bims-prolim 2025-08-31 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–08–31
ten papers selected by
Bruna Martins Garcia, CABIMER

S-palmitoylation in bone biology: emerging insights and therapeutic potential.
H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.
Targeting Lactylation: From Metabolic Reprogramming to Precision Therapeutics in Liver Diseases.
Lactylation: a novel driver of drug resistance in the tumor microenvironment.
Crosstalk between lactylation and RNA modifications in tumorigenesis: mechanisms and therapeutic implications.
Regulators of Cancer Progression: Succinylation.
S-glutathionylation in cancer: from fundamental mechanisms to clinical applications.
Integrating Bulk RNA and Single-cell transcriptome to explore the role of glycan-related genes in lung adenocarcinoma.
GFAT1 promotes the progression of hepatocellular carcinoma via enhancing the O-GlcNAcylation of VEZF1.
AKR1B10 dictates c-Myc stability to suppress colorectal cancer metastasis via PP2A nitration.

Biochem Pharmacol. 2025 Aug 21. pii: S0006-2952(25)00497-6. [Epub ahead of print]242(Pt 1): 117232

S-palmitoylation in bone biology: emerging insights and therapeutic potential.

Xing Ji, Chengyun Xu, Jiahao Luo, Xinhua Hu, Ximei Wu.

  S-Palmitoylation, the reversible covalent attachment of palmitate to cysteine residues, is a dynamic post-translational lipid modification that regulates the localization, stability, and function of a wide array of proteins. Although traditionally linked to membrane trafficking and signaling, recent preliminary studies have begun to reveal its potential role in bone biology, underscoring its significant research value. This review highlights current advances in detection methodologies-particularly the use of 3H labeling and acyl-biotin exchange (ABE) techniques-that have enabled more precise mapping of the palmitoyl-proteome. We also provide a chronological overview of pivotal discoveries that have gradually shaped our understanding of palmitoylation beyond classical paradigms. Building on this foundation, we focus on emerging insights into how S-palmitoylation influences osteoblast and osteoclast differentiation, thereby contributing to skeletal homeostasis. Special attention is given to the interplay between lipid metabolism and palmitoylation machinery in bone cells, suggesting that this modification may serve as a nutrient-sensitive regulatory node during bone remodeling. Finally, we explore the therapeutic potential of targeting palmitoylation pathways-through enzymatic inhibition, metabolic modulation, genetic approaches, and epigenetic regulation-as promising strategies to enhance bone regeneration and treat conditions such as osteoporosis and fracture nonunion.

Keywords:  Bone biology; Bone diseases; Osteoblasts; Osteoclasts; S-palmitoylation; Therapeutic targets

DOI:  https://doi.org/10.1016/j.bcp.2025.117232
J Exp Clin Cancer Res. 2025 Aug 23. 44(1): 252

H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.

Jiena Liu, Liuying Zhao, Meisi Yan, Shengye Jin, Lingmin Shang, Jianyu Wang, Qin Wang, Shilu Zhao, Zibo Shen, Tong Liu, Hao Wu, Da Pang.

  Metabolic reprogramming and epigenetic modification are two hallmarks of cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by lactate dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in cancer tissues and cells. Glycolytic genes, such as lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.

Keywords:  Breast cancer; Epigenetic modification; Glycolysis; Lactylation; Post-translational modifications

DOI:  https://doi.org/10.1186/s13046-025-03512-6
Biomolecules. 2025 Aug 16. pii: 1178. [Epub ahead of print]15(8):

Targeting Lactylation: From Metabolic Reprogramming to Precision Therapeutics in Liver Diseases.

Qinghai Tan, Mei Liu, Xiang Tao.

