upstream regulators SHP2 and SOS1. Comparisons of phosphoproteomes between cell lines revealed a core KRAS signaling signature and cell line-specific signaling networks. In all cell lines, phosphoproteomes were dominated by different degrees of autonomous, oncogenic KRAS activity. Comparison of phosphoproteomes after short and long drug exposures revealed the temporal dynamics of KRAS-MEK-ERK axis inhibition that resulted in cell cycle exit. This transition to a quiescent state occurred in the absence of substantial proteome remodeling but included broad changes in protein phosphorylation and ubiquitylation. The collective data reveal insights into oncogenic KRAS signaling, place many additional proteins into this functional context, and implicate cell cycle exit as a mechanism by which cells evade death upon KRAS signaling inhibition.

DOI: https://doi.org/10.1126/scisignal.adt6552
Methods Mol Biol. 2025 ;2947 223-239

Comprehensive Prediction of Protein Localization and Signal Peptides Using MULocDeep.

Lei Jiang, Weinan Zhang, Shuai Zeng, Yuexu Jiang, Dong Xu.

  Localization of a protein within a cell encompasses various processes and signaling events, including guidance of signal peptides. Accurate prediction of subcellular and suborganellar protein localization, as well as signal peptides, is crucial for understanding protein function and provides valuable insights into cellular mechanisms. Although many computational methods can predict either general protein localization, suborganellar localization, or signal peptides, the lack of comprehensive and intuitive interpretation, insufficient coverage of localization types, and issues related to ease of use are some common limitations. In this chapter, we introduce MULocDeep, an advanced web server designed for the prediction of protein localization at both subcellular and suborganellar levels, as well as the identification of signal peptides and their corresponding cleavage sites. This web server integrates a sophisticated protein large language model, enabling highly accurate predictions and facilitating the interpretation of results. The server also includes multiple interactive interfaces that enhance the clarity and accessibility of predictions, particularly concerning motif patterns within protein sequences. Furthermore, we demonstrate the practical functionality of the MULocDeep web server, providing detailed instructions on how to utilize the server and interpret the results for both localization and signal peptide prediction. The MULocDeep web server is publicly available at https://www.mu-loc.org/ .

Keywords:  Cleavage site; Deep learning; Protein large language model; Protein localization; Signal peptide; Subcellular; Suborganellar; Web server

DOI:  https://doi.org/10.1007/978-1-0716-4662-5_13
Nutrients. 2025 Jul 17. pii: 2346. [Epub ahead of print]17(14):

Probiotic Potentials and Protective Effects of Ligilactobacillus animalis LA-1 Against High-Fat Diet-Induced Obesity in Mice.

Qingya Wang, Yuyin Huang, Kun Meng, Haiou Zhang, Yunsheng Han, Rui Zhang, Xiling Han, Guohua Liu, Hongying Cai, Peilong Yang.

  Background/Objectives: Obesity is increasingly recognized as a global health concern due to its association with metabolic disorders and gut microbiota dysbiosis. While probiotics offer promise in regulating gut microbiota and improving host metabolism, strain-specific effects remain underexplored, particularly for canine-derived probiotics. This study aimed to isolate and characterize a novel probiotic strain, Ligilactobacillus animalis LA-1, and evaluate its anti-obesity effects and underlying mechanisms using a high-fat diet (HFD)-induced obese mouse model. Methods: LA-1 was isolated from the feces of a healthy dog and assessed for probiotic potential in vitro, including gastrointestinal tolerance, bile salt hydrolase activity, cholesterol-lowering capacity, and fatty acid absorption. Male C57BL/6J mice were fed either a standard chow diet or an HFD for 16 weeks, with HFD mice receiving oral LA-1 supplementation (2 × 109 CFU/day). Multi-omics analyses, including 16S rRNA gene sequencing, short-chain fatty acid (SCFA) quantification, and untargeted liver metabolomics, were employed to investigate the effects of LA-1 on gut microbiota composition, metabolic pathways, and obesity-related phenotypes. Results: LA-1 supplementation significantly alleviated HFD-induced weight gain, hepatic lipid accumulation, and adipose tissue hypertrophy, without affecting food intake. It improved serum lipid profiles, reduced liver injury markers, and partially restored gut microbiota composition, decreasing the Firmicutes/Bacteroidetes ratio and enriching SCFA-producing genera. Total SCFA levels, particularly acetate, propionate, and butyrate, increased following LA-1 treatment. Liver metabolomics revealed that LA-1 modulated pathways involved in lipid and amino acid metabolism, resulting in decreased levels of acetyl-CoA, triglycerides, and bile acids. Conclusions: L. animalis LA-1 exerts anti-obesity effects via gut microbiota modulation, enhanced SCFA production, and hepatic metabolic reprogramming. These findings highlight its potential as a targeted probiotic intervention for obesity and metabolic disorders.

Keywords:  Ligilactobacillus animalis LA-1; SCFAs; amino acid metabolism; gut microbiota; high-fat diet; obesity; probiotic activities

DOI:  https://doi.org/10.3390/nu17142346