bims-prolim 2025-12-07 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–12–07
eleven papers selected by
Bruna Martins Garcia, CABIMER

S-palmitoylation of MTDH regulates ferroptosis resistance in breast cancer cell.
Hepatoblastoma-Derived Exosomal FASN Affected the Differentiation of Hepatic Stellate Cells Into Cancer-Associated Fibroblasts by Regulating the Stability of HK2 and Mediating Histone Lactylation.
Acylation modification-mediated metabolism reprogramming in cancer.
Succinylation of CTBP1 Mediated by SIRT5 Suppresses MAT1A Expression to Promote the Progression of HCC.
Development and Validation of Palmitoylation-Related Genes in the Prognostic and Immunologic Characterization of Lung Adenocarcinoma.
Integrating single-cell RNA-Seq and machine learning to dissect a novel Palmitoylation-related prognostic signature of glioblastoma.
Polydatin upregulates ZDHHC19 to promote apoptosis of acute myeloid leukemia cells via mediating BID palmitoylation.
Lactylation at the crossroads of immune metabolism and epigenetic regulation: revealing its role in rheumatic immune diseases.
KAT2A accelerates lung cancer progression through succinylation of TGFβR2.
S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models.
Identification and validation of palmitoylation-related signature genes based on machine learning for prostate cancer.

J Lipid Res. 2025 Nov 27. pii: S0022-2275(25)00216-0. [Epub ahead of print] 100953

S-palmitoylation of MTDH regulates ferroptosis resistance in breast cancer cell.

Shaojun Pei, Wen Wang, Tingze Feng, Qiuping Wang, Yuhan Wang, Hong-Xu Liu, Xinmiao Liang, Hai-Long Piao.

  S-palmitoylation is a dynamic and reversible post-translational modification that plays crucial roles in cancer progression. Here, we found the oncogene of metadherin (MTDH) modulates lipid metabolism and ferroptosis by its S-palmitoylation. We demonstrate that MTDH is S-palmitoylated at Cys-75 in the endoplasmic reticulum by ZDHHC1/9 and S-depalmitoylated by APT1. The flexible loop and the α-helix length in the MTDH N-terminus affect its S-palmitoylation level. In addition, metabolomics analysis found that the S-palmitoylated MTDH increases intracellular levels of triglycerides, phosphatidylethanolamines, and phosphatidylcholines. However, the non-S-palmitoylation form of MTDH-CS enhanced the interaction of between MTDH and the ferroptosis enhancer of Acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby reducing ferroptosis sensitivity in breast cancer cell. Taken together, targeting MTDH S-palmitoylation may represent a novel strategy for breast cancer therapy.

Keywords:  MTDH; S-palmitoylation; breast cancer; ferroptosis; lipidomics

DOI:  https://doi.org/10.1016/j.jlr.2025.100953
Compr Physiol. 2025 Dec;15(6): e70080

Hepatoblastoma-Derived Exosomal FASN Affected the Differentiation of Hepatic Stellate Cells Into Cancer-Associated Fibroblasts by Regulating the Stability of HK2 and Mediating Histone Lactylation.

Qin Zhu, Yifan Zhou, Yuyin Wang, Xin Wu, Yu Hu, Hongyan Zai.

  Cancer-associated fibroblasts (CAFs) interact with tumor cells in the tumor microenvironment (TME), enhancing glycolysis in CAFs and tumor malignancy. However, the regulatory mechanisms between hepatoblastoma (HB) cells and CAFs are unclear. This study aimed to elucidate the crosstalk mechanism between HB cells and CAFs and identify a new therapeutic target for HB. Exosomes were successfully extracted from Huh-6/HepG2 cells, and hepatic stellate cells (LX2) were treated with conditioned medium or exosomes from these cells. We found that HB cells may stimulate the differentiation of LX2 cells into CAFs through exosomes and enhance histone lactylation. Additionally, HB cell exosome-derived fatty acid synthase (FASN) promoted the transformation of LX2 cells into CAFs and histone lactylation. Mechanistically, FASN affected the transformation of LX2 cells into CAFs and histone lactylation by regulating hexokinase 2 (HK2). FASN regulated HK2 stability by competitively combining with MARCHF1. Activated fibroblasts promoted HB progression by secreting CXCL1/CXCL5. In vivo experiments have demonstrated that HB cell exosome-derived FASN affected the transformation of LX2 cells into CAFs and histone lactylation. Clinical sample analysis revealed that FASN protein expression was significantly positively correlated with the levels of HK2, lactate, and H3K18la, thereby validating the clinical relevance of this regulatory pathway. In conclusion, HB-derived exosomal FASN affected the transformation of LX2 cells into CAFs by regulating the stability of HK2 and mediating histone lactylation, providing novel insights into the crosstalk between HB cells and CAFs and highlighting exosomal FASN as a potential therapeutic target for HB.

