bims-prolim 2025-08-17 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–08–17
fifteen papers selected by
Bruna Martins Garcia, CABIMER

Palmitoylation: an emerging therapeutic target bridging physiology and disease.
Palmitic acid and palmitoylation in cancer: Understanding, insights, and challenges.
The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.
ZDHHC12 Palmitoylates HDAC8 to Promote the Progression of Hepatocellular Carcinoma Associated with a Diet High in Saturated Fatty Acids.
S-palmitoylation: An oily modification guardinggenome stability.
METTL1 drives glioma progression by promoting N7-methylguanosine (m7G) modification of glycolysis-related enzyme PGK1.
Multi-omics-based construction of a palmitoylation-driven prognostic model reveals tumor immune phenotypes in osteosarcoma.
Lactylation-driven molecular taxonomy of melanoma: linking epigenetic modifications to immune evasion and clinical outcomes.
Lactate Dehydrogenase C4 Accelerates Triple-Negative Breast Cancer Progression by Promoting Acetyl-CoA Acyltransferase 2 Lactylation to Increase Free Fatty Acid Accumulation.
Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism.
Neddylation inhibitor MLN4924 enhances H3K18 lactylation via binding to LDH and downregulates ITGB4 to block metastasis.
O-GlcNAcylation of PRDX1 enhances its stability and promotes liver cancer progression via activating LRP6-mediated Wnt signaling.
Single-cell RNA sequencing reveals palmitoylation-driven cellular heterogeneity and prognostic biomarkers in lung adenocarcinoma.
Targeting glycosylation to enhance tumor immunotherapy.
Integrative multi-omics analysis N4-acetylcytidine modification landscape and the role of TMEM65 in breast cancer.

Cell Mol Biol Lett. 2025 Aug 15. 30(1): 98

Palmitoylation: an emerging therapeutic target bridging physiology and disease.

Weini Li, Jie Shen, Aojia Zhuang, Ruiheng Wang, Quanqi Li, Anas Rabata, Yanan Zhang, DuoYao Cao.

  Palmitoylation is a reversible post-translational lipid modification of proteins, catalyzed by the Zinc finger DHHC domain-containing (ZDHHC) family of palmitoyltransferases. Palmitoylation plays a pivotal role in regulating localization, stability, trafficking, and interactions, thereby contributing to a wide range of cellular processes. Dysregulation of palmitoylation has been implicated in numerous pathological conditions, including metabolic disorders, muscular diseases, mitochondrial disorders, cancer, and neurodegeneration. In this review, we summarize recent advances in understanding S-palmitoylation, emphasizing its critical roles in protein regulation, cellular and physiological processes, and its implications in both health and disease. Additionally, we highlight emerging therapeutic opportunities and novel strategies in therapeutic applications targeting this lipid modification.

Keywords:  Depalmitoylation; Disease pathogenesis; Palmitoylation; Targeted therapy

DOI:  https://doi.org/10.1186/s11658-025-00776-w
Innovation (Camb). 2025 Aug 04. 6(8): 100918

Palmitic acid and palmitoylation in cancer: Understanding, insights, and challenges.

Peipei Song, Qiwei Jiang, Xueji Wu, Lang Bu, Wei Xie, Wenyi Wei, Xiaofang Xing, Jianping Guo.

  Nutrients from dietary foods not only provide energy and building blocks, but also play critical roles in modulating diverse pathophysiological functions. They achieve these, in part, by accelerating cell signaling transduction processes via modulating various types of protein post-translational modifications (PTMs). Notably, accumulating evidence has identified palmitic acid (PA), a major component of high-fat diets, as a significant contributor to various human disorders, including diabetes and cancer. Hence, further understanding the roles of PA and its involvement in protein palmitoylation, a key PTM, is crucial for uncovering the mechanisms underlying these diseases and exploring potential clinical applications in cancer therapy. This review comprehensively summarizes recent advances in the understanding of PA homeostasis and palmitoylation in tumorigenesis. Specifically, it highlights the connections between palmitoylation and key processes such as oncogenic signaling pathways, cell death mechanisms, innate immune responses, and the tumor microenvironment. The review also emphasizes potential therapeutic strategies, including targeting PA homeostasis, palmitoylation-associated processes, or specific palmitoylated proteins for cancer treatment. Finally, the challenges in the field, such as the regulation of PA homeostasis and the dynamic detection or targeting of palmitoylation, are discussed, underscoring the need for further research to address these critical issues.

