bims-prolim 2025-05-11 papers

Issue of 2025–05–11
six papers selected by
Bruna Martins Garcia, CABIMER

Bone Joint Res. 2025 May 09. 14(5): 420-433

The role of palmitoylation modifications in the regulation of bone cell function, bone homeostasis, and osteoporosis.

Ximeng Wang, Yuxuan Zhang, Zhidi Lin, Hongli Wang, Guangyu Xu, Xiaosheng Ma.

Osteoporosis a is a metabolic bone disease caused by an imbalance in bone homeostasis, which is regulated by osteoblasts and osteoclasts. Protein palmitoylation modification is a post-translational modification that affects protein function, localization, and targeting by attaching palmitoyl groups to specific amino acid residues of proteins. Recent studies have shown that protein palmitoylation is involved in the regulation of osteoclast overproduction, osteoblast migration, osteogenic differentiation, dysfunctional autophagy, and endocrine hormone membrane receptors in osteoporosis. Exactly to what extent palmitoylation modifications can regulate osteoporosis, and whether palmitoylation inhibition can delay osteoporosis, is a key question that needs to be investigated urgently. In this review, we observed that palmitoylation modifications act mainly through two target cells - osteoblasts and osteoclasts - and that the targets of palmitoylation modifications are focused on plasma membrane proteins or cytosolic proteins of the target cells, which tend to assume the role of receiving extracellular signals. We also noted that different palmitoyl transferases acting on different substrate proteins exert conflicting regulation of osteoblast function. We concluded that the regulation of osteocyte function, bone homeostasis, and osteoporosis by palmitoylation modifications is multidimensional, diverse, and interconnected. Perfecting the palmitoylation modification network can enhance our ability to utilize post-translational modifications to resist osteoporosis and lay the foundation for targeting palmitoyl transferases to treat osteoporosis in the future.

DOI: https://doi.org/10.1302/2046-3758.145.BJR-2024-0259.R2

Molecules. 2025 Apr 15. pii: 1763. [Epub ahead of print]30(8):

Tumor Microenvironment Lactate: Is It a Cancer Progression Marker, Immunosuppressant, and Therapeutic Target?

Eugene Y Kim, Joyce Abides, Chandler R Keller, Steve R Martinez, Weimin Li.

The "Warburg effect" is a term coined a century ago for the preferential use of glycolysis over aerobic respiration in tumor cells for energy production, even under aerobic conditions. Although this is a less efficient mechanism of generating energy from glucose, aerobic glycolysis, in addition to the canonical anaerobic glycolysis, is an effective means of lactate production. The abundant waste product, lactate, yielded by the dual glycolysis in a tumor, has been discovered to be a major biomolecule that drives cancer progression. Lactate is a metabolic energy source that, via cell membrane lactate transporters, shuttles in and out of cancer cells as well as cancer cell-associated stromal cells and immune cells within the tumor microenvironment (TME). Additionally, lactate serves as a pH tuner, signaling ligand and transducer, epigenetic and gene transcription regulator, TME modifier, immune suppressor, chemoresistance modulator, and prognostic marker. With such broad functionalities, the production-consumption-reproduction of TME lactate fuels tumor growth and dissemination. Here, we elaborate on the lactate sources that contribute to the pool of lactate in the TME, the functions of TME lactate, the influence of the TME lactate on immune cell function and local tissue immunity, and anticancer therapeutic approaches adopting lactate manipulations and their efficacies. By scrutinizing these properties of the TME lactate and others that have been well addressed in the field, it is expected that a better weighing of the influence of the TME lactate on cancer development, progression, prognosis, and therapeutic efficacy can be achieved.

Keywords: cell metabolism; immune regulation; lactate; posttranslational modification; signaling and gene regulation; tumor microenvironment (TME)

DOI: https://doi.org/10.3390/molecules30081763

Mol Cancer. 2025 May 07. 24(1): 138

Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics.

Mengke Xu, Bo Xu.

Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.

Keywords: N-myristoylation; S-palmitoylation; S-prenylation; Lipidation; Tumor microenvironment

DOI: https://doi.org/10.1186/s12943-025-02309-7

Nat Commun. 2025 May 08. 16(1): 4254

Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion.

Yijian Yan, Jiali Yu, Weichao Wang, Ying Xu, Kole Tison, Rongxin Xiao, Sara Grove, Shuang Wei, Linda Vatan, Max Wicha, Ilona Kryczek, Weiping Zou.

