bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–11–16
eight papers selected by
Bruna Martins Garcia, CABIMER
  1. TOP2A promotes non-small cell lung cancer progression via LDHA-mediated glycolysis and histone lactylation.
  2. Protein acylation in inflammatory diseases: from mechanisms to therapeutic strategies.
  3. Targeting lactate metabolism to restore immune homeostasis: a precision therapeutic paradigm for rheumatoid arthritis.
  4. Construction of a prognostic model based on palmitoylation-related lncRNAs for assessing drug benefits in breast cancer.
  5. O-GlcNAcylation of SPOP regulates colorectal cancer progression and ferroptosis by mediating β-catenin degradation.
  6. Neddylation: from regulatory mechanisms to clinical implications in cancer.
  7. The Glyco-Switch of life: O-GlcNAcylation in cell fate decision.
  8. ALKBH5-mediated m6A demethylation of TXNDC5 drives malignant progression in gastric cancer.
  1. Transl Cancer Res. 2025 Oct 31. 14(10): 6919-6939
    TOP2A promotes non-small cell lung cancer progression via LDHA-mediated glycolysis and histone lactylation.
    Qiong Wu, Ye Fan, Weiqin Wang, Feng Hu.
       Background: Topoisomerase 2-alpha (TOP2A) has been connected to a variety of cancers, but its role in non-small cell lung cancer (NSCLC) metabolism remains unclear. This study intended to investigate the involvement of glycolysis and histone lactylation in NSCLC advancement by exploring important regulators such as TOP2A and lactate dehydrogenase A (LDHA).
    Methods: Bioinformatics analysis of The Cancer Genome Atlas (TCGA)-NSCLC, GSE33532, and GSE74706 datasets was performed to identify the hub gene TOP2A. The correlation between TOP2A and LDHA was then analyzed and their expression in NSCLC samples was verified. In vitro tests were conducted to study the expression and function of TOP2A by knockdown and overexpression experiments in NSCLC cells. Lactate generation, glucose absorption, and extracellular acidification rate (ECAR) were measured to evaluate glycolysis. Protein lactylation was assessed by western blot (WB) analysis.
    Results: Expression analysis showed a significant positive correlation between TOP2A and LDHA, and both genes were upregulated in NSCLC samples. TOP2A knockdown prevented the invasion, migration, and proliferation of NSCLC cells while reducing glycolytic activity as manifested by decreased ECAR, glucose uptake, as well as lactate production. Mechanistically, TOP2A regulated histone lactylation by modulating P300 expression and LDHA-mediated lactate production. TOP2A silencing reduced pan-lysine acetylation and H3K18 lactylation levels. Importantly, TOP2A overexpression partially rescued the inhibitory consequences of glycolytic inhibitors on NSCLC cell function and protein lactylation.
    Conclusions: Our results indicate a new function for TOP2A in promoting NSCLC progression through modulating glycolysis and histone lactylation, suggesting TOP2A as a possible therapeutic target to treat NSCLC.
    Keywords:  Topoisomerase 2-alpha (TOP2A); glycolysis; histone lactylation; lactate dehydrogenase A (LDHA); non-small cell lung cancer (NSCLC)
    DOI:  https://doi.org/10.21037/tcr-2025-702
  2. Cell Commun Signal. 2025 Nov 11. 23(1): 488
    Protein acylation in inflammatory diseases: from mechanisms to therapeutic strategies.
    Jiayi Ding, Huiyi Wang, Zhengkun Yang, Xiaoxuan Wang, Zhengguo Cao.