Keywords:  HK2; cancer‐associated fibroblasts; exosomal FASN; hepatoblastoma; lactic acid

DOI:  https://doi.org/10.1002/cph4.70080
iScience. 2025 Dec 19. 28(12): 113883

Acylation modification-mediated metabolism reprogramming in cancer.

Kaiwei Huang, Yunshan Wang, Bohao Li, Yuchen Xiu, Hanxiang Zhan, Guangwei Wei, Yangmiao Duan.

  With the development of high-resolution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), various modifications resulting from the reactivity of acyl-CoA intermediates with protein residues have been identified. Acylation modifications, a diverse type of post-translational modifications (PTMs), play pivotal roles in regulating protein functions and are critically involved in tumor metabolic reprogramming. These modifications exhibit significant regulatory effects in various cancers, and their dysregulation is closely associated with malignant tumor progression. In this review, we summarize existing evidence and describe how different types of acylation modifications, including succinylation, crotonylation, lactylation, palmitoylation, and β-hydroxybutyrylation, regulate protein functions and signaling pathways, thereby influencing tumor metabolism reprogramming. Future research into the regulatory functions of acylation modifications and their roles in tumor metabolism will help elucidate the molecular mechanisms of metabolic reprogramming and provide potential targets for developing novel diagnostic and therapeutic strategies for cancer.

Keywords:  Cancer; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2025.113883
Cell Physiol Biochem. 2025 Nov 29. 59(6): 857-866

Succinylation of CTBP1 Mediated by SIRT5 Suppresses MAT1A Expression to Promote the Progression of HCC.

Zhengcai Qiu, Qipeng Wang, Shangshang Li, Guang Lu, Jing Han.

   BACKGROUND/AIMS: Succinylation, a recently characterized post-translational modification (PTM), is a ubiquitously occurring protein modification implicated in diverse biological processes via regulation of protein function and gene expression. CTBP1 encodes C-terminal binding proteins and generates multiple splice variants. However, the functional significance of CTBP1 succinylation in hepatocellular carcinoma (HCC) remains unexplored.
METHODS: Protein succinylation levels were quantified using immunoprecipitation coupled with Western blotting and mass spectrometry. Site-directed mutagenesis identified critical lysine residues targeted by succinylation. Functional impacts of CTBP1 succinylation on HCC cell behaviors were evaluated through CCK8-based cell viability, wound healing, transwell migration, and invasion assays. Molecular mechanisms were elucidated via qRT-PCR and Western blot analyses.
RESULTS: Succinylation levels of CTBP1 were significantly elevated in HCC tumor tissues and cell lines relative to non-tumorous controls. Mass spectrometry and mutagenesis pinpointed K46 and K280 as the primary succinylation sites on CTBP1, with SIRT5 identified as the desuccinylase. Functionally, CTBP1 succinylation enhanced HCC cell proliferation, migration, and invasive potential. Mechanistically, this modification promoted tumor progression by suppressing MAT1A expression-a key regulator of hepatic differentiation and tumorigenesis.
CONCLUSION: Our study reveals that SIRT5-mediated CTBP1 succinylation drives HCC progression through MAT1A suppression, establishing a novel regulatory axis with therapeutic potential for HCC treatment.

Keywords:  Hepatocellular carcinoma ; Succinylation ; Post-translational modification ; Metastasis ; CTBP1

DOI:  https://doi.org/10.33594/000000832
Am J Clin Oncol. 2025 Dec 01.

