bims-prolim 2025-05-04 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–05–04
thirteen papers selected by
Bruna Martins Garcia, CABIMER

Lactylation in cancer progression and drug resistance.
The role of protein lactylation in brain health and disease: current advances and future directions.
Research progress on the regulatory role of lactate and lactylation in tumor microenvironment.
Lactate metabolism and lactylation in breast cancer: mechanisms and implications.
SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling.
S-acylation in apoptotic and non-apoptotic cell death: a central regulator of membrane dynamics and protein function.
Identification and Validation of Prognostic Genes Related to Histone Lactylation Modification in Glioblastoma: An Integrated Analysis of Transcriptome and Single-cell RNA Sequencing.
Comparative Glycoproteomic Analysis of Mouse 4T1 Breast Cancer Model.
Lactate-induced macrophage HMGB1 lactylation promotes neutrophil extracellular trap formation in sepsis-associated acute kidney injury.
N-deglycosylation targeting chimera (DGlyTAC): a strategy for immune checkpoint proteins inactivation by specifically removing N-glycan.
Palmitoylation in focus: bridging reproductive biology and translational research.
Deciphering the Metabolic Impact and Clinical Relevance of N-Glycosylation in Colorectal Cancer through Comprehensive Glycoproteomic Profiling.
Mannose inhibits PKM2 lactylation to induce pyroptosis in bladder cancer and activate antitumor immune responses.

Drug Resist Updat. 2025 Apr 21. pii: S1368-7646(25)00049-4. [Epub ahead of print]81 101248

Lactylation in cancer progression and drug resistance.

Yuxiu Sun, He Wang, Zhe Cui, Tingting Yu, Yuanming Song, Haolai Gao, Ruihong Tang, Xinlei Wang, Binru Li, Wenxin Li, Zhe Wang.

  Lactate plays a crucial role as an energy substrate, metabolite, and signaling molecule in cancer. Lactate has long been considered a byproduct of glycolysis. Still, the lactate shuttle hypothesis has changed the lactate paradigm, revealing the implications of lactate in cellular metabolism and cellular communications that can transcend the compartment barrier and occur within and between different cells, tissues, and organs. Due to the Warburg effect, the tumor produces a large amount of lactate, thus creating a low-nutrition, hypoxic, and low-pH tumor microenvironment (TME). Consequently, immunosuppressive networks are built to acquire immune evasion potential and regulate tumor growth. Lactylation is a newly discovered post-translational modification of lysine residues with the capacity for transcriptional regulation via histone modification and modulation of non-histone protein functions, which links gene regulation to cellular metabolism by aberrant metabolism activity and epigenetic modification. There is growing evidence that lactylation plays a crucial role in cancer progression and drug resistance. Targeting lactylation enzymes or metabolic pathways has shown promising effects in suppressing cancer progression and drug resistance, highlighting the therapeutic potential of this modification. Therefore, in this review, we offer a systematic overview of lactate homeostasis in physiological and pathological processes as well as discuss the influence of lactylation in cancer progression and drug resistance and underlying molecular mechanisms, providing a theoretical basis for further research.

Keywords:  Cancer progression; Drug resistance; Lactate; Lactylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.drup.2025.101248
Cell Death Discov. 2025 Apr 30. 11(1): 213

The role of protein lactylation in brain health and disease: current advances and future directions.

Mingrui Han, Wenfeng He, Wengen Zhu, Linjuan Guo.

Lactate, the end product of glycolysis, plays a crucial role in cellular signaling and metabolism. The discovery of lactylation, a novel post-translational modification, has uncovered the role of lactate in regulating diseases, especially in the brain. Lactylation connects genetic encoding with protein function, thereby influencing key biological processes. Increasing evidence supports lactate-mediated lactylation as a critical modulator in neurological disorders. This review offers an overview of lactate metabolism and lactylation, highlighting recent advances in understanding the regulatory enzymes of lactylation and their role in the central nervous system. We investigate the impact of lactylation on brain dysfunctions, including neurodegenerative diseases, cerebrovascular disorders, neuroinflammation, brain tumors, and psychiatric conditions. Moreover, we highlight the therapeutic potential of targeting lactylation in treating brain disorders and outline key research gaps and future directions needed to advance this promising field.

DOI: https://doi.org/10.1038/s41420-025-02408-w
Biochim Biophys Acta Rev Cancer. 2025 Apr 29. pii: S0304-419X(25)00081-2. [Epub ahead of print] 189339

Research progress on the regulatory role of lactate and lactylation in tumor microenvironment.

Chunyan Gao, Jiali Li, Baoen Shan.

