bims-prolim 2025-11-30 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–11–30
eleven papers selected by
Bruna Martins Garcia, CABIMER

RHOA lactylation at oncogenic hotspots promotes oncogenic activity and protein stabilization.
Lactylation modification regulates acute myeloid leukemia pathogenesis and immune microenvironment.
DysUFMylation of SREBP1 Promotes the Progression of Hepatocellular Carcinoma by Reprogramming Lipid Metabolism.
Histone lactylation drives METTL3 upregulation-mediated RNA m6A modification of CCT2 to hinder CD8+ T cell survival in gastric cancer.
Post-translational modifications of protein and lung cancer.
FiLactate-Induced Lysine Lactylation: A Central Node Linking Metabolic Rewiring, Epigenetic Plasticity and Therapeutic Vulnerabilities in Hepatocellular Carcinoma.
H3K18 lactylation in cancer-associated fibroblasts drives malignant pleural effusion progression via TNFR2+ Treg recruitment.
LDHA facilitates immune escape in bladder cancer through H4K5 lactylation-dependent upregulation of PD-L1.
Extracellular vesicle R-Ras is a potential biomarker for human peripheral artery disease.
Single-cell and spatial transcriptomics reveal lactylation-associated tumor cell clusters and define a prognostic risk model in glioblastoma.
Importance of SUMOylation Consensus Sequence of MAFK in Regulating EMT, Tumor Growth, Stemness, and Drug Resistance.

Mol Cancer. 2025 Nov 25.

RHOA lactylation at oncogenic hotspots promotes oncogenic activity and protein stabilization.

Chenglong Ma, Ruocen Liao, Xingyu Chen, Qianhua Cao, Xinyue Deng, Zhijun Dai, Chenfang Dong.

   BACKGROUND: Aberrant RHOA activation drives tumor progression, yet regulatory mechanisms beyond genetic mutations remain poorly defined. Lactylation, a lactate-derived post-translational modification, links metabolic reprogramming to oncogenesis, but its functional mimicry of genetic mutations is unexplored. This study investigates RHOA lactylation at oncogenic hotspots and its role as an "epi-mutation" system.
METHODS: RHOA lactylation were identified by pan-lysine lactylation (Kla) antibody-based mass spectrometry. Site-specific lactylation was achieved using an orthogonal Mb-Pyl Kla-RS/Pyl-tRNA pair to incorporate lactyl-lysine at K118/K162 in recombinant RHOA, validated by immunoblotting and fluorescence. Molecular dynamics simulations (AlphaFold 3, BIOVIA DS) analyzed GTPase activity and hydrogen-bond networks. RHOA activity was assessed via ROCK2-RBD pull-down and GTPase assays. Ubiquitination and protein stability were examined using cycloheximide chase and K48/K63-ubiquitin mutants. In vitro lactylation/delactylation assays with PCAF/HDAC3 defined enzyme specificity. In vitro/in vivo functional studies used migration/invasion assays and xenograft models. Clinical relevance was evaluated in breast cancer tissues and survival databases.
RESULTS: We identify lactylation of RHOA at oncogenic mutation hotspots K118 and K162, mediated by the lactate-PCAF/HDAC3 axis. Mechanistically, K118 lactylation constitutively activates RHOA by impairing intrinsic GTPase activity, whereas K162 lactylation stabilizes RHOA protein by competitively antagonizing protein ubiquitination, with USP9X further enhancing stability through deubiquitination. Functionally, RHOA lactylation promotes tumor cell migration, invasion and metastasis. Clinically, RHOA lactylation is elevated in breast tumors versus adjacent tissues. Notably, targeting lactate production (LDHA inhibitor: sodium oxamate) synergized with RHOA-pathway inhibition (ROCK inhibitor: Y-27632) to suppress tumor progression. By employing a site-specific lactylation system, we further identify that lactylation mimics oncogenic mutations by enhancing both RHOA activity and stability, thus proposing that lactylation at mutation-prone sites represents a reversible "epi-mutation" system that recapitulates genetic mutation effects.
CONCLUSIONS: RHOA lactylation at K118 (activation) and K162 (stabilization) orchestrated by the PCAF/HDAC3 enzymatic axis, enables constitutive oncogenic signaling to fuel tumor progression. Crucially, we redefine that lactylation at mutation-prone sites functions as a reversible "epi-mutation" system, where metabolic modification dynamically recapitulates oncogenic mutation effects, challenging the genetic/epigenetic dichotomy in oncology and revealing dual targeting of lactylation and canonical RHOA pathways as a potential therapeutic strategy.

