bims-prolim 2025-09-21 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–09–21
ten papers selected by
Bruna Martins Garcia, CABIMER

Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.
Different chains for different gains: How acyl chain diversity shapes S-acylated protein function.
Lactylation in Tumor Immune Escape and Immunotherapy: Multifaceted Functions and Therapeutic Strategies.
Lactate and lactylation in tumor immunity.
Deciphering protein long-chain S-acylation using mass spectrometry proteomics strategies.
Context-dependent roles of palmitoylation in acute respiratory distress syndrome: integrating inflammation, cell death and repair.
Bioinformatics Analysis and Experimental Validation of Lactylation Related Genes in Lung Adenocarcinoma.
AARS1/2: dual functions in protein translation and metabolic- immune regulation.
Citrullination in Tumor Metastasis, Inside and Outside the Cells.
Lactylation of CREB is required for FSH-induced proliferation and differentiation of ovarian granulosa cells.

Front Immunol. 2025 ;16 1652741

Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.

Rong Chen, Xiaohua Tang, Ying Wang, Bo Wang, Fei Mao.

  Protein palmitoylation is a reversible lipid modification in which palmitoyl esters are covalently attached to cysteine residues of proteins. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane binding, and interaction with other effector proteins. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), while the acyl-protein thioesterase family mediates depalmitoylation. Emerging evidence suggests that palmitoylation is critical for inflammatory signaling pathways, where palmitoylation is particularly important in the membrane localization of inflammation-associated proteins. Notably, dysregulation of palmitoylation has been associated with a variety of inflammatory diseases. Here, we provide an overview of the regulatory mechanisms of palmitoylation, explore the emerging role of palmitoylation in inflammatory signaling pathways, and examine the link between dysregulated palmitoylation and the pathogenesis of inflammatory diseases, including inflammatory bowel disease, autoimmune diseases, metabolic dysfunction-associated steatohepatitis, sepsis, Alzheimer's disease, Parkinson's disease, and diabetes. Finally, we discuss some of the challenges and opportunities facing the field. Targeting palmitoylation or its associated enzymes serves as a novel therapeutic approach for the treatment of inflammatory diseases.

Keywords:  acyl protein thioesterase; inflammation; inflammatory diseases; palmitoyl acyltransferases; posttranslational modifications; protein palmitoylation

DOI:  https://doi.org/10.3389/fimmu.2025.1652741
Prog Lipid Res. 2025 Sep 14. pii: S0163-7827(25)00036-0. [Epub ahead of print] 101354

Different chains for different gains: How acyl chain diversity shapes S-acylated protein function.

Carla Busquets Hernández, Alexandra Tsiotsia, Ludovico Pipitò, Luke H Chamberlain, Jennifer Greaves, Gemma Triola.

  S-Acylation is a critical post-translational modification involving the attachment of fatty acyl chains to a large and diverse array of soluble and membrane proteins. The last two decades have witnessed a substantial acceleration in our understanding of this process, fuelled by the discovery of acylation enzymes, mapping of the cellular S-acylome, and the development of new chemical biology methodologies to interrogate the mechanisms and functional outcomes of this lipid modification. This modification is often referred to as "S-Palmitoylation", however mass spectrometry analyses have provided compelling evidence that the acyl chains added to S-acylated proteins are diverse, that site-specific attachment of different acyl chains can be seen, and that exogenous fatty acids can modulate the lipid profile of the S-acylome. This heterogeneity is likely generated through a combination of enzyme specificities, Acyl CoA distribution and availability, and specific features of the modified substrate protein. Despite a limited number of functional studies, acyl chain differences can impact protein localisation and function, and could possibly contribute to the development and progression of disease. It is now clear that recognising and understanding the functional consequences of acyl chain heterogeneity is a pivotal step toward a more complete view of lipid-mediated protein regulation.

Keywords:  Fatty acids; Palmitoylation; Protein acyl transferases; Protein lipidation; S-acylation; Thioesterases

DOI:  https://doi.org/10.1016/j.plipres.2025.101354
Research (Wash D C). 2025 ;8 0793

Lactylation in Tumor Immune Escape and Immunotherapy: Multifaceted Functions and Therapeutic Strategies.

Qing Li, Runkang Zhao, Yang Shen, Dandan Guo, Lvdan Deng, Rongbing Cai, Zhijun Shen, Zhao Xie, Na Hang, Sentao Fu, Dehuan Zhang, Yihang Xu, Zhao Huang, Bufu Tang, Ling Wang.

Since its initial identification in 2019, lactylation has emerged as a critical posttranslation modification, attracting substantial research interest due to its diverse roles in biological processes. Lysine lactylation represents a recently characterized posttranslational modification wherein lactate moieties are covalently attached to protein lysine residues through both enzymatic and nonenzymatic pathways. Lactate, a primary glycolytic product, suggests a link between cell metabolism and protein function regulation. In neoplastic tissues, the Warburg effect induces preferential glucose-to-lactate metabolism in cancer cells, establishing hypoxic conditions and elevated lactate concentrations as defining characteristics of the tumor microenvironment. Extensive research has demonstrated lactate's pivotal role in tumor metastasis and patient outcomes, particularly through its influence on tumor immune microenvironment remodeling, although the precise molecular mechanisms remain under investigation. The characterization of lysine lactylation provides a novel framework for understanding these mechanisms and presents innovative opportunities for therapeutic intervention. This review examines the influence of lactylation on the tumor microenvironment and its effect in various malignancies and explores emerging therapeutic strategies, including genetic manipulation, small-molecule inhibitors, clinical pharmaceuticals, and nanoparticle-based approaches, offering new perspectives in cancer treatment.