B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We find that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors results in robust anti-tumor immunity and reduces tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primes lysosome activation and promotes lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib results in T cell activation and mitigates B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an important PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to promote B7-H4 degradation, thereby treating patients with B7-H4 expressing tumors.

DOI: https://doi.org/10.1038/s41467-025-58552-5

Front Cardiovasc Med. 2025 ;12 1567310

Comprehensive analysis of lactylation-related gene and immune microenvironment in atrial fibrillation.

Yazhe Ma, Youcheng Wang, Yuanjia Ke, Qingyan Zhao, Jie Fan, Yang Chen.

Background: Atrial fibrillation (AF) is a common arrhythmia associated with an increased risk of stroke, heart failure, and mortality. Immune infiltration plays a crucial role in AF pathogenesis, yet its mechanisms remain unclear. Lactylation, a novel post-translational modification, has been implicated in immune regulation, but its association with AF remains unexplored. This study aims to elucidate the relationship between lactylation and immune infiltration in AF and identify potential diagnostic biomarkers.
Methods: Gene expression data from left atrial tissue samples of AF and sinus rhythm (SR) patients were obtained from the Gene Expression Omnibus (GEO) database (GSE41177, GSE79768, GSE115574, GSE2240, GSE14975, and GSE128188). Differentially expressed genes (DEGs) between AF and SR samples were identified, followed by pathway enrichment and immune infiltration analysis. Correlation analysis and WGCNA were performed to assess interactions between lactylation-related genes and immune-associated DEGs. Machine learning models, including Random Forest and Support Vector Machine (SVM), were applied to select potential AF-related diagnostic biomarkers, and validated in the animal model (beagles; n = 6).
Results: A total of 5,648 DEGs were identified, including six lactylation-related genes (DDX39A, ARID3A, TKT, NUP50, G6PD, and VCAN). Co-expression and WGCNA analyses identified lactylation- and immune-associated gene modules in AF. Functional enrichment analysis highlighted immune-related pathways such as T cell activation and neutrophil degranulation. A five-gene diagnostic model (FOXK1, JAM3, LOC100288798, MCM4, and RCAN1) achieved high predictive accuracy (AUC = 0.969 in training, 0.907 in self-test, and 0.950, 0.760, 0.890 in independent datasets). Experimental validation confirmed the upregulated expression of these biomarkers in AF.
Conclusion: This study reveals a strong association between lactylation-related genes and immune infiltration in AF, suggesting their involvement in immune remodeling. The identified five-gene signature serves as a potential diagnostic biomarker set, offering novel insights into AF pathogenesis and contributing to improved diagnosis and targeted therapeutic strategies. Future studies integrating proteomic and single-cell analyses will further clarify the role of lactylation in AF.

Keywords: atrial fibrillation; diagnostic biomarkers; immune infiltration; lactylation; machine learning

DOI: https://doi.org/10.3389/fcvm.2025.1567310

Cell Commun Signal. 2025 May 05. 23(1): 214

Glycosylation as an intricate post-translational modification process takes part in glycoproteins related immunity.

Meng Tian, Xiaoyu Li, Liuchunyang Yu, JinXiu Qian, XiuYun Bai, Jue Yang, RongJun Deng, Cheng Lu, Hongyan Zhao, Yuanyan Liu.

Protein glycosylation, the most ubiquitous and diverse type of post-translational modification in eukaryotic cells, proteins are input into endoplasmic reticulum and Golgi apparatus for sorting and modification with intricate quality control, are then output for diverse functional glycoproteins that are utilized by cells to precisely regulate various biological processes. In order to maintain the precise spatial structure of glycoprotein, misfolded and unfolded glycoproteins are recognized, segregated and degraded to ensure the fidelity of protein folding and maturation. This review enumerates the role of five immune-related glycoproteins and reveals the relevance of glycosylation to their antigen presentation, immune effector function, immune recognition, receptor binding and activation, and cell adhesion and migration. With the knowledgement of glycoproteins in immune responses and etiologies, we propose several relevant therapeutic strategies on targeting glycosylation process for immunotherapy.

Keywords: Glycans; Glycoprotein; Glycosylation; Immune response; Immunotherapy; Quality control

DOI: https://doi.org/10.1186/s12964-025-02216-w