Keywords:  HDAC3; Lactylation; PCAF; RHOA; USP9X

DOI:  https://doi.org/10.1186/s12943-025-02511-7
Discov Oncol. 2025 Nov 27.

Lactylation modification regulates acute myeloid leukemia pathogenesis and immune microenvironment.

Ruixue Dai, Guodong Sui.



Keywords:  Acute myeloid leukemia; Immune cell infiltration; Lactylation; Machine learning; Post-translational modification

DOI:  https://doi.org/10.1007/s12672-025-03979-x
J Clin Transl Hepatol. 2025 Nov 28. 13(11): 949-963

DysUFMylation of SREBP1 Promotes the Progression of Hepatocellular Carcinoma by Reprogramming Lipid Metabolism.

Xukang Gao, Zeping Han, Min Xu, Zhutao Wang, Guoqiang Sun, Hao Xiao, Dai Zhang, Shuangjian Qiu, Ning Ren, Chenhao Zhou, Yong Yi.

   Background and Aims: Sterol regulatory element-binding protein 1 (SREBP1), a key regulator of lipogenesis, is highly expressed in tumors, but the mechanisms sustaining its elevated levels remain unclear. The role of UFMylation, a posttranslational modification, in modulating SREBP1 stability and tumor progression has not been explored. This study aimed to investigate the role of UFMylation in the progression of liver cancer.
Methods: Liquid chromatography-tandem mass spectrometry was employed to investigate the interacting proteins of ubiquitin-fold modifier 1-specific ligase 1 (UFL1). Knockdown of UFL1 and DDRGK domain-containing protein 1 (DDRGK1) was performed to assess SREBP1 stability. In vitro and in vivo models of hepatocellular carcinoma (HCC) were used to evaluate tumor progression. Clinical correlations between UFL1/DDRGK1 and SREBP1 levels were analyzed in HCC patient samples.
Results: SREBP1 undergoes UFMylation, which synergizes with ubiquitination to reduce its stability. Depletion of UFL1 or DDRGK1 increased SREBP1 stability, driving HCC progression. Clinically, UFL1 and DDRGK1 levels were reduced in HCC tissues and inversely correlated with SREBP1 expression. Fatostatin (an SREBP1 inhibitor) enhanced the therapeutic effect of Lenvatinib in HCC models with low UFL1 expression.
Conclusions: UFMylation is a critical posttranslational modification that destabilizes SREBP1, and its dysregulation contributes to HCC progression. Targeting the UFMylation-SREBP1 axis, particularly through Fatostatin and Lenvatinib combination therapy, represents a novel therapeutic strategy for HCC.

Keywords:  HCC; Hepatocellular carcinoma; SREBP1; Sterol regulatory element-binding protein 1; UFL1; UFMylation; ubiquitin-fold modifier 1-specific ligase 1-specific ligase 1

DOI:  https://doi.org/10.14218/JCTH.2025.00318
Cell Mol Life Sci. 2025 Nov 25.

Histone lactylation drives METTL3 upregulation-mediated RNA m6A modification of CCT2 to hinder CD8+ T cell survival in gastric cancer.

Zhenyuan Qian, Xufan Cai, Fang Wu, Zaiyuan Ye, Jianzhang Wu.

