bims-cesirm 2025-06-22 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–06–22
28 papers selected by
Tigist Tamir, University of North Carolina

GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.
Cancer Progression and the Calcium Signaling Toolkit: Expanding Dimensions and Perspectives.
Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.
Regulatory mechanisms of PFKFB2 in glycolysis and tumor metabolism: implications for cancer therapy.
Proteome-wide characterization of PTMs reveals host cell responses to viral infection and identifies putative antiviral drug targets.
Targeting metabolic reprogramming to overcome immune tolerance in melanoma immunotherapy.
Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
Systematic analysis of the effects of splicing on the diversity of post-translational modifications in protein isoforms using PTM-POSE.
Biological and metabolomic insights into RACGAP1-mediated growth and progression of clear cell renal cell carcinoma.
Metabolic enzyme-associated protein-protein interactions (mPPIs) in cancer: potential vulnerability for cancer treatment?
Single-cell multi-omics reveals that FABP1 + renal cell carcinoma drive tumor angiogenesis through the PLG-PLAT axis under fatty acid reprogramming.
Causal impact of genetically determined metabolites on kidney cancer and its subtypes: an integrated mendelian randomization and metabolomic study.
Lactylation: the regulatory code of cellular life activity and a barometer of diseases.
Oxaloacetate promotes the transition from glycolysis to gluconeogenesis through the Akt-FoxO1 and JNK/c-Jun-FoxO1 axes and inhibits the survival of liver cancer cells.
Aerobic Exercise Pretreatment Mitigates Acute Lung Injury through Metabolic Reprogramming, Anti-inflammatory Modulation, and 6-Keto-Prostaglandin F1α Regulation.
The crucial role of metabolic reprogramming in driving macrophage conversion in kidney disease.
USP33-mediated stabilization of c-Myc drives glycolytic reprogramming and promotes ovarian cancer progression.
The role and mechanism of fatty acid oxidation in cancer drug resistance.
Lactate and lactylation modifications in neurological disorders.
Metabolic profiling of glioblastoma and identification of G0S2 as a metabolic target.
Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment.
Circulating metabolomics reveals guanosine monophosphate synthetase (GMPS) as a novel therapeutic target in lung adenocarcinoma.
Recent Overview of Protein Palmitoylation and Profiling Methodologies.
Mitigation of Ferroptosis in Diabetic Kidney Disease Through Mesenchymal Stem Cell Intervention via the Smad2/3/METTL3/S1PR1 Axis.
A Comprehensive Data Processing Pipeline for Phosphoproteomics in Viral Infection Studies.
SIRT3 regulates CPT1a acetylation and fatty acid oxidation in renal tubular epithelial cells under diabetic condition.
Sex-specific metabolic responses to high-fat diet in mice with NOX4 deficiency.
PUMA reduces FASN ubiquitination to promote lipid accumulation and tumor progression in human clear cell renal cell carcinoma.

Mol Cell Oncol. 2025 ;12(1): 2518773

GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.

Jenna N Duttenhefner, Katie M Reindl.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.

Keywords:  Pancreatic ductal adenocarcinoma; glutathione S-transferase pi 1 (GSTP1); metabolic reprogramming; metabolomics; therapeutic targeting

DOI:  https://doi.org/10.1080/23723556.2025.2518773
Cold Spring Harb Perspect Biol. 2025 Jun 16. pii: a041767. [Epub ahead of print]

Cancer Progression and the Calcium Signaling Toolkit: Expanding Dimensions and Perspectives.

Mélanie Robitaille, Gregory R Monteith.

Calcium signaling is a key controller of numerous cellular events and is intricately linked to many processes that are critical pathways in cancer progression. This review revisits the calcium signaling toolkit in cancer, with a focus on calcium regulation of processes that go beyond the originally defined "classic" hallmarks of cancer such as those associated with proliferation, metastasis, and resistance to cell death pathways. We will consider calcium signaling in the context of the more recently proposed hallmarks of cancer, emerging hallmarks, and cancer-enabling characteristics. This broader examination of calcium signaling and its toolkit members will encompass processes such as metabolic reprogramming, evasion of immune destruction, cellular phenotypic plasticity, senescence, genome instability, and nonmutational epigenetic reprogramming. These cancer features and their interactions with calcium signaling will frequently be analyzed through the lenses of therapy resistance and the complexities of the tumor microenvironment.

DOI: https://doi.org/10.1101/cshperspect.a041767
Int J Med Sci. 2025 ;22(11): 2852-2876

Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.

Xinyi Chen, Mu Yang, Lu Wang, Jingyao Tu, Xianglin Yuan.

  Metabolic reprogramming enables cancer cells to adapt to the tumor microenvironment, facilitating their survival, proliferation, and resistance to therapy. While glucose has long been considered the primary substrate for cancer cell metabolism, recent studies have highlighted the role of fructose as an alternative carbon source. Fructose metabolism, particularly through key enzymes such as ketohexokinase (KHK) and aldolase B (ALDOB), along with the fructose transporter GLUT5, supports tumor growth, metastasis, and therapeutic resistance. This review explores the mechanisms by which fructose metabolism influences cancer progression, focusing on its metabolic pathways and its impact on the tumor microenvironment. By promoting glycolysis, lipid biosynthesis, and nucleotide production, fructose metabolism enhances the metabolic adaptability of cancer cells, especially in glucose-deprived conditions. A comprehensive understanding of these processes offers potential insights into therapeutic strategies targeting fructose metabolism for cancer treatment. However, further studies are required to fully elucidate the complex role of fructose in various malignancies.

Keywords:  aldolase; fructose metabolism; glucose transporter; ketohexokinase; metabolic reprogramming; tumor metabolism

DOI:  https://doi.org/10.7150/ijms.108549
Carcinogenesis. 2025 Apr 03. pii: bgaf022. [Epub ahead of print]46(2):

Regulatory mechanisms of PFKFB2 in glycolysis and tumor metabolism: implications for cancer therapy.

Qiuwen Lou, Jie Chang, Yi Pan, Yuzhuo Gong, Wenxia Xu, Minfeng Tong, Lude Wang, Fengfeng Jiang.