      Protein acylation, a critical subset of post-translational modifications (PTMs), serves as a dynamic regulatory mechanism linking cellular metabolism, epigenetic regulation, and inflammatory responses. This review systematically elucidates the roles of protein acylation modifications-including acetylation, lactylation, succinylation, propionylation, crotonylation, malonylation, butyrylation, S-palmitoylation, and myristoylation-in the pathogenesis of inflammatory diseases. These modifications, orchestrated by acyltransferases (writers), deacylases (erasers), and recognition proteins (readers), regulate immune cell functionality and disease progression. In immune cells, specific acylation patterns govern inflammatory responses by modulating polarization, cytokine production, and signaling pathways. Furthermore, dysregulated protein acylation contributes to the pathogenesis of inflammatory diseases such as sepsis, periodontitis, inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis through disrupting immune homeostasis, driving metabolic reprogramming, and impairing tissue repair. Emerging therapeutic strategies targeting acylation-related enzymes or leveraging nanoparticle-based drug delivery systems show promise in restoring balanced PTM dynamics and alleviating disease progression. By systematically mapping protein acylation networks across immune and diseased cells, this review provides insights into novel diagnostic biomarkers and therapeutic interventions for inflammatory diseases.
    Keywords:  Inflammatory diseases; Post-translational modifications; Protein acylation
    DOI:  https://doi.org/10.1186/s12964-025-02484-6
  3. Front Immunol. 2025 ;16 1696932
    Targeting lactate metabolism to restore immune homeostasis: a precision therapeutic paradigm for rheumatoid arthritis.
    Lin Zheng, Xinyu A, Shiyu Ma, Bo Xu, Zheng Xiang, Boran Cao, Jun Shen, Xirui Xu, Yiwei Cheng, Lei Ran, Qi Shi, Yanqin Bian, Lianbo Xiao.
      The accumulation of lactate in synovial microenvironment of rheumatoid arthritis (RA) patients is closely correlated with disease activity, with elevated lactate levels serving as both biomarkers and pathogenic mediators in RA progression. In recent years, mounting evidence has demonstrated that lactate-driven metabolic reprogramming constitutes the central hub of the immune-metabolic-bone destruction axis in RA. The accumulation of lactate in the synovial microenvironment triggers a cascade of immunoregulatory effects, and these metabolic alterations create a self-perpetuating cycle of inflammation and tissue destruction, which represents the fundamental cause of RA chronicity. Therefore, lactate metabolism has been identified as a therapeutic target, opening new avenues for precision medicine approaches in RA treatment. Novel therapeutic strategies targeting lactate dehydrogenase A (LDHA) inhibitors, monocarboxylate transporters (MCTs), and enzymes that regulate lactylation have shown promising preclinical results. Furthermore, combination therapies pairing metabolic modulators with conventional biologics demonstrate synergistic effects in suppressing inflammatory pathways while improving drug penetration into synovial tissues. Additionally, patient stratification based on lactate metabolic profiles enables personalized treatment approaches. In summary, targeting lactate metabolism represents a paradigm shift in RA treatment from symptom management toward metabolic restoration. The integration of metabolic modulators with existing therapeutic regimens holds promise for achieving sustained remission and preventing long-term joint damage.
    Keywords:  immune homeostasis; lactate metabolism; lactylation; metabolic reprogramming; precision therapy; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fimmu.2025.1696932
  4. Front Immunol. 2025 ;16 1656593
    Construction of a prognostic model based on palmitoylation-related lncRNAs for assessing drug benefits in breast cancer.
    Yan Wang, Mengsi Zhang, Yuqin Zhou, Zaozhuo Li, Xinglin Yi, Lin Ren, Yi Zhang.
       Background: The lncRNAs associated with protein palmitoylation in breast cancer (BC) remain largely unexplored.
    Methods: We retrieved transcriptome, proteome, and mutation data from TCGA-BRCA (BC), identified 592 palmitoylation-related lncRNAs (PRLs), constructed a prognostic model (PmPRLs) based on their characteristics. According to the score of the median risk, the "High-"and "Low" risk groups were distinguished. The predictive potential of PmPRLs for the prognosis of BC was determined through Kaplan-Meier (KM) survival analysis, ROC curve analysis, and risk scoring verification using the training set and validation set. The differences of PmPRLs in different risk groups were illustrated by using gene mutation frequency, immune function, tumour immune dysfunction and rejection (TIDE) score and drug sensitivity analysis. Based on this model, key feature LncRNAs were screened out. After the identified LncRNAs were verified by the external dataset TANRIC, a series of tumour phenotypic experiments were conducted to comprehensively demonstrate their role in tumourigenesis and development.