Keywords:  ZDHHC; metabolic homeostasis; palmitic acid; palmitoylation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xinn.2025.100918
J Biol Chem. 2025 Aug 09. pii: S0021-9258(25)02433-0. [Epub ahead of print] 110582

The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.

Adrija J Navarro-Traxler, Laura Ghisolfi, Evan C Lien, Alex Toker.

  The PI3K/AKT signaling pathway is frequently dysregulated in cancer and controls key cellular processes such as survival, proliferation, metabolism and growth. Protein glycosylation is essential for proper protein folding and is also often deregulated in cancer. Cancer cells depend on increased protein folding to sustain oncogene-driven proliferation rates. The N-glycosyltransferase asparagine-linked glycosylation 3 homolog (ALG3), a rate-limiting enzyme during glycan biosynthesis, catalyzes the addition of the first mannose to glycans in an alpha-1,3 linkage. Here we show that ALG3 is phosphorylated downstream of the PI3K/AKT pathway in both growth factor-stimulated cells and PI3K/AKT-hyperactive cancer cells. AKT directly phosphorylates ALG3 in the amino terminal region at Ser11/Ser13. CRISPR/Cas9-mediated depletion of ALG3 leads to improper glycan formation and induction of endoplasmic reticulum stress, the unfolded protein response, and impaired cell proliferation. Phosphorylation of ALG3 at Ser11/Ser13 is required for glycosylation of cell surface receptors EGFR, HER3 and E-cadherin. These findings provide a direct link between PI3K/AKT signaling and protein glycosylation in cancer cells.

Keywords:  AKT; ALG3; N-glycosylation; PI3-kinase; glycans; phosphorylation; signaling

DOI:  https://doi.org/10.1016/j.jbc.2025.110582
Adv Sci (Weinh). 2025 Aug 11. e05702

ZDHHC12 Palmitoylates HDAC8 to Promote the Progression of Hepatocellular Carcinoma Associated with a Diet High in Saturated Fatty Acids.

Xin Jin, Yulong Hong, Yongqi Zhao, Wensheng Shi, Ruilin Liu, Xinyu You, Chong Yang, Yu Zhang.

  Excessive intake of saturated fatty acids (SFAs)-commonly associated with diets rich in fried foods and red meat-significantly increases the risk of hepatocellular carcinoma (HCC). Palmitic acid (PA), the most prevalent type of SFA, is selected as the representative model for this study. Palmitoyltransferases play crucial roles in protein palmitoylation mediated by PA; however, the most significantly altered palmitoyltransferase under high-SFA dietary conditions remains unidentified. This study reveals zinc finger DHHC-type palmitoyltransferase 12 (ZDHHC12) as a key protein in PA-driven HCC progression that functions by stabilizing the oncogenic histone deacetylase 8 (HDAC8). Mechanistically, PA supplementation upregulates ZDHHC12 expression by activating the transcription factor SWI/SNF-related BAF chromatin remodeling complex subunit ATPase 4 (SMARCA4). ZDHHC12 mediates HDAC8 palmitoylation at cysteine 244, thereby inhibiting its lysosomal degradation and ultimately promoting HCC progression. This study reveals that ZDHHC12 is a critical mediator of PA-induced HCC progression and that targeting HDAC8 can suppress this process. These findings offer a potential therapeutic strategy for HCC patients with high dietary intake of SFAs, particularly PA.

Keywords:  HCC; HDAC8; ZDHHC12; palmitic acid

DOI:  https://doi.org/10.1002/advs.202505702
DNA Repair (Amst). 2025 Aug 08. pii: S1568-7864(25)00079-5. [Epub ahead of print]153 103883

S-palmitoylation: An oily modification guardinggenome stability.