  Glycolysis is a crucial metabolic process that facilitates the rapid proliferation of cancer cells. Phosphofructokinase-1 (PFK-1) is the key rate-limiting enzyme in glycolysis, with fructose-2,6-diphosphate (F-2,6-BP) acting as its most effective regulator. The levels of F-2,6-BP are closely correlated with the activity of 6-phosphate fructose-2-kinase/fructose-2,6-diphosphatase (PFK-2/FBPase-2, PFKFB). The PFKFB family consists of four isoenzymes: PFKFB1-4. Most evidence suggests that PFKFB activity is essential for activating glycolytic and oncogenic properties in tumor cells. However, previous studies have focused predominantly on PFKFB3 and PFKFB4, with relatively few investigating PFKFB2. The role of PFKFB2 in cancer is complex and multifaceted, encompassing various aspects of tumor metabolism, cell migration, invasion, and the immune response. Consequently, this review aims to summarize the current understanding of the gene structure and biological function of PFKFB2 and to explore its pathogenic mechanisms in different cancers. Additionally, we highlight the metabolic signaling pathways associated with PFKFB2. This review seeks to provide insights into the current status of PFKFB2 and to assist in identifying new targets for cancer therapy.

Keywords:  6-BP; Cancer; F-2; Glycolysis; PFKFB2

DOI:  https://doi.org/10.1093/carcin/bgaf022
Front Immunol. 2025 ;16 1587106

Proteome-wide characterization of PTMs reveals host cell responses to viral infection and identifies putative antiviral drug targets.

Xiaolu Li, Adam Kabza, Ashley N Ives, Julianne Thiel, Katrina M Waters, Wei-Jun Qian, Amy C Sims, Tong Zhang.

  Post-translational modifications (PTMs) are biochemical modifications that can significantly alter protein structure, function, stability, localization, and interactions with other molecules, thereby activating or inactivating intracellular processes. A growing body of research has begun to highlight the role of PTMs, including phosphorylation, ubiquitination, acetylation, and redox modifications, during virus-host interactions. Collectively, these PTMs regulate key steps in mounting the host immune response and control critical host pathways required for productive viral replication. This has led to the conception of antiviral therapeutics that focus on controlling host protein PTMs, potentially offering pathogen-agnostic treatment options and revolutionizing our capacity to prevent virus transmission. On the other hand, viruses can hijack the host cellular PTM machinery to modify viral proteins in promoting viral replication and evading immune surveillance. PTM regulation during virus-host interactions is complex and poorly mapped, and the development of effective PTM-targeted antiviral drugs will require a more comprehensive understanding of the cellular pathways essential for virus replication. In this review, we discuss the roles of PTMs in virus infection and how technological advances in mass spectrometry-based proteomics can capture systems-level PTM changes during viral infection. Additionally, we explore how such knowledge is leveraged to identify PTM-targeted candidates for developing antiviral drugs. Looking ahead, studies focusing on the discovery and functional elucidation of PTMs, either on the host or viral proteins, will not only deepen our understanding of molecular pathology but also pave the way for developing better drugs to fight emerging viruses.

Keywords:  PTMs; acetylation; antiviral drug; phosphorylation; proteome; redox; ubiquitination; viral infection

DOI:  https://doi.org/10.3389/fimmu.2025.1587106
Front Immunol. 2025 ;16 1597770

Targeting metabolic reprogramming to overcome immune tolerance in melanoma immunotherapy.

Qinchen Wang, Lei Shi, Daoming Shi, Ningzheng Tai, Xu Wang.

  Significant advances in the treatment of melanoma, the most aggressive form of skin cancer, have been achieved via immunotherapy. Despite these improvements, therapeutic resistance remains a formidable challenge, compromising the treatment efficacy and patient outcomes. This review delves into the intricate mechanisms driving immunotherapy resistance in melanoma, emphasizing alterations in key metabolic pathways, changes within the tumor microenvironment, and the critical role of the gut microbiota. This review also examines how metabolic reprogramming supports tumor proliferation and immune evasion, it highlights the impact of extracellular acidification and angiogenic processes on resistance development. By synthesizing current insights, this review emphasizes the importance of targeting these multifaceted interactions to overcome resistance, thereby paving the way for more effective and durable therapeutic strategies in melanoma treatment.

Keywords:  gut microbiota; immune tolerance; immunotherapy; melanoma; metabolic pathways; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1597770
Biochim Biophys Acta Rev Cancer. 2025 Jun 11. pii: S0304-419X(25)00115-5. [Epub ahead of print]1880(4): 189373

Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.

Fan Gao, Kang Sun, Sicheng Wang, Xiaozhen Zhang, Xueli Bai.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.

Keywords:  GPR81; Lactate metabolism; Lactylation; Metabolic reprogramming; PDAC; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189373
Cell Syst. 2025 Jun 06. pii: S2405-4712(25)00151-6. [Epub ahead of print] 101318

Systematic analysis of the effects of splicing on the diversity of post-translational modifications in protein isoforms using PTM-POSE.

Sam Crowl, Maeve Bella Coleman, Andrew Chaphiv, Ben T Jordan, Kristen M Naegle.

  Post-translational modifications (PTMs) and splicing are both important regulatory processes controlling protein function; therefore, we developed PTM-POSE (PTM projection onto splice events) to explore the interplay between them. PTM-POSE identifies potential PTM sites associated with alternative isoforms or splice events, enabling comprehensive analysis of how PTMs affect isoform function, protein interactions, and enzymatic regulation. Through systematic analysis of Ensembl transcripts with PTM-POSE, we highlighted two key mechanisms by which splicing diversifies PTMs across isoforms-exclusion of a PTM site (32%) or alteration of the flanking sequences surrounding the PTM (2%). In experiment-specific analysis of PTM-associated splicing events, we identified the potential rewiring of protein-interaction and kinase-substrate networks, suggesting coordinated connections between PTM signaling. We provide our tool and associated data publicly to enable further exploration of splicing-PTM relationships. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords:  ESRP1; SGK; alternative splicing; cancer; linear motifs; phosphorylation; post-translational modifications; protein isoforms

DOI:  https://doi.org/10.1016/j.cels.2025.101318
Am J Physiol Cell Physiol. 2025 Jun 16.

Biological and metabolomic insights into RACGAP1-mediated growth and progression of clear cell renal cell carcinoma.

Wanyi Li, Lingling Gan, Wenting Zang, Yan Chen, Bei Xu.