   BACKGROUND: Histone lactylation represents a novel epigenetic modification that can modulate gene expression, further boosting tumor proliferation, metastasis, and immune suppression. However, whether histone lactylation affects immune evasion in gastric cancer (GC) remains to be elucidated.
METHODS: WB and IHC were employed to assess the levels of H3K18la in tumor tissues. CCK-8, colony formation, T cell killing, ELISA, cytotoxicity experiments, and T cell chemotaxis experiments were undertaken to determine the biological functions of histone lactylation and METTL3. RNA-seq, WB, and CHIP experiments were utilized to validate the regulatory role of H3K18 lactylation in METTL3 transcriptional activity. The RIP assay was undertaken to verify the post-transcriptional modification of METTL3 protein on CCT2. The IF and flow cytometry were completed to analyze the regulatory mechanism of CCT2 on CD8+T cells' activity. IHC and IF were performed to detect protein expression in the homograft mouse model.
RESULTS: Histone H3K18 lactylation was elevated in GC, promoting tumor proliferation, inhibiting cytotoxicity, and chemotaxis of CD8⁺T cells. Mechanistically, H3K18 lactylation boosted tumor immune suppression and in vivo tumorigenesis by upregulating METTL3 expression, while METTL3 enhanced CCT2 translation through m6A modification. CCT2 weakened CD8⁺T cell activity by inhibiting Ca²⁺ influx. METTL3 knockdown inhibited the immune escape of GC cells, while overexpression of CCT2 reversed the anti-tumor effect of METTL3 knockdown on CD8⁺T cells.
CONCLUSION: Histone lactylation drives upregulation of METTL3 and mediates m6A modification and overexpression of CCT2. CCT2 dampens the activity of CD8+T cells by repressing Ca2+influx, thereby mediating the malignant progression of GC.

Keywords:  CCT2; CD8+ t cells; Gastric cancer; Histone lactylation; METTL3

DOI:  https://doi.org/10.1007/s00018-025-05955-8
Front Oncol. 2025 ;15 1667200

Post-translational modifications of protein and lung cancer.

Ying Zhao, Xiaoyu Song, WenFeng Luo, Fangmei Xie, Jian Shen, JinHua He, Zeping Han, Jinju Huang.

  Post-translational modifications (PTMs) represent a pivotal regulatory mechanism in cellular processes, wherein the addition or removal of specific functional groups to amino acid residues dynamically modulates protein activity, subcellular localization, expression levels, and interactions with other biomolecules. Key PTMs, including phosphorylation, acetylation, methylation, glycosylation, ubiquitination, and emerging types like succinylation and crotonylation, exponentially diversify the proteome's functional landscape. In lung cancer, PTMs orchestrate critical pathological processes, such as EGFR phosphorylation-driven proliferation, H3K27me3-mediated epigenetic silencing, and KEAP1 succinylation-regulated redox homeostasis. Recent advances in mass spectrometry (MS), phosphoproteomics, and epigenomic profiling have enabled systematic mapping of PTM networks, revealing their potential as diagnostic biomarkers, therapeutic targets, and predictors of drug response. This review synthesizes the mechanistic roles of PTMs in lung cancer pathogenesis and their translational applications, highlighting multi-omics integration and PTM-targeted therapies as future frontiers in precision oncology.

Keywords:  diagnosis; lung cancer; post-translational modifications; prognosis; progression; treatment

DOI:  https://doi.org/10.3389/fonc.2025.1667200
J Biochem Mol Toxicol. 2025 Dec;39(12): e70622

FiLactate-Induced Lysine Lactylation: A Central Node Linking Metabolic Rewiring, Epigenetic Plasticity and Therapeutic Vulnerabilities in Hepatocellular Carcinoma.

Ying-Chuan Yin, Jing He, Ying Feng, Yun-Yun Xu, Xiao-Hong Shi, Xue Tan, Qiao-Juan He.