Development and Validation of Palmitoylation-Related Genes in the Prognostic and Immunologic Characterization of Lung Adenocarcinoma.

Pingjing Li, Yun Xiong.

   OBJECTIVES: Lung adenocarcinoma (LUAD), which is the most frequently diagnosed form of lung cancer, constitutes a major global health challenge due to its significant mortality rate. Palmitoylation, as a key post-translational modification of proteins, plays an important role in tumor progression. However, its influence on sculpting the tumor immune microenvironment (TME) and its subsequent impact on patient prognosis remains incompletely understood.
METHODS: This study was based on the TCGA-LUAD and GSE72094 cohort data sets to explore the potential role of palmitoylation-related genes (PRGs) in LUAD. Through the integration of differential analysis, weighted gene coexpression network analysis (WGCNA), univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) regression analysis, prognostic genes for LUAD were screened. Furthermore, the infiltration patterns of immune cells across different groups were assessed by applying the ssGSEA and CIBERSORT algorithms. To elucidate the potential biological processes mediated by PRGs in LUAD pathogenesis, GSEA, GO and KEGG enrichment analyses, were used. In addition, the consensus clustering method was utilized for identify molecular subtypes of LUAD.
RESULTS: This study identified 5 PRGs as prognostic genes for LUAD and constructed a robust prognostic model. Immune infiltration analysis indicated that the level of immune cell infiltration in patients of the high-risk group was significantly lower. Further enrichment analysis showed that the upregulated differentially expressed genes (DEGs) in the high and low risk groups were related to the cytoskeleton, while the downregulated DEGs were related to lipid metabolism. In addition, this study successfully classified LUAD into 2 molecular subtypes with significant differences.
CONCLUSIONS: Our research delves into the intricate TME and molecular mechanisms of LUAD, providing new insights into the pathologic mechanism and treatment strategies of LUAD.

Keywords:  immune landscape; lung adenocarcinoma; molecular subtype; palmitoylation; prognostic model

DOI:  https://doi.org/10.1097/COC.0000000000001273
BMC Neurol. 2025 Dec 04.

Integrating single-cell RNA-Seq and machine learning to dissect a novel Palmitoylation-related prognostic signature of glioblastoma.

Zhu Zhang, Haojie Zheng, Chunli Yang, Zhiying Lin.

   BACKGROUND: Glioblastoma (GBM) represents a profoundly aggressive and heterogeneous brain neoplasm linked to a bleak prognosis. Palmitoylation plays a key role in the development and progression of GBM, but its molecular mechanism and prognostic significance in GBM are still not fully understood. This study aims to explore the prognostic biomarkers of GBM based on palmitoylation-related genes.
METHODS: Eight scoring methods, including AUCell, UCell, singscore, ssGSEA, JASMINE, VAM, scSE, and viper, were used to score each sample. In addition, the palmitoylation score calculated by the AUCell algorithm is selected as the representative. In order to screen the genes related to GBM survival and build a risk prognosis model, 101 algorithms constructed by 10 kinds of machine learning are arranged and combined for variable screening and model building, and then immune infiltration and immunotherapy evaluation, drug screening, and molecular docking are carried out.
RESULTS: We observed that macrophages in GBM cell types have the highest palmitoylation score. The secondary dimensionality reduction clustering of macrophages showed that the palmitoylation of PLCG2 + macrophages was significantly higher than that of other subtypes, and three core prognostic genes (ZDHHC2, ZDHHC4, ZDHHC20) were screened out by machine learning. A higher risk score is significantly related to worse clinical status and most immune labels. Among them, ZDHHC2 was significantly up-regulated in GBM in several verification groups. Molecular docking found that quercetin was the best targeted drug for ZDHHC2.
CONCLUSION: This study revealed for the first time the heterogeneity of palmitoylation at the GBM single-cell level. The identification of ZDHHC2, ZDHHC4, and ZDHHC20 as key regulators of palmitoylation in GBM emphasized their potential as biomarkers and therapeutic targets.