  Rac-GTPase-activating protein 1 (RACGAP1) is a member of the Rho GTPase-activating protein (GAP) family, which is involved in the process of cytokinesis. But its precise function in clear cell renal cell carcinoma (ccRCC) has not been extensively investigated. In this study, we found that RACGAP1 was regulated by centrosomal protein CEP55 and markedly facilitated the growth and progression of ccRCC in vitro and in vivo. In addition, RACGAP1 knockdown induces G1 phase arrest, resulting in mitotic disorder and subsequent apoptosis. These findings indicated that RACGAP1, a cell cycle-related gene, is crucial for the survival and growth of ccRCC. Furthermore, renal cancer is closely associated with metabolic processes. As demonstrated by our serum-targeted metabolomics study, RACGAP1 dysfunction altered the levels of multiple amino acids/amino acid derivatives, acylcarnitines, fatty acids/acyls, nucleotides and their metabolites. Spatial metabolomics data further confirmed that down-regulation of RACGAP1 expression could inhibit ccRCC growth not only by reprogramming fatty acid and nucleotide metabolism, but also by interfering with lipid metabolism. More importantly, we detected higher levels of glutamine, acylcarnitines and lipids in the tumor margin region, suggesting intra-tumor metabolic heterogeneity in ccRCC. In conclusion, this study elucidated the biological function of RACGAP1 in promoting ccRCC progression, and revealed the regulatory mechanism of RACGAP1 in interfering with metabolic pathways from the perspective of multidimensional metabolomics. These findings will provide new targets and a theoretical basis for the treatment of RCC.

Keywords:  Metabolomics; Oncology; RACGAP1; cell-cycle regulation; clear cell renal cell carcinoma; spatial metabolomics; targeted metabolomics

DOI:  https://doi.org/10.1152/ajpcell.00066.2025
Acta Pharmacol Sin. 2025 Jun 20.

Metabolic enzyme-associated protein-protein interactions (mPPIs) in cancer: potential vulnerability for cancer treatment?

Yu-Ting Tang, Tian-Yi Chen, Zi-Yi Liu, Ming-Yu Luo, Miao-Miao Gong, Ying Shen.

  Cancer metastasis and drug resistance are intricately linked processes that drive cancer progression and poor prognosis. One of the hallmarks of cancer is metabolic reprogramming, which evolves at various stages of tumor metastasis and drug resistance progression. This reprogramming involves the dysregulation of metabolic enzymes, which not only regulate the metabolic status in cancer cells, but also play multifunctional roles through influencing downstream signaling networks, acting as protein kinases, post-translational modifications and multiple biological processes, thereby exacerbating cancer malignancy. This review focuses on the metabolic enzyme-associated protein-protein interactions (mPPIs) during tumor metastasis and therapeutic resistance, and discusses the roles of key enzymes in glycolysis, the serine synthesis pathway, the pentose phosphate pathway, the glucuronate pathway and the sorbitol pathway. Understanding the distinct multifunctionality of these metabolic enzymes is crucial for gaining valuable insights into cancer pathogenesis and identifying potential therapeutic vulnerability to combat metastatic progression and overcome therapy resistance.

Keywords:  cancer metastasis; drug resistance; glucose metabolism; metabolic enzyme-associated protein-protein interactions; metabolic enzymes

DOI:  https://doi.org/10.1038/s41401-025-01601-y
Mol Cancer. 2025 Jun 16. 24(1): 179

Single-cell multi-omics reveals that FABP1 + renal cell carcinoma drive tumor angiogenesis through the PLG-PLAT axis under fatty acid reprogramming.

Yiqiu Wang, Yingchun Liang, Min Li, Jiayi Lu, Sian Zhou, Yaoyu Yu, Changwei Yang, Xinhuang Hou.

  Renal cell carcinoma is characterized by a poor prognosis. Recently, renal cell carcinoma has been recognized as a metabolic disease associated with fatty acid metabolic reprogramming, although in-depth studies on this topic are still lacking. We found that fatty acid metabolism reprogramming in renal cell carcinoma is primarily characterized by high expression of FABP1. FABP1 + tumors significantly impact survival and display distinct differentiation trajectories compared to other tumor subclusters. They show elevated expression of angiogenesis and cell migration signals, with PLG-PLAT-mediated interactions with endothelial cells notably enhanced. Spatial transcriptomics show a prominent co-localization of FABP1 + tumors with endothelial cells, and their spatial distribution closely aligns with that of PLAT + endothelial cells. FABP1 + tumors exhibit a unique pattern in spatial transcriptomics, enriched in Extracellular Matrix and angiogenesis-related pathways. Through receptor-ligand interaction analysis, a novel PLG-PLAT functional axis was found between tumor epithelial cells and endothelial cells. Based on results of experiments, we infer that FABP1 + tumors can promote plasmin-related tumor angiogenesis by triggering the PLG-PLAT signaling axis. Finally, utilizing preclinical models, we suggest that targeting the FABP1-PLG-PLAT axis may serve as promising strategy enhancing the sensitivity of Tyrosine Kinase Inhibitor therapy.

Keywords:  FABP1; Fatty acid metabolism; Multi-Omics; Renal cell carcinoma; Tumor angiogenesis

DOI:  https://doi.org/10.1186/s12943-025-02377-9
Am J Cancer Res. 2025 ;15(5): 2222-2242

Causal impact of genetically determined metabolites on kidney cancer and its subtypes: an integrated mendelian randomization and metabolomic study.

Zheng Wang, Zhao Huangfu, Tao Liu, Yuan Li, Yuchen Gao, Xinxin Gan, Xiaofeng Wu, Shu Chen, Xiaomin Li, Linhui Wang, Xiaofeng Gao.