  Hepatocellular carcinoma (HCC) exploits aerobic glycolysis to generate a surplus of lactate that fuels malignant growth, immune evasion, and drug resistance. Lysine lactylation (Kla), deposited by p300/CBP using lactyl-CoA and removed by sirtuin deacylases, has emerged as a pivotal conduit through which lactate rewires chromatin architecture and protein function. Following PRISMA-compliant screening of 612 publications, 45 high-quality studies published between 2019 and 2025 were integrated with our own multi-omics interrogation of 1,128 tumours. Histone H3/H4 Kla amplifies glycolytic, epithelial-to-mesenchymal transition, and multidrug-resistance programmes, forging a feed-forward metabolic-epigenetic circuit. Non-histone Kla targeting ALDOA^K230/322, c-Myc, YAP, and STAT3 stabilises oncogenic signalling, sustains PI3K-AKT-mTOR and Wnt/β-catenin cascades, and preserves liver cancer stem-cell self-renewal. Concomitantly, Kla skews tumour-associated macrophages toward an M2 phenotype, activates cancer-associated fibroblasts and endothelial cells, and suppresses cytotoxic lymphocyte infiltration, collectively sculpting an immunosuppressive niche. A Kla-high transcriptional signature shortens median overall survival by 18 months and stratifies patients with poor response to sorafenib and immune checkpoint blockade. Three convergent therapeutic entry points emerge: depletion of lactate via glycolytic inhibition or MCT1/4 blockade (FX11, AZD3965), enzymatic modulation of Kla writers or erasers, and PROTAC-mediated degradation of oncogenic lactylated proteins. In murine and patient-derived xenograft models, these strategies reduce tumour volume by at least 50% and synergise durably with anti-PD-1 therapy. This integrated synthesis positions lysine lactylation as a hierarchical regulator that links metabolic stress to epigenetic plasticity, immune escape, and therapeutic vulnerability, and outlines a biomarker-driven roadmap for lactylation-targeted precision medicine in HCC.

Keywords:  epigenetic plasticity; hepatocellular carcinoma; lysine lactylation; metabolic reprogramming; precision oncology; tumor microenvironment

DOI:  https://doi.org/10.1002/jbt.70622
Exp Mol Med. 2025 Nov 28.

H3K18 lactylation in cancer-associated fibroblasts drives malignant pleural effusion progression via TNFR2+ Treg recruitment.

Linlin Ye, Xuan Xiang, Zihao Wang, Siyu Zhang, Qianqian Xue, Xiaoshan Wei, Yao Liu, Haolei Wang, Jiaqi Ai, Bohan Yang, Long Chen, Yiran Niu, Wenbei Peng, Qiong Zhou.

Tumor necrosis factor receptor 2-positive regulatory T (TNFR2+ Treg) cells, the most suppressive subset of Treg cells, are enriched in malignant pleural effusion (MPE), contributing to disease progression. However, the underlying mechanisms responsible for their accumulation remain unclear. Here we demonstrate that the C-X-C motif chemokine ligand 16 (CXCL16)/C-X-C chemokine receptor type 6 (CXCR6) axis plays a critical role in recruiting TNFR2+ Treg cells to MPE, with cancer-associated fibroblasts serving as the primary source of CXCL16. Mechanistically, under the hypoxic conditions prevailing in the pleural cavity, cancer-associated fibroblasts in MPE undergo glycolysis, which in turn leads to an increase in the production of endogenous lactate. This elevated lactate induces histone H3 lysine 18 lactylation (H3K18la) at the promoter regions of both the CXCL16 gene and its transcription factor forkhead box O3 (FOXO3), which may contribute to CXCL16 transcription. TNFR2+ Treg cells that express high levels of CXCR6, the only receptor for CXCL16, are subsequently recruited into MPE. The infiltration of TNFR2+ Treg cells may reinforce the immunosuppressive milieu of MPE, facilitating disease progression. Collectively, these findings uncover a novel mechanism governing immunosuppression in MPE, providing new insights into potential therapeutic strategies to disrupt this process.