DOI: https://doi.org/10.34133/research.0793
Front Med. 2025 Sep 20.

Lactate and lactylation in tumor immunity.

Liu Song, Lingjuan Sun, Song Chen, Peixiang Lan.

  The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

Keywords:  TME; immunosuppressive immune cells; lactate; lactylation; tumor immunity

DOI:  https://doi.org/10.1007/s11684-025-1148-0
RSC Chem Biol. 2025 Sep 08.

Deciphering protein long-chain S-acylation using mass spectrometry proteomics strategies.

Anneroos E Nederstigt, Samiksha Sardana, Marc P Baggelaar.

Protein long-chain S-acylation, the reversible attachment of fatty acids such as palmitate to cysteine residues via thioester bonds, is a widespread post-translational modification that plays a crucial role in regulating protein localization, trafficking, and stability. Despite its prevalence and biological relevance, the study of long-chain S-acylation has long lagged behind that of other dynamic PTMs due to the hydrophobic nature and lability of the lipid modification, which complicate conventional proteomic workflows. Recent advances in mass spectrometry-based strategies have significantly expanded the toolbox for studying long-chain S-acylation, with improved workflows enabling more sensitive, site-specific, and quantitative analysis. This review summarizes key developments from the past decade across both direct and indirect mass spectrometry-based strategies, including acyl-biotin exchange, lipid metabolic labeling, and novel enrichment and fragmentation methods. We also highlight emerging challenges in distinguishing lipid-specific modifications, achieving robust quantification, and mitigating artifacts from in vitro systems, while outlining future directions to advance functional and therapeutic exploration of the S-acyl-(prote)ome.

DOI: https://doi.org/10.1039/d5cb00146c
Eur Respir Rev. 2025 Jul;pii: 250086. [Epub ahead of print]34(177):

Context-dependent roles of palmitoylation in acute respiratory distress syndrome: integrating inflammation, cell death and repair.

Qimin Ma, Yusong Wang, Feng Zhu.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by dysregulated inflammation, immune imbalance and impaired alveolar repair. Despite advances in supportive care, effective targeted therapies remain limited. Palmitoylation, a reversible lipid-based post-translational modification, has recently emerged as a regulatory mechanism in ARDS pathogenesis. Acting in a context-dependent manner, palmitoylation affects key processes, including immune activation, programmed cell death and epithelial remodelling. Accumulating evidence suggests that palmitoylation may exert dual roles in ARDS: it can promote inflammation and immune evasion in the early phase, while contributing to resolution and tissue repair during later stages. This review summarises current findings regarding the spatial and temporal regulation of palmitoylation in immune and structural cells involved in ARDS, including its effects on inflammasome activation, epithelial-immune interactions and fibrotic progression. Therapeutic approaches under investigation include selective inhibition of palmitoyltransferases (zinc finger aspartate-histidine-histidine-cysteine motif-containing-type palmitoyltransferase family), modulation of depalmitoylation enzymes and substrate-targeted strategies. Several preclinical studies support the feasibility of targeting palmitoylation to reduce lung injury and improve immune regulation. Overall, palmitoylation represents a potential regulatory node in ARDS pathophysiology. Further research is required to clarify its cell-specific functions and to assess the translational potential of palmitoylation-based interventions.

DOI: https://doi.org/10.1183/16000617.0086-2025
Cancer Manag Res. 2025 ;17 1947-1960

Bioinformatics Analysis and Experimental Validation of Lactylation Related Genes in Lung Adenocarcinoma.

Li Gao, Yadi Zhang, Fengrui Wu, Bin Liu, Xin Xie.

   Purpose: Lactylation, a novel post-translational modification, is dysregulated in various tumors and influences lung cancer progression. However, its role in lung adenocarcinoma (LUAD) remains unclear. Based on multi-omics analysis results, this study investigated lactylation levels in LUAD tissues and explored the dual research positioning of lactylation as a prognostic marker and therapeutic target.
Methods: Lactylation levels in LUAD tissue microarrays were assessed using immunohistochemistry and immunofluorescence. Western blot analysis validated these findings. Differential expression analysis of lactylation-related genes was conducted using The Cancer Genome Atlas (TCGA, n=365), based on |log2 fold-change (FC)|≥2. KEGG pathway analysis identified key biological pathways, and COX regression analysis pinpointed prognostic genes. Single-cell RNA sequencing data from the GEO database validated these genes, with mitochondrial gene threshold <20%.
Results: Lactylation levels were significantly elevated in LUAD tissues compared to adjacent non-cancerous tissues, as shown by immunohistochemistry and confirmed by Western blot analysis. Differential analysis identified 17 lactylation-related genes enriched in pathways such as AMPK signaling and cellular senescence. COX regression analysis identified five risk genes: KIF2C, MKI67, HMGA1, PFKP, and CCNA2. Validation with single-cell RNA sequencing data revealed high expression levels of these genes in LUAD tissues and the LUAD cell line H1299. Functional validation revealed that the 5 genes panel significantly regulates global lactylation modification in vitro.
Conclusion: LUAD tissues exhibit elevated lactylation levels, suggesting their potential as prognostic biomarkers. The identified genes-KIF2C, MKI67, HMGA1, PFKP, and CCNA2-are highly expressed in cancerous tissues and correlate with LUAD prognosis. These findings highlight their value as tumor biomarkers and therapeutic targets, offering new opportunities for targeted LUAD treatments.