  Metabolic dysregulation is a hallmark of kidney cancer, yet the causal roles of specific metabolites in its major subtypes remain unclear. This study aimed to elucidate the causal relationships between circulating metabolites and the three primary subtypes of kidney cancer - clear cell renal cell carcinoma (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC) - and to identify potential diagnostic and therapeutic targets. A total of 1,400 circulating metabolites and metabolic ratios were evaluated as exposures, with kidney cancer outcomes derived from the FinnGen database. Genetic instruments were selected from genome-wide association studies (GWAS) and harmonized with outcome data. Mendelian randomization (MR) analyses were conducted using the inverse-variance weighted (IVW) method as the primary approach, supported by multiple sensitivity analyses, including Cochran's Q test, MR-Egger regression, leave-one-out analysis, and MR-PRESSO. To correct for multiple testing, metabolites were stratified into absolute levels and metabolic ratios, and the Benjamini-Hochberg false discovery rate (FDR) procedure was applied separately within each category. Causally associated metabolites were further analyzed via KEGG pathway enrichment. For clinical validation, untargeted metabolomic profiling was performed on paired tumors and adjacent normal tissues from 48 patients with ccRCC. In total, 85 metabolites were found to be causally associated with kidney cancer, including 57 for ccRCC, 71 for pRCC, and 51 for chRCC. After FDR correction, three metabolites remained statistically significant: carnitine (overall RCC: OR = 1.25, PFDR = 0.032), trigonelline (overall RCC: OR = 1.25, PFDR = 0.049), and gamma-glutamylthreonine (chRCC: OR = 2.90, PFDR = 0.012). KEGG analysis revealed significant enrichment in the valine, leucine, and isoleucine biosynthesis pathway for ccRCC (P = 1.2 × 10-5), and pyrimidine metabolism for chRCC (P = 6.5 × 10-6). Metabolomic profiling of ccRCC tissues confirmed aberrant levels of seven metabolites, including elevated 2-hydroxyglutarate (fold change [FC] = 3.1, P = 0.001) and reduced citrate (FC = 0.4, P = 0.001), both associated with disease progression. In conclusion, this integrative study identified carnitine and trigonelline as potential contributors to RCC progression, while gamma-glutamylthreonine appears to be specifically involved in chRCC pathogenesis. Additionally, altered expression of sphingosine 1-phosphate, acetylcarnitine, gamma-glutamylglutamine, and N-acetylcytidine in ccRCC highlights key metabolic disruptions and underscores their potential as novel biomarkers and therapeutic targets in kidney cancer.

Keywords:  Mendelian randomization (MR); Metabolomics; carnitine; clear cell renal cell carcinoma (ccRCC); kidney cancer; metabolic pathways; sphingosine

DOI:  https://doi.org/10.62347/VUZH4644
Cell Oncol (Dordr). 2025 Jun 16.

Lactylation: the regulatory code of cellular life activity and a barometer of diseases.

Xuebing Xu, Xuming Wu, Dandan Jin, Jie Ji, Tong Wu, Mengxiang Huang, Junpeng Zhao, Zihan Shi, Lirong Zhou, XuYang He, Yuxuan Huang, Shihai Xuan, Mingbing Xiao, Xiaolei Cao.

Lactylation is a novel post-translational modification of proteins, which has attracted extensive attention since its discovery. Lactylation takes lactate, a common metabolite, as its substrate and mediates the modification under the action of lactyltransferases. Although lactylation modification was initially found to undergo in histones, subsequent studies have shown that this novel modification is not limited to specific protein classes, and can undergo in both histone and non-histone proteins. Lactylation has been proved to play an important regulatory role in a variety of diseases, including tumors, metabolic disorders, cardiovascular diseases, and neurodegenerative diseases. Given the tumor properties of its substrate lactate, lactylation has been most extensively studied in tumors, and as a result, we have gained a deeper understanding of the potential molecular mechanisms and regulatory roles of lactylation in tumors. In this paper, we will summarize the regulatory and functional mechanisms of lactylation, explain the cellular processes in which lactylation is involved and its association with various diseases, and look forward to the future clinical application of lactylation.

DOI: https://doi.org/10.1007/s13402-025-01083-4
Int Immunopharmacol. 2025 Jun 12. pii: S1567-5769(25)01041-0. [Epub ahead of print]161 115051

Oxaloacetate promotes the transition from glycolysis to gluconeogenesis through the Akt-FoxO1 and JNK/c-Jun-FoxO1 axes and inhibits the survival of liver cancer cells.

Zeyu Miao, Yan Liu, Yang Xu, Jiarui Bu, Qing Yang.

   BACKGROUND: Unlike other gluconeogenesis activators, oxaloacetate serves as both a metabolic intermediate and a signaling molecule, offering unique advantages in cancer therapy. This study explores the therapeutic potential of oxaloacetate in hepatocellular carcinoma, focusing on its impact on glucose metabolism, cell apoptosis, and intracellular signaling pathways.
METHODS: Utilizing bioinformatics analysis, we evaluated the metabolic flux of glucose in tumors and conducted differential and prognostic analyses of gluconeogenesis genes. Techniques such as transfection were employed to manipulate FoxO1 expression and Akt activity. GSH and NAC were used as antioxidants. Key enzyme activities, FoxO1 expression, cell viability, apoptosis-related proteins, ROS levels, and cell cycle progression were measured. Additionally, TUNEL apoptosis staining was performed.
RESULTS: Oxaloacetate promotes a glucose metabolic shift toward gluconeogenesis and induces apoptosis in cancer cells via FoxO1. In a mouse xenograft model, oxaloacetate treatment significantly reduced tumor size. Notably, tumors overexpressing Akt were larger, but their growth was also diminished following oxaloacetate treatment. FoxO1 expression and apoptosis-related proteins were elevated in oxaloacetate treated tumors. Oxaloacetate inhibits Akt phosphorylation and activates the JNK/c-Jun pathway, enhancing FoxO1 activity through dual mechanisms.
CONCLUSIONS: Oxaloacetate not only inhibits tumor proliferation through metabolic pathways but also acts as a signaling molecule influencing tumor growth via multiple signaling cascades. It disrupts liver cancer cell energy homeostasis and selectively targets glycolysis-addicted cancer cells. Furthermore, its endogenous presence and prior demonstration of safety in humans at relatively high doses highlight its potential for clinical translation in cancer therapy.

Keywords:  FoxO1; Gluconeogenesis; Liver cancer; Oxaloacetate

DOI:  https://doi.org/10.1016/j.intimp.2025.115051
Free Radic Biol Med. 2025 Jun 16. pii: S0891-5849(25)00773-7. [Epub ahead of print]

Aerobic Exercise Pretreatment Mitigates Acute Lung Injury through Metabolic Reprogramming, Anti-inflammatory Modulation, and 6-Keto-Prostaglandin F1α Regulation.

Xishuai Wang, Shunqiang Nong, Qibao Zheng, Congcong Zhao, Chao Yi, Simin Li, Lunan Zhao, Xiliang Kong, Yuehui Zhou, Depeng Dong, Weina Niu, Zhuo Chen, Cong Liu, Wei Zhao, Zhuo Sun, Jie Wei, Yang Lv, Lichang Yang, Xin Jin, Shanshan Cai, Di Wu, Fugao Jiang.