Keywords:  Glioblastoma; Machine learning algorithms; Molecular docking; Palmitoylation; Single-cell sequencing data

DOI:  https://doi.org/10.1186/s12883-025-04551-4
Cell Commun Signal. 2025 Dec 06.

Polydatin upregulates ZDHHC19 to promote apoptosis of acute myeloid leukemia cells via mediating BID palmitoylation.

Wenhui Zhang, Zhongwen Liu, Xiaohang Pei, Peiyuan Hao, Ling Jiang, Mingyue Shi, Xiaoli Yuan, Zunmin Zhu.



Keywords:  Acute myeloid leukemia; BID; Palmitoylation; Polydatin; ZDHHC19

DOI:  https://doi.org/10.1186/s12964-025-02579-0
J Transl Med. 2025 Nov 29.

Lactylation at the crossroads of immune metabolism and epigenetic regulation: revealing its role in rheumatic immune diseases.

Ziheng Zhu, Chuanbing Huang, Junjie Chen, Lei Wan, Chuanwei Zhang, Jianing Wang.

   BACKGROUND: Lactate was traditionally regarded as merely the end product of glycolysis; however, recent discoveries of lactylation have revealed that lactate can also directly serve as a substrate for epigenetic modification, filling a critical gap in the understanding of "metabolite-epigenetic regulation." In rheumatic immune diseases such as rheumatoid arthritis and systemic lupus erythematosus, the affected tissues, including the joint synovium and internal organs, are typically hypoxic. These regions demonstrate pronounced inflammatory infiltration and metabolic reprogramming, leading to the accumulation of lactate within the local microenvironment. In this context, lactylation directly links the metabolic state (lactate levels) of the microenvironment with epigenetic regulation of gene expression. This offers valuable insights into how metabolic cues specifically modulate the functions of immune cells, including polarization, activation, and cytokine secretion, as well as the behavior of tissue-resident cells, such as synovial fibroblasts. Conventional immunosuppressants demonstrate limited efficacy in correcting such metabolic abnormalities; thus, exploring novel mechanisms and therapeutic targets at the intersection of metabolism and epigenetics is urgently needed. Investigating the mechanistic role of lactylation, therefore, represents a crucial step toward developing innovative therapies for rheumatic autoimmune disorders.
METHODS: This review systematically summarizes the pivotal functions of lactylation within the immune-metabolic and epigenetic regulatory networks, examining its influence on metabolic pathways, chromatin modification, and disease progression. Furthermore, it discusses the modulatory roles of lactylation in immune cell activity, signaling pathway activation, and the generation of disease-specific modification patterns.
RESULTS: In summary, current evidence indicates that lactylation serves as a molecular bridge connecting "immunometabolism-epigenetic dysregulation-chronic inflammation." Its tissue specificity and diverse modification substrates contribute to a complex regulatory network. Therefore, targeting the lactylation regulatory axis may enable the conversion of pathological metabolic features into therapeutic opportunities.
CONCLUSION: Future research should emphasize single-cell lactylome profiling and the development of tissue-specific delivery systems to elucidate better and control the dual physiological and pathological functions of lactylation.

Keywords:  Epigenetic regulation; Immune diseases; Immune metabolism; Lactylation; Metabolic reprogramming; Rheumatic diseases

DOI:  https://doi.org/10.1186/s12967-025-07498-9
Tissue Cell. 2025 Nov 28. pii: S0040-8166(25)00536-1. [Epub ahead of print]99 103254

KAT2A accelerates lung cancer progression through succinylation of TGFβR2.

Mingqiang Shen, Qingqing Sun, Jinjiao Zhang, Tengfang Zhang, Lei Zhang.

  Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is one of the leading causes of cancer-related mortality worldwide. Succinylation has been implicated in the pathogenesis of NSCLC at the molecular level. The succinyltransferase lysine acetyltransferase 2 A (KAT2A) exhibits oncogenic properties in diverse cancers; however, its role in NSCLC development remains unclear. This study employed bioinformatics techniques, clinical specimens, and NSCLC cell lines to analyze KAT2A expression. Cell malignancy was assessed using the cell counting kit-8 (CCK-8) and colony-formation assays. Glycolytic activity was evaluated by measuring glucose uptake, lactate production, extracellular acidification rate, and oxygen consumption rate. The underlying mechanisms were explored using quantitative real-time polymerase chain reaction, immunoblotting, immunoprecipitation, immunofluorescence, and cycloheximide chase assays. The results showed that KAT2A expression was notably higher in NSCLC and was linked to poor prognosis. Knockdown of KAT2A suppressed NSCLC cell growth and glycolysis. Mechanistically, KAT2A knockdown reduced the succinylation of transforming growth factor beta receptor 2 (TGFβR2) at lysine 493, leading to decreased expression of TGFβR2. A mutation at this site attenuated the oncogenic and glycolytic effects induced by TGFβR2 overexpression. Moreover, in vivo experiments demonstrated that KAT2A knockdown markedly inhibited tumor growth. Our findings suggest that KAT2A functions as an oncogenic driver in NSCLC by modulating the succinylation of TGFβR2, underscoring its potential as a therapeutic target.

Keywords:  Glycolysis; KAT2A; Non-small cell lung cancer; Succinylation; TGFβR2

DOI:  https://doi.org/10.1016/j.tice.2025.103254
J Clin Invest. 2025 Dec 01. pii: e188249. [Epub ahead of print]135(23):

S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models.

Hongjin Li, Jianke Lyu, Yu Sun, Chengqian Yin, Yuewen Li, Weiqiang Chen, Suan-Sin Foo, Xianfang Wu, Colin R Goding, Shuyang Chen.

  The intratumor microenvironment shapes the metastatic potential of cancer cells and their susceptibility to any immune response. Yet, the nature of the signals within the microenvironment that control anticancer immunity and how they are regulated is poorly understood. Here, using melanoma as a model, we investigate the involvement in metastatic dissemination and the immune-modulatory microenvironment of Protein S-Acyl Transferases as an underexplored class of potential therapeutic targets. We find that ZDHHC13 suppresses metastatic dissemination by palmitoylation of CTNND1, leading to stabilization of E-cadherin. Importantly, ZDHHC13 also reshapes the tumor immune microenvironment by suppressing lysophosphatidylcholine (LPC) synthesis in melanoma cells, leading to inhibition of M2-like tumor-associated macrophages that we show degrade E-cadherin via MMP12 expression. Consequently, ZDHHC13 activity suppresses tumor growth and metastasis in immunocompetent mice. Our study highlights the therapeutic potential of targeting the ZDHHC13-E-cadherin axis and its downstream metabolic and immune-modulatory mechanisms, offering additional strategies to inhibit melanoma progression and metastasis.

Keywords:  Immunology; Immunotherapy; Molecular biology; Oncology; Skin cancer

DOI:  https://doi.org/10.1172/JCI188249
PLoS One. 2025 ;20(12): e0338407

Identification and validation of palmitoylation-related signature genes based on machine learning for prostate cancer.

Qijun Wo, Jiafeng Shou, Jun Shi, Lei Shi, YunKai Yang, Yifan Wang, Liping Xie.

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with challenges in diagnosis and treatment due to tumor heterogeneity. This study identifies palmitoylation-related signature genes as potential diagnostic and therapeutic targets. Integrating GEO datasets, six differentially expressed genes (DEGs) linked to palmitoylation were identified. Machine learning algorithms (LASSO, RF, SVM) selected three core genes: TRPM4, LAMB3, and APOE. A diagnostic model based on these genes achieved an AUC of 0.929, demonstrating robust accuracy in distinguishing PCa from normal tissues. Functional analysis revealed roles in lipid metabolism and immune modulation, with ssGSEA highlighting correlations between key genes and immune cell infiltration. Experimental validation showed that LAMB3 overexpression suppressed PCa cell proliferation, migration, and invasion, while knockdown enhanced these processes. Molecular docking identified diethylstilbestrol as a potential therapeutic agent targeting LAMB3 and APOE. These findings emphasize the clinical relevance of palmitoylation-related genes in PCa diagnosis and therapy, offering novel biomarkers and insights for personalized treatment strategies.

DOI: https://doi.org/10.1371/journal.pone.0338407