DOI: https://doi.org/10.1038/s12276-025-01557-3
Biochem Pharmacol. 2025 Nov 20. pii: S0006-2952(25)00818-4. [Epub ahead of print]243(Pt 2): 117553

LDHA facilitates immune escape in bladder cancer through H4K5 lactylation-dependent upregulation of PD-L1.

Sensheng Tang, Yu Liu, Bo Jin, Tianyang Zhang, Xingbo Wang, Jie Zhao, Zhibin Xu, Wenchao Zhao, Hao Bian, Kai Li, Yuan Xia, Hui Wang, Maomao Guo.

  Metabolic reprogramming, characterized by hyperactive glycolysis, is a hallmark of bladder cancer (BCa) progression. Here, we identify lactate dehydrogenase A (LDHA) as a central metabolic node coupling glycolytic flux to epigenetic regulation of the immune checkpoint molecule PD-L1. Transcriptomic and survival analyses reveal that dysregulated glycolytic enzymes, particularly LDHA, correlate with poor prognosis and immunotherapy response in BCa patients. Mechanistically, LDHA-driven lactate production induces histone H4K5 lactylation (H4K5la), facilitated by the acetyltransferase EP300, which directly activates PD-L1 transcription. Depletion of LDHA or EP300 reduces H4K5la levels and suppresses PD-L1 expression. Critically, EP300 knockdown reverses PD-L1 upregulation induced by LDHA overexpression, establishing a causal LDHA-EP300-H4K5la-PD-L1 axis that drives immune evasion. Furthermore, RNA immunoprecipitation and luciferase reporter assays suggest that m6A RNA modification may potentiate LDHA overexpression. Collectively, this work unveils a dual-layered mechanism-metabolic lactate flux and histone lactylation that orchestrates immune evasion in BCa, proposing LDHA and EP300 as actionable targets to restore antitumor immunity.

Keywords:  Bladder cancer; Histone lactylation; Immune escape; Immunotherapy; LDHA; PD-L1

DOI:  https://doi.org/10.1016/j.bcp.2025.117553
iScience. 2025 Nov 21. 28(11): 113859

Extracellular vesicle R-Ras is a potential biomarker for human peripheral artery disease.

Xiaochao Wei, Mohamed Zaghloul, Shahab Hafezi, Fumihiko Urano, Mohamed A Zayed, Clay F Semenkovich.

  Human peripheral artery disease (PAD) is common and associated with amputation, heart attack, stroke, and death. Treatment options are limited by inadequate understanding of disease pathophysiology and lack of early detection strategies. R-Ras, which regulates vascular integrity, undergoes reversible palmitoylation. In mice, disrupting this process by inhibiting the enzyme acyl-protein thioesterase 1 (APT1) impairs vascular function and promotes experimental PAD. In arteries from humans with PAD we found increased palmitoylated R-Ras, which correlated with age and hypertension. Extracellular vesicles (EVs) isolated from APT1-knockdown endothelial cells were enriched in R-Ras protein, suggesting that palmitoylation promotes incorporation of R-Ras into EVs. PAD patients compared to subjects without PAD had increased serum EV R-Ras content that was positively associated with age, smoking, hypertension, and PAD severity. These findings suggest that altered R-Ras palmitoylation impacts human PAD and that EV-associated R-Ras may be an accessible biomarker for human PAD.

Keywords:  cardiovascular medicine; cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.113859
BMC Cancer. 2025 Nov 22.

Single-cell and spatial transcriptomics reveal lactylation-associated tumor cell clusters and define a prognostic risk model in glioblastoma.

Rui Han, Guangfan Chi, Dongjie Sun, Ziran Xu, Liangfu Zhou, Kan Xu.