    Results: We identified 2 key feature lncRNAs, AC016394.2 and AC022150.4, as the most significant prognostic factors. Both of these lncRNAs exhibited high expression levels in the TCGA and TANRIC datasets and were closely associated with tumour cell growth, proliferation, and migration. More importantly, based on co-expression analysis, we proposed that AC016394.2 and AC022150.4 may respectively regulate SEC24C and ZNF611. Furthermore, these two lncRNAs enhanced the palmitoylation modification of these proteins.
    Conclusion: The insights regarding the potential roles of AC016394.2 and AC022150.4 can enhance our understanding of the mechanisms towards the pathogenesis and progression of BC.
    Keywords:  breast cancer; drug benefits; palmitoylation-related lncRNA; potential therapeutic targets; prognostic model
    DOI:  https://doi.org/10.3389/fimmu.2025.1656593
  5. Cell Death Discov. 2025 Nov 10. 11(1): 526
    O-GlcNAcylation of SPOP regulates colorectal cancer progression and ferroptosis by mediating β-catenin degradation.
    Xiuyuan Zhang, Yuwei Ding, Qizhen Ye, Saimeng Shi, Ning Zhu, Shanshan Weng, Jiaqi Chen, Wangxiong Hu, Ying Yuan.
      Current therapeutic approaches for colorectal cancer (CRC) face challenges such as recurrence and drug resistance. Ferroptosis, a novel form of cell death, is a promising therapeutic approach for CRC. SPOP plays an important biological role as a substrate-binding protein of the E3 ubiquitin ligase complex CRL3, but its therapeutic effects in CRC patients and its ability to modulate ferroptosis remain largely unknown. This study demonstrated that SPOP functions as a tumor suppressor in CRC and that SPOP inhibits the proliferation and metastasis of CRC cells and increases their sensitivity to ferroptosis. Transcriptome analysis suggested that Wnt signaling may be a potential target for the function of SPOP. Further data revealed that SPOP knockdown increased β-catenin protein levels, and the clinical data indicated that SPOP expression had the opposite effect on β-catenin protein levels. Molecular biology experiments suggest that SPOP promotes polyubiquitination and degradation of the K508 site of β-catenin. Interestingly, O-GlcNAcylation of SPOP reduces its protein stability and affects SPOP binding to β-catenin, and SPOP also promotes CRC ferroptosis by inhibiting the β-catenin/SLC7A11 axis. Combined treatment with the SPOP-targeted drug maprotiline and a ferroptosis inducer has synergistic antitumor efficacy in CRC cells and xenografts. Our study reveals the multifaceted function of SPOP in CRC, and the activation of SPOP may be a feasible strategy to increase the sensitivity of CRC to ferroptosis inducers.
    DOI:  https://doi.org/10.1038/s41420-025-02832-y
  6. J Adv Res. 2025 Nov 12. pii: S2090-1232(25)00905-1. [Epub ahead of print]
    Neddylation: from regulatory mechanisms to clinical implications in cancer.
    Ming Zhang, Peng Qiu, Yunxiang Feng, Tao Yang, Wei Yao, Zhengdong Deng, Jianming Wang.
       BACKGROUND: Neddylation is a critical post-translational modification that is frequently hyperactivated in various human cancers. By modifying key substrates such as Cullins and non-Cullin proteins, this pathway plas a central role in regulating protein stability, cellular signaling transduction, and core biological processes. Its dysregulation directly drives tumorigenesis and progression, making it a highly promising therapeutic target.