  The tumor microenvironment (TME) arises from the dynamic interactions between tumor cells and the surrounding medium, including a variety of cell types and extracellular components, which have an important impact on the genesis and development of tumors. A key player in TME is lactate, a metabolic byproduct of glycolysis, which serves as a significant energy source. Lactate has direct implications on the survival and differentiation of immune cells, the metabolic reprogramming and progression of tumor cells. Moreover, lactylation, a unique post-translational modification, exerts a regulatory effect on TME by affecting gene transcription via adding lactate groups to both histone and non-histone proteins. This review systematically and comprehensively synthesizes emerging evidence on how the lactate-lactylation axis drives immune evasion, therapy resistance, and TME remodeling, highlighting the therapeutic targets related to lactate and lactylation that dismantle this metabolic-epigenetic crosstalk.

Keywords:  Lactate; Lactylation; Metabolic regulation; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189339
Cancer Metastasis Rev. 2025 Apr 28. 44(2): 48

Lactate metabolism and lactylation in breast cancer: mechanisms and implications.

Yifan Qiao, Yijia Liu, Ran Ran, Yan Zhou, Jin Gong, Lijuan Liu, Yusi Zhang, Hui Wang, Yuan Fan, Yihan Fan, Gengrui Nan, Peng Zhang, Jin Yang.

  As the end-product of glycolysis, lactate serves as a regulator of protein lactylation in addition to being an energy substrate, metabolite, and signaling molecule in cancer. The reprogramming of glucose metabolism and the Warburg effect in breast cancer results in extensive lactate production and accumulation, making it likely that lactylation in tumor tissue is also abnormal. This review summarizes evidence on lactylation derived from studies of lactate metabolism and disease, highlighting the role of lactate in the tumor microenvironment of breast cancer and detailing the levels of lactylation and cancer-promoting mechanisms across various tumors. The roles of lactate and lactylation, along with potential intervention mechanisms, are presented and discussed, offering valuable insights for future research on the role of lactylation in tumors.

Keywords:  Breast cancer; Drugs; Lactate; Lactylation; TME

DOI:  https://doi.org/10.1007/s10555-025-10264-4
Adv Sci (Weinh). 2025 Apr 29. e2412553

SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling.

Mengzhu Lv, Xiaodan Yang, Congcong Xu, Qingru Song, Hailian Zhao, Tianjiao Sun, Jingtao Liu, Yuan Zhang, Guogui Sun, Yuanchao Xue, Zhiqian Zhang.

  Mitochondria Sirtuins including SIRT4 erase a variety of posttranslational modifications from mitochondria proteins, leading to metabolic reprogramming that acts as a tumor suppressor, oncogenic promotor, or both. However, the factors and the underlying mechanisms that stimulate and relay such a signaling cascade are poorly understood. Here, we reveal that the voltage-gated calcium channel subunit α2δ1-mediated calcium signaling can upregulate the expression of SIRT4, which is highly expressed in α2δ1-positive pancreatic tumor-initiating cells (TICs). Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties of pancreatic cancer cells by directly deacetylating ENO1 at K358, leading to attenuated ENO1's RNA-binding capacity, enhanced glycolytic substrate 2-PG affinity, and subsequently robust catalytic activity with boosted glycolytic ability and increased production of lactate acid. Interestingly, both SIRT4 and deacetylated mimetic of ENO1-K358 can increase the lactylation of histones at multiple sites including H3K9 and H3K18 sites, which resulted in epigenetic reprogramming to directly activate a variety of pathways that are essential for stemness. Hence, the study links α2δ1-mediated calcium signaling to SIRT4-mediated histone lactylation epigenetic reprogramming in promoting the stem cell-like properties of pancreatic cancer, which holds significant potential for the development of novel therapeutic strategies by targeting TICs of pancreatic cancer.

Keywords:  SIRT4; glycolysis; histones lactylation; tumor‐initiating cells

DOI:  https://doi.org/10.1002/advs.202412553
Biochem Soc Trans. 2025 Apr 29. pii: BST20253012. [Epub ahead of print]53(2):

S-acylation in apoptotic and non-apoptotic cell death: a central regulator of membrane dynamics and protein function.

Rojae Manhertz-Patterson, G Ekin Atilla-Gokcumen.

  Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular membranes, changing the local environment of protein interactions. Among these modifications, S-acylation has emerged as a key regulator of various cellular processes, including different forms of cell death. In this mini-review, we highlight the role of S-acylation in apoptosis and its emerging contributions to necroptosis and pyroptosis. While traditionally associated with the incorporation of palmitic acid (palmitoylation), recent findings indicate that other fatty acids can also participate in S-acylation, expanding its functional repertoire. In apoptosis, S-acylation influences the localization and function of key regulators such as Bcl-2-associated X protein and other proteins modulating their role in mitochondrial permeabilization and death receptor signaling. Similarly, in necroptosis, S-acylation of mixed lineage kinase domain-like protein (MLKL) with palmitic acid and very long-chain fatty acids enhances membrane binding and membrane permeabilization, contributing to cell death and inflammatory responses. Recent studies also highlight the role of S-acylation in pyroptosis, where S-acylated gasdermin D facilitates membrane localization and pore assembly upon inflammasome activation. Blocking palmitoylation has shown to suppress pyroptosis and cytokine release, reducing inflammatory activity and tissue damage in septic models. Collectively, these findings underscore S-acylation as a shared and important regulatory mechanism across cell death pathways affecting membrane association of key signaling proteins and membrane dynamics, and offer insights into the spatial and temporal control of protein function.

Keywords:   S-acylation; apoptosis; cell death; necroptosis; palmitoylation; pyroptosis

DOI:  https://doi.org/10.1042/BST20253012
J Cancer. 2025 ;16(7): 2145-2166

Identification and Validation of Prognostic Genes Related to Histone Lactylation Modification in Glioblastoma: An Integrated Analysis of Transcriptome and Single-cell RNA Sequencing.

Wenfeng He, Ruihong Chen, Guangliang Chen, Lihan Zhang, Yuhang Qian, Jie Zhou, Jianhua Peng, Vincent Kam Wai Wong, Yong Jiang.

  Background: The impact of histone lactylation modification (HLM) on glioblastoma (GBM) progression is not well understood. This study aimed to identify HLM-associated prognostic genes in GBM and explore their mechanisms of action. Methods: The presence and role of lactylation in glioma clinical tissue samples and its correlation with GBM progression were analysed through immunohistochemical staining and Western blotting. Sequencing data for GBM were obtained from publicly available databases. An initial correlation analysis was performed between global HLM levels and GBM. Differentially expressed HLM-related genes (HLMRGs) in GBM were identified by intersecting differentially expressed genes (DEGs) from the TCGA-GBM dataset, key module genes derived from weighted gene coexpression network analysis (WGCNA), and previously reported HLMRGs. Prognostic genes were subsequently identified through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses, which formed the basis for constructing a risk prediction model. Associations between HLMRGs and GBM were further evaluated via single-cell RNA sequencing (scRNA-seq) datasets. Complementary analyses, including functional enrichment, immune infiltration, somatic mutation, and nomogram-based survival prediction, were conducted alongside in vitro experiments. Additionally, drug sensitivity and Chinese medicine prediction analyses were performed to identify potential therapeutic agents for GBM. Results: We detected a significant increase in global lactylation levels in GBM, which correlated with patient survival. We identified 227 differentially expressed HLMRGs from the intersection of 3,343 differentially expressed genes and 948 key module genes, indicating strong prognostic potential. Notably, genes such as SNCAIP, TMEM100, NLRP11, HOXC11, and HOXD10 were highly expressed in GBM. Functional analysis suggested that HLMRGs are involved primarily in pathways related to cytokine‒cytokine receptor interactions, cell cycle regulation, and cellular interactions, including microglial differentiation states. Further connections were established between HLMRGs and infiltrating immune cells, particularly type 1 T helper (Th1) cells, as well as mutations in genes such as PTEN. The potential therapeutic agents identified included ATRA and Can Sha. Conclusion: The HLM-related gene risk prediction model shows substantial promise for improving patient management in GBM, providing crucial insights for clinical prognostic evaluations and immunotherapeutic approaches in GBM.

Keywords:  Glioblastoma; Histone lactylation modification; Prognostic genes; Single-cell RNA sequencing

DOI:  https://doi.org/10.7150/jca.110646
Curr Med Chem. 2025 Apr 29.

Comparative Glycoproteomic Analysis of Mouse 4T1 Breast Cancer Model.

Aik-Aun Tan, Yin-Ling Wong, Subash C B Gopinath, Lik Voon Kiew, Sreenivasan Sasidharan, Yeng Chen.