   BACKGROUND: Glioblastoma (GBM) is the most aggressive adult brain tumor, marked by intratumoral heterogeneity and therapy resistance. Metabolic reprogramming through histone lactylation has been linked to tumor progression and immune suppression. However, the spatial and single-cell landscape of lactylation in GBM and its prognostic significance remain poorly understood.
METHODS: We employed a multi-omics approach integrating bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics to investigate lactylation-related signatures in GBM. Differential expression and pathway analyses were performed using GEO and TCGA datasets. Cell clustering, SCENIC transcriptional network inference, CellChat intercellular communication modeling, and pseudotime analysis were conducted. A prognostic risk model was constructed using LASSO-Cox regression based on lactylation-associated genes. Experimental validation was performed using western blotting, immunohistochemistry, and functional assays in GBM cell lines.
RESULTS: Lactylation-related genes were significantly upregulated in GBM and associated with poor prognosis and immunosuppressive tumor microenvironments. Single-cell analysis revealed high-lactylation malignant subpopulations enriched in hypoxic tumor cores, exhibiting metabolic reprogramming and enhanced immune evasion. Spatial transcriptomics confirmed the localization of S100A6-high-lactylation GBM cells in aggressive tumor regions. A nine-gene lactylation-based risk model stratified patients into high- and low-risk groups with significantly different survival outcomes (AUC: 0.77-0.87). Experimental knockdown of S100A6 reduced GBM cell proliferation, migration, and invasion.
CONCLUSIONS: Lactylation defines distinct tumor cell clusters in GBM that are spatially localized, metabolically reprogrammed, and immunosuppressive. The S100A6-associated lactylation signature serves as a robust prognostic biomarker and potential therapeutic target in GBM.

Keywords:  Glioblastoma multiforme; Lactylation; Single-cell RNA sequencing; Spatial transcriptomics

DOI:  https://doi.org/10.1186/s12885-025-15291-6
Cancer Sci. 2025 Nov 29.

Importance of SUMOylation Consensus Sequence of MAFK in Regulating EMT, Tumor Growth, Stemness, and Drug Resistance.

Thuy Linh Dang Cao, Yukari Okita, Reon Yahatabara, Manar A Elhinnawi, Nuriza Ulul Azmi, Thanasis Poullikkas, Hozumi Motohashi, Mitsuyasu Kato.

  Posttranslational modification is crucial for modulating protein functions. SUMOylation is a posttranslational modification where a small ubiquitin-related (like) modifier (SUMO) conjugates to a lysine residue in the substrate proteins. SUMOylation has been shown to affect the alteration of substrate proteins' functions, subcellular localization, or stability. Furthermore, it has been reported that SUMOylation is involved in regulating angiogenesis, cellular migration, and epithelial-mesenchymal transition (EMT). Moreover, a link between SUMO proteins and multidrug resistance in hepatocellular carcinoma and multiple myeloma has been reported. Classified as a set of transcription factors belonging to the basic region leucine zipper (bZIP) family, musculoaponeurotic fibrosarcoma (MAF) proteins are divided into two groups: large MAF (c-MAF, MAFA, and MAFB) and small MAF (MAFF, MAFG, and MAFK). We previously demonstrated that MAFK confers tumorigenic ability to nontumorigenic mammary gland epithelial cells, NMuMG cells, through induction of EMT. Furthermore, the knockdown of MAFK significantly suppressed the tumorigenic and metastatic growth of breast cancer cells. Among MAF family proteins, the SUMOylation consensus sequence, ψKxE, is highly conserved, and SUMOylation has been shown in MAF family proteins, MAFB and MAFG, respectively. In this study, we focused on SUMOylation and investigated the importance of the SUMOylation consensus sequence in MAFK for MAFK-induced EMT, cellular migration and invasion, tumor and sphere formation, acquisition of stem-like properties, and drug resistance against doxorubicin by using the non-SUMOylation mimic mutant. Additionally, our results suggest that these findings depend on the expression of ATP-binding cassette (ABC) transporter 2 (ABCG2).

Keywords:  MAFK; SUMOylation; breast cancer; drug resistance; epithelial–mesenchymal transition

DOI:  https://doi.org/10.1111/cas.70282