  Lactylation, a recently identified post-translational modification (PTM) triggered by excessive lactate accumulation, has emerged as a crucial regulator linking metabolic reprogramming to pathological processes in liver diseases. In hepatic contexts, aberrant lactylation contributes to a range of pathological processes, including inflammation, dysregulation of lipid metabolism, angiogenesis, and fibrosis. Importantly, lactylation has been shown to impact tumor growth, metastasis, and therapy resistance by modulating oncogene expression, metabolic adaptation, stemness, angiogenesis, and altering the tumor microenvironment (TME). This review synthesizes current knowledge on the biochemical mechanisms of lactylation, encompassing both enzymatic and non-enzymatic pathways, and its roles in specific liver diseases. From a therapeutic perspective, targeting lactate availability and transport, as well as the enzymes regulating lactylation, has demonstrated promise in preclinical models. Additionally, combinatorial approaches and natural compounds have shown efficacy in disrupting lactylation-driven pathways, providing insights into future research directions for hepatic diseases. Although the emerging role of lactylation is gaining attention, its spatiotemporal dynamics and potential for clinical translation are not yet well comprehended. This review aims to synthesize the multifaceted roles of lactylation, thereby bridging mechanistic insights with actionable therapeutic strategies for liver diseases.

Keywords:  lactate; lactylation; liver diseases; metabolic regulation; post-translational modification

DOI:  https://doi.org/10.3390/biom15081178
Cancer Drug Resist. 2025 ;8 39

Lactylation: a novel driver of drug resistance in the tumor microenvironment.

Chunwei Li, Ziqiang Liu, Dezheng Kong, Zhengze Li, Lifeng Li.

  Lactylation, a novel lactate-derived lysine post-translational modification (PTM), has emerged as a critical epigenetic regulator driving drug resistance within the tumor microenvironment (TME). This review systematically delineates the enzymatic underpinnings of lactylation, its induction via the glycolysis-lactate axis influenced by key TME features (hypoxia, inflammation), and its multifaceted roles in promoting resistance. Specifically, lactylation orchestrates transcriptional reprogramming of resistance-associated genes (e.g., oncogenes, immune checkpoints, epithelial-mesenchymal transition factors), enhances DNA damage repair capacity (e.g., via NBS1/MRE11 lactylation), activates pro-survival autophagy, and modulates immunosuppressive signaling pathways (e.g., PI3K/AKT, NF-κB, JAK/STAT). Furthermore, it facilitates critical resistance phenotypes including immune evasion, metastasis, and angiogenesis. The review summarizes emerging therapeutic strategies targeting lactylation, such as inhibition of lactate production (LDHA/LDHB), lactate transport (MCT1/4), lactyltransferases (e.g., p300), or downstream effectors, highlighting their potential to overcome multifactorial resistance. However, elucidating the context-dependent roles, crosstalk with other PTMs, and developing specific inhibitors remain crucial for translating these insights into effective clinical interventions against resistant tumors.

Keywords:  Lactylation; drug resistance; epigenetic; tumor microenvironment

DOI:  https://doi.org/10.20517/cdr.2025.90
Biomark Res. 2025 Aug 26. 13(1): 110

Crosstalk between lactylation and RNA modifications in tumorigenesis: mechanisms and therapeutic implications.

Shantong Liu, Qianquan Ma, Chong Zeng, Haoyu Li, Jun Su, Zhihao Song, Ruyu Yan, Zijin Zhao, Songhai Tian, Wei Huang.

  Complex crosstalk occurs between protein and nucleic acid modifications, with lactylation, an emerging post-translational modification (PTM), being implicated in tumor progression. However, the mechanisms mediating the crosstalk between lactylation and RNA modifications and their roles in disease pathogenesis remain largely unresolved. In this review, we summarize current advances in the regulatory interactions between lactylation and RNA modifications, explore their functional implications in cancer biology, and discuss the therapeutic potential of targeting these modifications individually or in combination. This work aims to provide a comprehensive overview of their mechanistic involvement in cancer and to inform novel strategies for precision-targeted therapy.

Keywords:  Crosstalk; Lactylation modification; Positive feedback loop; RNA modification; Targeted therapy

DOI:  https://doi.org/10.1186/s40364-025-00824-9
Cancers (Basel). 2025 Aug 14. pii: 2652. [Epub ahead of print]17(16):

Regulators of Cancer Progression: Succinylation.

Jie Gao, Wei Yu.