    AIM OF REVIEW: This review aims to systematically elucidate: (1) the processes of neddylation and its regulatory mechanisms on cellular and protein functions; (2) how this pathway promotes malignant progression and tumorigenesis by driving multiple cancer hallmarks; and (3) the development of drugs targeting different neddylation components, along with associated clinical trial progress and toxicity challenges, while also discussing its future prospects in precision oncology.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: This review constructs a multi-dimensional pathogenic network of neddylation at a systematic level, providing a comprehensive elaboration of its molecular basis in governing key cancer characteristics through modulating protein functions and cellular activities. Simultaneously, we focus on targeted therapeutic strategies against this pathway, analyzing the clinical potential and future directions of novel cancer treatment approaches based on preclinical and clinical evidence from inhibitors such as MLN4924 and TAS4464.
    Keywords:  Cancer hallmarks; Cullin-RING ligases; Neddylation; Precision oncology; Therapeutic targeting
    DOI:  https://doi.org/10.1016/j.jare.2025.11.010
  7. Glycobiology. 2025 Nov 06. pii: cwaf061. [Epub ahead of print]35(11):
    The Glyco-Switch of life: O-GlcNAcylation in cell fate decision.
    Ao Wang, Matthew Young, Jiaoyang Jiang.
      O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a unique type of protein glycosylation that intricately links cellular metabolism to various signaling pathways. This reversible, nutrient-sensitive modification dynamically regulates a wide range of biological processes, including apoptosis, cell proliferation, and differentiation. Recent studies have made substantial progress in elucidating the pivotal roles of O-GlcNAcylation in modulating key oncogenes and signaling cascades. Aberrant O-GlcNAc cycling has been associated with a variety of pathological conditions, including cancer, metabolic disorders, and neurodegenerative diseases, underscoring its critical influence on cell fate decisions. In this review, we will highlight recent advances in understanding how O-GlcNAcylation modulates major cell fate regulating pathways, including nuclear factor kappaB (NF-κB), Notch, G protein-coupled receptor (GPCR) signaling, and transforming growth factor beta (TGF-β). We propose that O-GlcNAcylation integrates extracellular signals with intracellular metabolic states, functioning as an essential "Glyco-Switch" sensor that modulates cell fate decisions in both physiological and pathological contexts.
    Keywords:  G protein–coupled receptor (GPCR) signaling; Notch; O-GlcNAcylation; cell fate decision; nuclear factor kappaB (NF-κB)
    DOI:  https://doi.org/10.1093/glycob/cwaf061
  8. Epigenomics. 2025 Nov 11. 1-12
    ALKBH5-mediated m6A demethylation of TXNDC5 drives malignant progression in gastric cancer.
    Wenkun Peng, Xiaoquan Wei, Feifei Zhou, Hongwei Xu.
       BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. N6-methyladenosine (m6A) modification plays a critical role in post-transcriptional gene regulation. This study aimed to elucidate the molecular mechanism by which the RNA demethylase ALKBH5 regulates GC progression through m6A modification of thioredoxin domain-containing protein 5 (TXNDC5).
    METHODS: Differential expression models of ALKBH5 and TXNDC5 were established in GC cells using RNA interference and gene overexpression. Methylated RNA immunoprecipitation (MeRIP-qPCR), qPCR, and Western blot were performed to assess ALKBH5-mediated m6A modification and its effect on TXNDC5 expression. Functional assays, including proliferation, migration, and invasion, as well as a xenograft mouse model, were used to evaluate their roles in GC progression.
    RESULTS: ALKBH5 was significantly upregulated in GC tissues and cells. Overexpression of ALKBH5 stabilized TXNDC5 expression in an m6A-dependent manner, thereby promoting malignant phenotypes. Conversely, ALKBH5 knockdown increased m6A methylation of TXNDC5, reduced TXNDC5 protein expression, and suppressed GC cell proliferation, migration, and invasion. In vivo experiments confirmed that loss of ALKBH5 impaired tumor growth.
    CONCLUSIONS: Our findings demonstrate that the ALKBH5-TXNDC5 axis drives GC progression through m6A-dependent regulation, highlighting ALKBH5 as a potential therapeutic target for GC.
    Keywords:  ALKBH5; TXNDC5; gastric cancer; m6A; posttranscriptional modification
    DOI:  https://doi.org/10.1080/17501911.2025.2586450
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