   OBJECTIVE: Although moderate physical exercise improves outcomes in pulmonary diseases such as acute lung injury (ALI), the underlying mechanisms, particularly those involving metabolic reprogramming, remain poorly defined. We investigated the impact of aerobic exercise (AE) pretreatment on metabolic pathways, inflammatory responses, and survival in ALI.
METHODS: ALI model mice were induced through intratracheal lipopolysaccharide (LPS) after a 4-week AE protocol. Key assessments included histopathological evaluation, cytokine quantification, survival analysis, and serum metabolomic profiling.
RESULTS: AE pretreatment significantly reduced mortality, attenuated lung damage, and suppressed neutrophil-driven inflammation. Mechanistically, AE restored LPS-induced metabolic dysregulation by normalizing ATP/ADP and NAD+/NADH ratios, phosphocreatine levels, and glucose-insulin homeostasis, in addition to decreasing lactate accumulation. Metabolomic analysis identified 991 differentially expressed metabolites (DEMs) between the Con and ALI groups, predominantly enriched in metabolic pathways, biosynthesis of unsaturated fatty acids, and linoleic acid metabolism, with arachidonic acid emerging as a critical upregulated hub node. In addition, 190 DEMs were identified between the AE+ALI and ALI groups, predominantly enriched in linoleic acid metabolism, metabolic pathways, and arachidonic acid metabolism, with linoleic acid and arachidonic acid emerging as critical upregulated hub nodes. AE pretreatment markedly suppressed the LPS-induced activation of the linoleic acid-arachidonic acid-6-keto-PGF1α signaling axis, which was aberrantly upregulated during ALI progression. Suppressing 6-keto-PGF1α activity using U51605 markedly alleviated the inflammatory response and tissue damage associated with ALI.
CONCLUSIONS: AE pretreatment confers protection against ALI by orchestrating metabolic reprogramming to enhance anti-inflammatory responses. AE pretreatment attenuates LPS-induced ALI by reprogramming linoleic acid and arachidonic acid metabolism, thereby suppressing 6-keto-PGF1α biosynthesis. Pharmacological inhibition of 6-keto-PGF1α significantly alleviated ALI severity and mortality. These findings highlight AE as a preventive strategy and identify 6-keto-PGF1α as a therapeutic target for inflammatory lung injury.

Keywords:  acute lung injury; aerobic exercise pretreatment; linoleic acid-arachidonic acid-6-keto-PGF1α signaling axis; metabolic reprogramming; metabolomics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.024
Cell Mol Biol Lett. 2025 Jun 16. 30(1): 72

The crucial role of metabolic reprogramming in driving macrophage conversion in kidney disease.

Na Gong, Wenjuan Wang, Yifei Fu, Xumin Zheng, Xinru Guo, Yuhao Chen, Yan Chen, Shengchun Zheng, Guangyan Cai.

  Interstitial fibrosis after acute kidney injury is an ongoing pathological process of chronic inflammatory injury and repair. Macrophages participate in renal inflammation, repair and fibrosis by continuously changing their phenotype and function. The tissue microenvironment of kidney injury induces changes in key metabolic enzymes, pathways and metabolites in macrophages, leading to phenotypic and functional conversions, but the detailed mechanisms are unclear. However, in the early phase of acute kidney injury, macrophages shift to a pro-inflammatory role relying on glycolysis and pentose phosphate pathways. The tissue microenvironment regulates the suppression of glycolysis-related genes and the up-regulation of oxidative phosphorylation and tricarboxylic acid cycle genes in macrophages, resulting in a gradual shift to an anti-inflammatory phenotype, which is involved in tissue repair and remodelling. In the late stage of injury, if macrophages continue to be overactive, they will be involved in renal fibrosis. The concomitant enhancement of nucleotide and amino acid metabolism, especially arginine and glutamine metabolism, is critical for the macrophage function and phenotypic transition during the above injury process. Macrophage metabolic reprogramming therefore provides new therapeutic targets for intervention in inflammatory injury and interstitial fibrosis in kidney disease.

Keywords:  Inflammation; Injury and repair; Kidney fibrosis; Macrophages; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s11658-025-00746-2
Biochim Biophys Acta Gen Subj. 2025 Jun 16. pii: S0304-4165(25)00075-3. [Epub ahead of print] 130830

USP33-mediated stabilization of c-Myc drives glycolytic reprogramming and promotes ovarian cancer progression.

Dejia Chen, Yue Zhao, Xiaobo Zhang, Xiaocheng Shi, Yiming Liu, Ge Lou.

  Ovarian cancer (OC) is one of the most lethal gynecological malignancies, characterized by late-stage presentation, high recurrence rates, and a lack of effective early diagnostic markers. Recent evidence suggests that deubiquitinating enzymes (DUBs) play pivotal roles in tumor development and metabolic reprogramming. Here, we identify and characterize the function of the deubiquitinase USP33 in regulating c-Myc stability and glycolytic metabolism in OC. Through quantitative PCR (qPCR) and Western blot analyses, we show that USP33 is significantly upregulated in both OC tissues and cell lines compared to normal controls. Functional assays reveal that USP33 knockdown markedly inhibits cell proliferation, migration, and invasion while promoting apoptosis. Metabolically, USP33 silencing reduces glucose uptake, lactate production, and the extracellular acidification rate, consistent with downregulation of key glycolytic enzymes (LDHA, GLUT1, and PKM2). Mechanistically, co-immunoprecipitation and ubiquitination assays demonstrate that USP33 interacts with and deubiquitinates c-Myc at K48-linked chains, thereby stabilizing c-Myc protein levels and enhancing its transcriptional activity. Moreover, c-Myc overexpression rescues the inhibitory effects of USP33 knockdown on both glycolysis and malignant phenotypes. Clinically, high USP33 expression correlates with poor prognosis, suggesting that the USP33-c-Myc axis may serve as both a prognostic biomarker and a potential therapeutic target. Taken together, our findings highlight a critical role for USP33 in OC pathogenesis by mediating c-Myc-driven glycolytic reprogramming, and they provide new insights for developing targeted treatment strategies aimed at disrupting this pathway.