   BACKGROUND: Glycosylation is a post-translational modification process that plays a fundamental role in malignant transformation. Moreover, aberrant glycosylation is known to be associated with cancer progression. Thus, the characterization of cancer-specific protein glycosylation profiles might reveal important diagnostic and/or prognostic biomarkers for cancer.
OBJECTIVE: In the present study, we have analysed serum protein and glycoprotein profiles during breast cancer progression using a mouse model. Specifically, 4T1 tumour cells were injected into the mammary fat pad of BALB/c mice to induce tumours.
METHODS: Sera samples were subsequently collected weekly for four weeks and examined using two-dimensional electrophoresis (2D-E) coupled with lectin-based analysis, followed by mass spectrometry.
RESULTS: This glycoproteomic profiling identified eight differentially expressed proteins, of which alpha-1 protease inhibitor 2, contraption (CON), haptoglobin (HP), and kininogen-1 were significantly up-regulated during the first 4 weeks of tumour progression. Notably, aberrantly N-glycosylated prothrombin was also detected in sera samples from all mice over the 4 weeks post-tumour injection. Additionally, O-glycosylated alpha-2-macroglobulin, CON, and HP were detected in weeks 1 and 2, whereas O-glycosylated alpha-2-HS-glycoprotein and CON were detected on weeks 3 and 4 post-implantation.
CONCLUSION: Our findings indicate that the combination of 2D-E with lectin-based chromatography represents an effective approach for identifying prognostic biomarkers for breast cancer.

Keywords:  4T1 model; Breast cancer; glycoproteomic; glycosylation; lectin.

DOI:  https://doi.org/10.2174/0109298673360978250329065548
Cell Biol Toxicol. 2025 Apr 30. 41(1): 78

Lactate-induced macrophage HMGB1 lactylation promotes neutrophil extracellular trap formation in sepsis-associated acute kidney injury.

Siwei Wei, Zijuan Dai, Lei Wu, Zhen Xiang, Xiaoxiao Yang, Liubing Jiang, Zhen Du.

   BACKGROUND: Neutrophils play a key role in sepsis-associated acute kidney injury (SAKI), a common and life-threatening complication of organ failure. High mobility group box 1 (HMGB1) modulates inflammatory responses and the formation of neutrophil extracellular traps (NETs). The present work aimed to explore whether HMGB1 lactylation promotes NET formation and exacerbates SAKI.
METHODS: Venous blood samples were collected from healthy volunteers and SAKI patients. A SAKI mouse model was established using the cecal ligation and puncture method. A coculture system of macrophage-derived exosomes and neutrophils was established. Macrophage-derived exosomes were isolated and identified. ELISAs, immunofluorescence staining, coimmunoprecipitation, and Western blotting were utilized to determine protein levels.
RESULTS: Elevated blood lactate levels were associated with increased HMGB1 levels in patients with SAKI. In mouse models, lactate increased HMGB1 expression, promoted NET formation, and exacerbated SAKI. Lactate stimulated M1 macrophages to secrete exosomes, leading to the accumulation and release of HMGB1 in the cytoplasm. Additionally, lactate promoted HMGB1 lactylation in macrophages, triggering the release of mitochondrial DNA from neutrophils and activating the cyclic GMP‒AMP synthase/stimulator of interferon genes pathway.
CONCLUSION: This study revealed that lactate-induced HMGB1 lactylation in macrophages plays a role in promoting NET formation in SAKI through the cGAS/STING pathway. These findings suggest that HMGB1 could be a potential target for therapeutic intervention in SAKI.

Keywords:  Acute kidney injury; HMGB1; Lactylation; Macrophages; Neutrophil Extracellular Trap; Sepsis

DOI:  https://doi.org/10.1007/s10565-025-10026-6
Signal Transduct Target Ther. 2025 Apr 28. 10(1): 139

N-deglycosylation targeting chimera (DGlyTAC): a strategy for immune checkpoint proteins inactivation by specifically removing N-glycan.

Li Li, Jiajia Wu, Weiqian Cao, Wei Zhang, Qi Wu, Yaxu Li, Yanrong Yang, Zezhi Shan, Zening Zheng, Xin Ge, Liang Lin, Ping Wang.

Among the leading methods for triggering therapeutic anti-cancer immunity is the inhibition of immune checkpoint pathways. N-glycosylation is found to be essential for the function of various immune checkpoint proteins, playing a critical role in their stability and interaction with immune cells. Removing the N-glycans of these proteins seems to be an alternative therapy, but there is a lack of a de-N-glycosylation technique for target protein specificity, which limits its clinical application. Here, we developed a novel technique for specifically removing N-glycans from a target protein on the cell surface, named deglycosylation targeting chimera (DGlyTAC), which employs a fusing protein consisting of Peptide-N-glycosidase F (PNGF) and target-specific nanobody/affibody (Nb/Af). The DGlyTAC technique was developed to target a range of glycosylated surface proteins, especially these immune checkpoints-CD24, CD47, and PD-L1, which minimally affected the overall N-glycosylation landscape and the N-glycosylation of other representative membrane proteins, ensuring high specificity and minimal off-target effects. Importantly, DGlyTAC technique was successfully applied to lead inactivation of these immune checkpoints, especially PD-L1, and showed more potential in cancer immunotherapy than inhibitors. Finally, PD-L1 targeted DGlyTAC showed therapeutic effects on several tumors in vivo, even better than PD-L1 antibody. Overall, we created a novel target-specific N-glysocylation erasing technique that establishes a modular strategy for directing membrane proteins inactivation, with broad implications on tumor immune therapeutics.