  Lysine succinylation is a recently discovered post-translational protein modification, the process of which requires the participation of various enzymes. The close association between cancer and protein post-translational modifications (PTMs), such as acetylation and phosphorylation, has been extensively investigated and well-established. In recent years, growing attention has been directed toward the role of succinylation in cancer progression. Accumulating evidence demonstrates that protein succinylation and desuccinylation play critical roles in promoting the development of various cancers, including lung, prostate, and renal cancers. Notably, the primary substrates undergoing succinylation are non-histone proteins. Therefore, elucidating the functions of cancer-related succinylated proteins is essential for identifying novel therapeutic targets. This review comprehensively summarizes current research advances regarding protein succinylation in common cancers and discusses the progress in developing succinylation-targeting drugs. Specifically, we focus on the molecular mechanisms by which succinylation regulates cancer progression, along with the identification of key succinylation sites. Our discussion aims to provide valuable insights for future research and the development of innovative cancer treatments.

Keywords:  cancer; drug; succinylation; tumor

DOI:  https://doi.org/10.3390/cancers17162652
Pharmacol Res. 2025 Aug 24. pii: S1043-6618(25)00349-4. [Epub ahead of print]220 107924

S-glutathionylation in cancer: from fundamental mechanisms to clinical applications.

Shuai Dong, Li Linghu, Desheng Xiao, Shuang Liu, Yongguang Tao.

  Glutathione (GSH) is a thiol-containing antioxidant composed of glutamic acid, cysteine and glycine. GSH can form a disulfide bond with the cysteine sulfhydryl group of a protein, resulting in S-glutathionylation (-SSG). S-glutathionylation is a reversible posttranslational modification that plays important roles in redox regulation, detoxification, cell signaling pathway regulation, cell death, infection and inflammation. Recent studies have shown that GSH and glutathionylation also have a significant effect on a variety of common cancers. GSH has the potential to serve as an auxiliary diagnostic tool for cancer. S-glutathionylation can regulate the level of the modified protein to regulate tumor cell proliferation and patient survival. In addition, glutathionylation can affect resistance to anticancer clinical drugs, as well as immunotherapy. These findings provide a new therapeutic target for cancer treatment. This review comprehensively reviews the key roles of glutathionylation and its potential mechanisms in a variety of common cancers. Finally, we discuss in depth the role of glutathionylation in resistance to radiotherapy, chemotherapy, targeted drugs and immune checkpoint inhibitors. This study provides a theoretical basis for the development of new cancer treatment drugs.

Keywords:  Cancer; Drug resistance; Glutathione; Glutathionylation

DOI:  https://doi.org/10.1016/j.phrs.2025.107924
J Cancer. 2025 ;16(11): 3314-3328

Integrating Bulk RNA and Single-cell transcriptome to explore the role of glycan-related genes in lung adenocarcinoma.

Keyun Zhu, Changqing Yang, Guixin Wang, XingKai Wang, Chengbin Lin, Yingxi Li, Ningning He, Yao Tian, Weiyu Shen.

  Background: Despite significant advancements in the diagnosis and therapeutic management of lung adenocarcinoma (LUAD), patient outcomes continue to be suboptimal, primarily attributable to the intricate of the tumor microenvironment (TME). Recently, attention has been paid to the role of glycans and their glycosylation modifications in tumor progression. Methods: In the present investigation, we performed analyses to identify 13 glycan-related genes with prognostic significance in LUAD. High- and low-risk groups were distinguished by a constructed model of glycan-related genes. Single-cell analysis was performed to investigate the TME in LUAD. Drug screening analysis was utilized to predict potential candidate drugs. Results: High-risk patients exhibited aggressive tumor progression. Further single-cell analysis revealed that tumor cells expressing high-risk glycan-related genes displayed enhanced interactions with immune and stromal cells, suggesting that aberrant glycosylation and glycan biosynthesis may contribute to worse outcomes in LUAD by promoting immune suppression. Furthermore, based on the molecular characteristics, we identified several potential candidate drugs for personalized treatment, including docetaxel, alpelisib, and gefitinib. Conclusion: Our study found that glycan-related genes could alter the composition of immune cell infiltration in LUAD tumor tissues and might affect the interaction between immune cells and tumor cells through intercellular section signals, resulting in the inability of immune cells to normally initiate immune responses against tumor cells. These findings offer new biological perspectives of glycan-related genes in shaping the TME and potential targets for personalized LUAD treatment.