Keywords:  C-Myc; Deubiquitination; Glycolysis; Metabolic reprogramming; Ovarian cancer; SP33

DOI:  https://doi.org/10.1016/j.bbagen.2025.130830
Cell Death Discov. 2025 Jun 13. 11(1): 277

The role and mechanism of fatty acid oxidation in cancer drug resistance.

Yun Lei, Shuang Cai, Jia-Kui Zhang, Si-Qi Ding, Zhan-He Zhang, Chun-Dong Zhang, Dong-Qiu Dai, Yong-Shuang Li.

Cancer is a leading cause of death globally. While drug treatment is the most commonly used method for cancer therapy, it is often hampered by drug resistance. Consequently, the mechanisms of drug resistance in cancer therapy have become a focus of current research. The mechanisms underlying cancer drug resistance are complex and may involve genetic mutation, immune escape, and metabolic reprogramming, amongst others. Metabolic reprogramming is an important marker of tumor cells, and an increasing number of studies have shown that cancer drug resistance is correlated with metabolic reprogramming, especially when fatty acid oxidation (FAO) is involved. More importantly, many preclinical studies have shown that when anti-tumor drugs are combined with FAO inhibitors, cancer cell resistance to drugs can be reversed and the effectiveness of tumor therapy is enhanced. This review provides a comprehensive overview of the mechanisms by which FAO leads to cancer resistance as well as potential targets for inhibition of FAO.

DOI: https://doi.org/10.1038/s41420-025-02554-1
Neural Regen Res. 2025 Jun 19.

Lactate and lactylation modifications in neurological disorders.

Yu Gu, Keyang Chen, Chunyan Lei, Xinglong Yang, Lu Wang, Linhu Zhao, Wen Jiang, Qionghua Deng.

   ABSTRACT: Research into lactylation modifications across various target organs in both health and disease has gained significant attention. Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications. Lactate, once considered merely a byproduct of anaerobic metabolism, has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system. Furthermore, recent studies have emphasized the significant role of lactate in numerous neurological diseases, including Alzheimer's disease, Parkinson's disease, acute cerebral ischemic stroke, multiple sclerosis, Huntington's disease, and myasthenia gravis. The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases, aiming to clarify their mechanisms of action and identify potential therapeutic targets. As such, this work provides an overview of the metabolic regulatory roles of lactate in various disorders, emphasizing its involvement in the regulation of brain function. Additionally, the specific mechanisms of brain lactate metabolism are discussed, suggesting the unique roles of lactate in modulating brain function. As a critical aspect of lactate function, lactylation modifications, including both histone and non-histone lactylation, are explored, with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications, such as lactylation writers and erasers. The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized, revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders. Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.

Keywords:  astrocyte-neuron lactate shuttle theory; brain functions; brain lactate metabolism; central nervous system; histone lysine lactylation; monocarboxylate transporters; nervous system; neurodegenerative diseases; non-histone lysine lactylation; post-translational modifications

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01344
Front Oncol. 2025 ;15 1572040

Metabolic profiling of glioblastoma and identification of G0S2 as a metabolic target.

Jianlei Kang, Yujie Xu, Qitai Zhao, Ying Wang, Zhenyan He, Xin Xu.

   Introduction: Metabolic reprogramming is a hallmark of cancer, yet its role in glioma remains poorly understood. Gliomas are characterized by a highly immunosuppressive tumor microenvironment (TME) and poor prognosis. This study systematically explores the relationship between glioma metabolomics, tumor phenotype, and the immune microenvironment.
Methods: Bulk RNA sequencing data were retrieved from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). Single-cell gene set enrichment analysis (ssGSEA) was employed to quantify seven nutrient metabolic pathways and immune infiltration. Consensus clustering was applied to group gliomas based on metabolic gene expression, and survival analysis was performed to evaluate survival differences across these clusters. A predictive model was constructed and validated using our cohort. Finally, we knocked out G0S2 in glioma cells and performed RNA sequencing to investigate differentially activated pathways. Additionally, in vivo experiments were conducted to explore the antitumor effects of G0S2 knockout in combination with PD-1 monoclonal antibody.
Results: Significant metabolic differences were identified between low-grade gliomas (LGG) and glioblastomas (GBM), with consistent findings across both databases. We found that LGGs and GBMs exhibit distinct metabolic patterns. Consensus clustering revealed three metabolic subgroups, with the C3 subgroup demonstrating poor survival and enhanced infiltration of immunosuppressive cells. The predictive model showed robust performance in forecasting the survival of glioma patients. Functional analysis identified G0S2 as a key metabolic regulator highly expressed in gliomas. G0S2 knockout activated the type I interferon signaling pathway, enhanced CD8+ T cell functionality, and synergized with anti-PD-1 therapy, resulting in suppressed tumor growth and prolonged survival in vivo.
Conclusion: These findings provide a comprehensive analysis of glioma metabolic patterns and identify G0S2 as a promising therapeutic target.

Keywords:  GOS2; glioma; metabolic reprogramming; predictive model; type I interferon

DOI:  https://doi.org/10.3389/fonc.2025.1572040
Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2427211122

Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment.

Judit Liaño-Pons, Elisa Garde-Lapido, Fenja L Fahrig, Merle Jäckering, Ye Yuan, Stina Andersson, Lea Schort, Maria Esteve, Sofie Mohlin, Oscar C Bedoya-Reina, Marie Arsenian-Henriksson.

  Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of the MYCN oncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming in NB, including upregulation of antioxidant enzymes. Here, we identify peroxiredoxin 6 (PRDX6) as a promising therapeutic target in NB. Pharmacological inhibition of PRDX6 reduces MYCN levels, induces apoptosis, and promotes neuronal differentiation accompanied by lipid droplet accumulation, essential for the phenotypic reprogramming. Moreover, combined inhibition of PRDX6 and glutathione S-transferase Pi 1 (GSTP1), a key antioxidant enzyme needed for PRDX6 activation, demonstrated synergistic effects both in vitro and in vivo. This strategy results in neuronal maturation as well as activity and initiates downstream pathways distinct from the ones triggered by retinoic acid, the differentiation-inducing agent currently used in clinical practice for NB. Notably, both PRDX6 and GSTP1 are highly expressed in the developing murine adrenal gland, as well as in high-risk, MYCN-amplified NB, correlating with an undifferentiated state and poor prognosis. Together, our results provide insights into the potential of PRDX6 and GSTP1 as therapeutic targets for differentiation induction for children with NB.