Keywords:  LUAD; lactylation; prognostic signature; single-cell sequencing

DOI:  https://doi.org/10.2147/CMAR.S533289
Yi Chuan. 2025 Sep;47(9): 967-978

AARS1/2: dual functions in protein translation and metabolic- immune regulation.

Zong-Wang Zhang, Jing-Wei Xiong.

  Highly precise regulation of protein synthesis is critical for the homeostasis and functionality of living organisms. Alanyl-tRNA synthase (AARS1/2) plays a crucial role in this process. AARS1/2 are a class of enzymes that synthesize alanyl-tRNA in cells, participating in protein synthesis encoded by genes, and catalyzing the propionylation of lysine residues in proteins, thereby regulating protein function. This article reviews the research progress on the involvement of AARS1/2 in disease progression induced by protein mistranslation and in the regulation of the metabolic-immune interaction network, aiming to better understand the pathophysiological mechanisms of AARS1/2 and to provide a reference for the development of potential therapeutic drugs.

Keywords:  AARS1/2; metabolism; protein lactylation; protein translation; tumor

DOI:  https://doi.org/10.16288/j.yczz.25-034
Cancer Sci. 2025 Sep 14.

Citrullination in Tumor Metastasis, Inside and Outside the Cells.

Takeshi Tomita, Priyanka Sharma, Sachie Hiratsuka.

  Tumor metastasis remains a poor prognosis because it occurs in all tissues and is difficult to diagnose or prevent before metastatic tumor nodules form. Metastasis is a multi-step process involving tumor cells, bone marrow-derived cells, and tissue resident cells, making it a biological three-body problem. It has been shown that a pre-metastatic soil/niche (PMN) is formed in metastatic tissue before tumor cells physically appear at the metastatic site, and suppressing this PMN is key to preventing metastasis. Recent studies highlighted the importance of protein citrullination, an irreversible post-translational modification of proteins, in tumor metastasis. Peptidyl arginine deiminase (PADI) catalyzes the modification of arginine to citrulline. In this enzymatic reaction, the amino acid residue's net charge changes, inducing a structural change in the protein. This review discusses the role of protein citrullination in cancer metastasis. Intracellular citrullination regulates gene expression and genome structure by citrullinating RNA polymerase and histones, while extracellular citrullination provides a pro-metastatic environment. These factors play an important role in PMN formation. Additionally, we discuss PADI inhibitors and anti-metastatic immune cells from the viewpoint of metastasis prevention.

Keywords:  citrullination; metastasis; peptidyl arginine deiminase; pre‐metastatic soil

DOI:  https://doi.org/10.1111/cas.70197
Nucleic Acids Res. 2025 Sep 05. pii: gkaf882. [Epub ahead of print]53(17):

Lactylation of CREB is required for FSH-induced proliferation and differentiation of ovarian granulosa cells.

Gang Wu, Min Chen, Tong He, Yitong Pan, Chengyu Li, Zhaojun Liu, Hongmin Li, Yanan Sheng, Weilong Dai, Ming Shen, Honglin Liu.

Follicle-stimulating hormone (FSH) promotes follicular development by inducing the proliferation and differentiation of granulosa cells (GCs). This process is primarily attributed to the activation of the canonical G protein-coupled receptor (GPCR)/adenylyl cyclase/cAMP/PKA/CREB signaling pathway. Here, we revealed a novel mechanism wherein FSH promotes GCs proliferation and differentiation by stimulating cAMP response element-binding protein (CREB) lactylation. Specifically, FSH induced CREB lactylation at lysine 136 (K136la), leading to CREB phosphorylation at serine 133, which facilitated CREB/CBP/P300 complex formation for transcription activation. Moreover, K136la alone directly recruited CBP/P300, triggering transcriptional surges of proliferation and differentiation genes by binding with the cAMP response element (CRE), thereby stimulating GCs proliferation and differentiation. By contrast, a CREB mutation at K136 eliminated these effects. Blocking CREB lactylation using oxamate or C646 in vivo suppressed GCs proliferation, differentiation, and follicular development in mouse ovaries. These findings highlight the important role of lactylation between metabolic regulation and folliculogenesis, and its importance in mediating GPCR signaling, providing a theoretical basis for treating female infertility associated with defective follicular development.

DOI: https://doi.org/10.1093/nar/gkaf882