Keywords:  glycan; glycosylation; immune regulation; lung adenocarcinoma; prognosis; treatment

DOI:  https://doi.org/10.7150/jca.115989
Cell Death Dis. 2025 Aug 26. 16(1): 647

GFAT1 promotes the progression of hepatocellular carcinoma via enhancing the O-GlcNAcylation of VEZF1.

Jia-Yao Yang, Rong Zhang, Zhi-Rong Zhang, Shan Li, De-Ao Gong, Chen-Hao Li, Chang Chen, Lu-Yi Huang, Ai-Long Huang, Ni Tang, Kai Wang.

Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the first rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), is a pivotal regulator of HBP flux. Despite its established significance, the molecular underpinnings of GFAT1's role in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we found that GFAT1 was upregulated in HCC, and high GFAT1 level was correlated with poor patient prognosis. Our in vitro and in vivo studies demonstrated that GFAT1 facilitated hepatoma cell proliferation and invasion by enhancing HBP and O-GlcNAcylation through its enzymatic activity. Global profiling of O-GlcNAcylation identified vascular endothelial zinc finger protein 1 (VEZF1) as a key substrate heavily O-GlcNAcylated in GFAT1-overexpressing hepatoma cells. Notably, O-GlcNAcylation at specific serine residues (Ser123 and Ser124) within VEZF1 attenuated its proteasomal degradation, thereby enhancing its protein stability and promoting tensin 1 (TNS1) transcription in HCC. In addition, we designed a bioactive VEZF1-derived peptide to competitively inhibit GFAT1-mediated O-GlcNAcylation of VEZF1. This intervention effectively reduced TNS1 expression and suppressed the progression of HCC in a mouse model. Collectively, our findings underscore the therapeutic potential of targeting the GFAT1-VEZF1-TNS1 signaling axis in HCC.

DOI: https://doi.org/10.1038/s41419-025-07975-5
Sci Adv. 2025 Aug 22. 11(34): eadv6937

AKR1B10 dictates c-Myc stability to suppress colorectal cancer metastasis via PP2A nitration.

Xiaoxue Wu, Shaoqing Huang, Jialing Gao, Shuting Huang, Lulu Chen, Ziyi Zhao, Ruihan Pu, Xiaojing Ma, Xianzhi Liu, Weiling He, Mei Song.

Metabolic enzymes, critical for cellular homeostasis, are frequently co-opted in a disease-specific manner to drive cancer progression. Here, we identify aldo-keto reductase family 1 member B10 (AKR1B10), down-regulated in gastrointestinal cancers, as a pivotal metastasis suppressor correlating with improved colorectal cancer (CRC) prognosis. Mechanistically, AKR1B10 activates protein phosphatase 2A (PP2A) by preventing redox-regulated nitration of its B56α subunit, preserving holoenzyme assembly and enabling c-Myc dephosphorylation at serine-62. Loss of AKR1B10 disrupts this pathway, stabilizing c-Myc, which drives integrin signaling and metastatic dissemination in CRC. We further demonstrate that lysine-125 of AKR1B10 is essential for its interaction with PP2A-Cα and B56α nitration, thereby attenuating CRC metastatic aggressiveness. Pharmacological restoration of PP2A activity effectively mitigates metastasis associated with AKR1B10 loss. In addition, c-Myc transcriptionally represses AKR1B10, establishing a feedback loop that sustains its down-regulation and enhances metastatic progression. This study uncovers an antimetastatic mechanism involving AKR1B10-mediated PP2A activation and highlights its potential as a biomarker and therapeutic target.

DOI: https://doi.org/10.1126/sciadv.adv6937