Keywords:  antioxidants; childhood cancer; differentiation-inducing therapy; neuroblastoma; oxidative stress

DOI:  https://doi.org/10.1073/pnas.2427211122
J Pathol. 2025 Jun 20.

Circulating metabolomics reveals guanosine monophosphate synthetase (GMPS) as a novel therapeutic target in lung adenocarcinoma.

Mengjie Yu, Dou Yang, Danxia Zhu, Yue Wang, Minmin Cao, Jingfeng Zhu, Wei Zhu, Guangji Wang, Jiye Aa.

  Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alterations in early-stage LUAD. Using an unbiased, large-scale metabolomics analysis of 2,531 plasma and serum samples from three independent clinical centers, we identified significant perturbations in purine metabolism that characterized reprogrammed metabolism in early-stage LUAD. Additionally, hypoxanthine (p < 0.001) and xanthine (p < 0.05) were identified as two typical early risk indicators, with odd ratios (ORs) more than 2.8 and 1.45, respectively. Guanosine monophosphate synthetase (GMPS) was identified as a pivotal factor in the early development and malignant progression of LUAD. Progression of LUAD was significantly attenuated by GMPS knockdown and markedly exacerbated by its overexpression. Further data indicated that GMPS primarily contributed to the reprogrammed metabolic phenotypes of LUAD through its enzymatic activity and subsequent production of purine nucleotides, based on the relative abundance of the labeled isotope metabolites. Collectively, dysregulated purine metabolism emerged as a key characteristic of early-stage LUAD, and targeting GMPS activity may offer a promising therapeutic potential for LUAD treatment. © 2025 The Pathological Society of Great Britain and Ireland.

Keywords:  GMPS; LUAD; hypoxanthine; metabolomics; purine metabolism; xanthine

DOI:  https://doi.org/10.1002/path.6442
Methods Mol Biol. 2025 ;2921 361-370

Recent Overview of Protein Palmitoylation and Profiling Methodologies.

Changyan Jin, Qiaoling Yuan, Zhipeng Tao.

  Protein palmitoylation is a reversible posttranslational modification in which a palmitoyl group (a 16-carbon saturated fatty acid) is covalently attached to cysteine residues on proteins, typically through a thioester bond. This modification affects the protein's hydrophobicity, influencing its membrane association, localization, stability, trafficking, and overall function. Dysregulation of palmitoylation has been implicated in diseases such as cancer, neurodegenerative diseases, and cardiovascular disorders. In this review, we summarize the recent findings related to protein palmitoylation and its biological functions. More importantly, we examine proteomic studies that utilize active-based protein profiling (ABPP) to design novel probes or inhibitors aimed at enhancing the accuracy and efficiency of large-scale analyses of protein palmitoylation. These advancements will facilitate the findings of novel therapeutic targets and the designing of targeted therapies, providing increasingly critical insights into the role of this modification in health and diseases.

Keywords:  Active-based protein profiling; Chemical probes; Palmitoylation

DOI:  https://doi.org/10.1007/978-1-0716-4502-4_20
FASEB J. 2025 Jun 30. 39(12): e70714

Mitigation of Ferroptosis in Diabetic Kidney Disease Through Mesenchymal Stem Cell Intervention via the Smad2/3/METTL3/S1PR1 Axis.

Li-Lan Huang, Yue-Yuan Hou, Ji Yang, Xing-Na Liao, Jin-Sha Ma, Wen-Chao Wang, Yi-Xiao Quan, Hong-Ying Jiang, Yi-Hua Bai.

  Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and is associated with heightened cardiovascular risk and increased overall mortality. Although mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in DKD, their precise mechanisms of action have not been fully elucidated. This study aimed to investigate the involvement of Smad signaling, N6-methyladenosine (m6A) modifications, and ferroptosis in MSC-mediated treatment of DKD. Cellular and animal models of DKD were used to evaluate MSC intervention effects, supported by gene knockdown and overexpression experiments. Protein expression and phosphorylation levels of Smad2/3, m6A-associated enzymes, and markers of ferroptosis were assessed. Additionally, transcriptional targets associated with ferroptosis were identified through integrated transcriptome and m6A methylation sequencing analyses, followed by subsequent validation. Elevated Smad2/3 phosphorylation and ferroptosis were observed in DKD, while MSC interventions effectively alleviated these processes, resulting in improved renal lesions. Furthermore, MSC treatment reduced the heightened levels of m6A modification observed in DKD. Mechanistic investigations identified methyltransferase-like 3 (METTL3) as a key regulator of m6A modification in DKD. Suppression of METTL3 reversed the upregulated m6A modification and ferroptosis induced by Smad2 overexpression. Importantly, sphingosine-1-phosphate receptor 1 (S1PR1) was identified as a protective target gene against ferroptosis in DKD. In DKD models, Smad2 facilitated the m6A modification of the S1PR1 gene by interacting with METTL3 following its nuclear translocation, thereby influencing S1PR1 expression and promoting cellular ferroptosis. Intervention with MSCs mitigated this process, providing further insights into the regulatory mechanisms through which MSCs modulate ferroptosis in podocytes affected by DKD.

Keywords:   S1PR1 ; METTL3; Smads; diabetic kidney disease; ferroptosis; human umbilical cord mesenchymal stem cells

DOI:  https://doi.org/10.1096/fj.202403207R
Methods Mol Biol. 2025 ;2921 275-291

A Comprehensive Data Processing Pipeline for Phosphoproteomics in Viral Infection Studies.

Sini Huuskonen, Xiaonan Liu, Kari Salokas, Antti Tuhkala, Salla Keskitalo, Markku Varjosalo.

  This protocol outlines a comprehensive methodology for investigating cellular responses to viral infections through quantitative global and phosphoproteome analysis. Phosphorylation, a crucial posttranslational modification, regulates various cellular processes and plays a key role in virus-host interactions. To study the phosphorylation events, we have developed an analysis pipeline, and the subsequent steps detail sample preparation techniques for obtaining high-quality protein samples suitable for phosphoproteomic analysis. These include lysing virus-infected cells, processing protein samples through reduction, alkylation, digestion, and desalting, and enriching phosphopeptides using CAE-Ti-IMAC microspheres. High-throughput DIA-PASEF MS-analysis using TimsTOF Pro 2 facilitates sensitive detection of phosphorylation events, enabling a comprehensive understanding of viral infection, replication, and cytotoxicity in the host cell. The protocol also integrates the DIA-NN program for processing and analyzing MS data. Overall, this protocol provides a robust framework for identifying potential therapeutic targets within these altered pathways for elucidating the molecular mechanisms underlying viral pathogenesis and host immune evasion.