DOI: https://doi.org/10.1038/s41392-025-02219-6
Biol Res. 2025 Apr 28. 58(1): 22

Palmitoylation in focus: bridging reproductive biology and translational research.

Suriyaraj Shanmugasundaram Prema, Deepankumar Shanmugamprema.



Keywords:  Calcium; Protein palmitoylation; Protein tyrosine phosphorylation; Reactive oxygen species; Sperm motility

DOI:  https://doi.org/10.1186/s40659-025-00601-w
Adv Sci (Weinh). 2025 Apr 26. e2415645

Deciphering the Metabolic Impact and Clinical Relevance of N-Glycosylation in Colorectal Cancer through Comprehensive Glycoproteomic Profiling.

Guobin Liu, Lu Chen, Jingxiang Zhao, Yue Jiang, Yarong Guo, Xiang Mao, Xuelian Ren, Kun Liu, Qi Mei, Qunyi Li, He Huang.

  Colorectal cancer (CRC) progression is driven by complex metabolic alterations, including aberrant N-glycosylation patterns that critically influence tumor development. However, the metabolic and functional roles of N-glycosylation in CRC remain poorly understood. Herein, comprehensive proteomic and N-linked intact glycoproteomics analyses are performed on 45 CRC tumors, and normal adjacent tissues (NATs) are matched, identifying 7125 intact N-glycopeptides from 704 glycoproteins. Through analysis of glycoform expression profiles and structural characteristics, a glycosylation site-protein function association network is constructed to uncover metabolic dysregulation driven by N-glycosylation in CRC. Moreover, an arithmetic model is developed that integrates N-glycan expression patterns, which effectively distinguishes tumors from NATs, reflecting metabolic reprogramming in cancer. These findings identify Chloride Channel Accessory 1 (CLCA1) and Olfactomedin 4 (OLFM4) as potential metabolic biomarkers for CRC diagnosis. Immunohistochemistry and Cox regression analyses validated the prognostic power of these markers. Notably, the critical role of specific N-glycosylation at N196 of Adipocyte plasma membrane-associated protein (APMAP) is highlighted, a key player in tumor metabolism and CRC progression, providing a potential target for therapeutic intervention. These findings offer valuable insights into the metabolic roles of N-glycosylation in CRC, advancing biomarker discovery, enhancing metabolic-based diagnostic precision, and improving personalized treatment strategies targeting cancer metabolism.

Keywords:  clinical relevance; colorectal cancer; functions; glycoproteomics; intact N‐glycopeptides

DOI:  https://doi.org/10.1002/advs.202415645
Commun Biol. 2025 May 01. 8(1): 689

Mannose inhibits PKM2 lactylation to induce pyroptosis in bladder cancer and activate antitumor immune responses.

Haoyi Jin, Pingeng Wu, Chengcheng Lv, Shouyi Zhang, Yunchao Zhang, Changqi Li, Ruxu Gao, Guangyi Shan, Huan Bi, Hong Chang, Xi Liu, Yu Zeng.

Bladder cancer therapy remains challenging due to poor efficacy and frequent recurrence. Mannose, a naturally occurring monosaccharide, has demonstrated antitumor effects in various cancers, yet its mechanism of action in bladder cancer is unclear. This study explored the inhibitory effects of mannose on bladder cancer. We found mannose significantly inhibited the growth of bladder cancer cells, xenografts, and organoids. Mannose directly binds to PKM2, inhibiting its enzymatic activity and reducing lactate production. This reduction in lactate led to decreased PKM2 lactylation and increased acetylation, causing PKM2 to translocate to the nucleus. Nuclear PKM2 activated the NF-κB pathway, inducing NLRP1/Caspase-1/GSDMD/IL-1β-dependent pyroptosis. Additionally, mannose promoted antitumor immune responses by inducing pyroptosis and enhancing the efficacy of immune checkpoint inhibitors. These findings highlight the use of mannose as a potent antitumor agent and a promising therapeutic strategy for bladder cancer.

DOI: https://doi.org/10.1038/s42003-025-08130-8