Keywords:  DIA-PASEF MS-analysis; Phosphopeptide enrichment; Phosphoproteomics; Phosphorylation; Posttranslational modifications (PTMs); Protein kinases; SARS-CoV-2; Viral infections; Virus-host interactions

DOI:  https://doi.org/10.1007/978-1-0716-4502-4_15
Mol Biol Rep. 2025 Jun 16. 52(1): 603

SIRT3 regulates CPT1a acetylation and fatty acid oxidation in renal tubular epithelial cells under diabetic condition.

Shuqing Yang, Xingyue Wang, Yu Zhang, Qingqing Ke, Weifang Su, Yang Zhou, Lei Jiang, Chunsun Dai, Ping Wen.

   BACKGROUND: The pathophysiology of renal tubular injury in diabetic kidney disease involves complex interactions between metabolic dysregulation, inflammation, and oxidative stress. Dysregulation of FAO leads to the accumulation of toxic metabolites, which may exacerbate mitochondrial dysfunction and contribute to cellular injury. CPT1a is a pivotal enzyme in FAO. Dysfunction of CPT1a impairs the translocation of long-chain fatty acyl-CoA into the mitochondria, which ultimately leads to tubular injury. Acetylation is a critical post-translational modification of proteins in essential cellular processes. In this study, we aimed to investigate the regulatory role of SIRT3 in CPT1a and its protective role against tubular injury in mice with diabetic kidney disease.
METHODS AND RESULTS: We found that decreased SIRT3 expression was accompanied by elevated acetylation in the renal tubules of diabetic mice. Acetylome analysis using LC-MS/MS showed that mitochondrial proteins were hyper-acetylated in the tubules of diabetic mice. Specifically, CPT1a was hyperacetylated at lysines 86 and 639 in tubular epithelial cells of diabetic mice and was regulated by SIRT3. Furthermore, proximal tubular epithelial cells-specific Sirt3 knockout diabetic mice showed more pronounced lipid accumulation in the renal tubules and more significant urinary protein. The integrated optical density per area for SIRT3 was positively correlated with glomerular filtration rate and negatively correlated with urinary protein levels in humans.
CONCLUSIONS: The study findings revealed that SIRT3 is downregulated in renal tubules during diabetes and interferes with the activity of CPT1a through deacetylation, disrupting fatty acid metabolism in the tubules and ultimately leading to tubular injury.

Keywords:  Acetylation; CPT1a; Diabetes; SIRT3; Tubular epithelial cells

DOI:  https://doi.org/10.1007/s11033-025-10712-y
Redox Biol. 2025 Jun 06. pii: S2213-2317(25)00211-3. [Epub ahead of print]85 103698

Sex-specific metabolic responses to high-fat diet in mice with NOX4 deficiency.

Jacob M Bond, Martina Dzubanova, Adele K Addington, Charles P Najt, Elizabeth R Gilbert, Michaela Tencerova, Siobhan M Craige.

Reactive oxygen species (ROS) are critical mediators of cellular signaling that regulate metabolic homeostasis, including lipid uptake, synthesis, and storage. NADPH oxidase 4 (NOX4), a significant enzymatic source of ROS, has been identified as a redox-sensitive regulator of glucose and lipid metabolism. However, its contribution to sex-specific metabolic regulation remains poorly defined. This study compared how NOX4 knock-out (NOX4 KO) shifted systemic and tissue-specific metabolic phenotypes between male and female mice fed with a high-fat diet (HFD) for 20-weeks. We observed that male NOX4 mice on HFD exhibited reduced adiposity, diminished liver lipid accumulation, and improved glucose and insulin tolerance compared to male WT mice on HFD. In contrast, female NOX4 KO mice developed increased adiposity and lipid accumulation in peripheral adipose depots, accompanied by impaired glucose tolerance. Gene expression profiling in skeletal muscle and liver revealed distinct, sex-specific patterns of changes in genes related to lipid uptake, synthesis, and storage, possibly implicating differential activation of PPAR signaling pathways supportive of in vivo data. These findings identify NOX4 as a central regulator of sexually dimorphic lipid metabolism, acting through redox-sensitive transcriptional networks to shape divergent metabolic responses to HFD.

DOI: https://doi.org/10.1016/j.redox.2025.103698
Cell Death Dis. 2025 Jun 19. 16(1): 460

PUMA reduces FASN ubiquitination to promote lipid accumulation and tumor progression in human clear cell renal cell carcinoma.

Qianqian Luo, Qi Wang, Jian Shi, Qingyang Lv, Zirui Dong, Wen Li, Yaru Xia, Jingchong Liu, Hongmei Yang.

While the p53 upregulated modulator of apoptosis (PUMA) is traditionally recognized for promoting cell apoptosis and enhancing chemotherapy efficacy in various cancers, its role in clear cell renal cell carcinoma (ccRCC) remains unclear due to ccRCC's chemotherapy resistance. In this study, we discover a novel oncogenic role for PUMA in ccRCC, diverging from its known apoptotic function, through assessments of public datasets, clinical tissue samples, and cell line experiments. Abnormally high expression of PUMA positively correlates with clinical stages and poor prognosis. Notably, PUMA's role in ccRCC appears to be independent of apoptosis. Instead, it facilitates tumor progression and lipid accumulation through mechanisms involving the key metabolic regulator, fatty acid synthase (FASN). Specifically, the N44-102 amino acid sequence of PUMA, distinct from the previously studied BH3 domain, is crucial for its interaction with FASN. As a mechanism, PUMA stabilizes FASN by binding to ubiquitin-specific protease 15 (USP15), reducing FASN ubiquitination and degradation, thereby forming the PUMA-USP15-FASN axis. These findings challenge the established view of PUMA's role in cancer biology. Furthermore, PUMA knockdown significantly inhibits tumor growth and enhances the sensitivity of ccRCC tumors to metabolic inhibition. These results position PUMA as a novel metabolic regulator and a potential therapeutic target in ccRCC. The combined inhibition of PUMA and FASN further supports the therapeutic potential of targeting this metabolic axis.

DOI: https://doi.org/10.1038/s41419-025-07782-y