Xiyuan Zheng, Xinying Wu, Lei Wang, Haohong Ouyang, Yeltokova Damira, Bin Peng, Xingzhi Xu.

  S-palmitoylation is a dynamic post-translational lipid modification that regulates key cellular processes. It is mediated by aspartate-histidine-histidine-cysteine-family palmitoyltransferases (PATs) and reversed by acyl-protein thioesterases (APTs). This modification influences protein stability, function, subcellular trafficking, and membrane interactions. Emerging evidence identifies protein palmitoylation as a key regulator of genomic stability and integrity: it modulates DNA repair pathways, replication fork dynamics, and stress response mechanisms. Consequently, dysregulated palmitoylation cycles can lead to an impaired replication stress response, and chromosomal instability, which might drive oncogenesis. In this review, we examine the critical roles of S-palmitoylation in maintaining genome stability and speculate on its therapeutic potential in counteracting malignancy-associated genomic instability.

Keywords:  Cancer; DNA damage response; Genomic instability; Palmitoylation

DOI:  https://doi.org/10.1016/j.dnarep.2025.103883
Pathol Res Pract. 2025 Aug 08. pii: S0344-0338(25)00367-X. [Epub ahead of print]274 156174

METTL1 drives glioma progression by promoting N7-methylguanosine (m7G) modification of glycolysis-related enzyme PGK1.

Bo Fan, Yakun Wang, Xiaoning Qin, Zhongjie Yan, Wei Du.

  Glioma is a common brain malignancy with a poor prognosis. N7-methylguanosine (m7G) modification is involved in cancer progression, and methyltransferase 1 (METTL1) is a m7G methyltransferase. Here, we aimed to study the role of METTL1 in glioma and the potential mechanism. The proliferation of glioma cells was evaluated using cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) assays, and the glycolysis was assessed using glucose uptake and lactate content kits and seahorse analysis. The regulation of METTL1 on phosphoglycerate kinase 1 (PGK1) was analyzed using methylated RNA immunoprecipitation, RNA immunoprecipitation, quantitative real-time polymerase chain reaction, western blotting, and RNA stability assay. The results showed that METTL1 expression was upregulated in glioma tissues and cells. Silencing of METTL1 inhibited the proliferation and glycolysis of glioma cells and impeded tumor growth in mice. Moreover, METTL1 knockdown suppressed internal m7G modification of PGK1 and decreased its half-life. PGK1 overexpression counteracted the inhibition of glioma cell proliferation and glycolysis induced by METTL1 knockdown. In conclusion, METTL1 functions as an oncogene to accelerate glioma progression by promoting m7G modification of PGK1, providing a potential therapeutic target for glioma.

Keywords:  Glioma; Glycolysis; M7G modification; METTL1; PGK1

DOI:  https://doi.org/10.1016/j.prp.2025.156174
Discov Oncol. 2025 Aug 13. 16(1): 1544

Multi-omics-based construction of a palmitoylation-driven prognostic model reveals tumor immune phenotypes in osteosarcoma.

Jingyu Chen, Feihu Chen, Haiping Zhang, Yuanlong Hu, Xingyu Zhou, Xijia Weng, Guofeng Bao, Xiaomin Ding.

   BACKGROUND: Osteosarcoma (OS), the leading primary malignancy of bone in adolescents, is known for its aggressive metastatic behavior and poor responsiveness to conventional therapies. As a lipid-mediated post-translational modification, protein palmitoylation has gained attention for its pivotal role in modulating oncogenic signaling pathways and facilitating tumor immune escape. However, its prognostic value and functional role in OS remain unclear.
METHODS: Transcriptomic and clinical data from the TARGET and GEO cohorts were used to identify palmitoylation-related prognostic genes. The palmitoylation-related prognostic signature (PPS) was constructed using univariate Cox and LASSO regression. The model was validated by GSE39058 and assessed via survival analysis, ROC curves, and nomogram construction. Functional enrichment (GO, KEGG, GSVA) and immune infiltration analyses were performed. Single-cell expression profiles were explored using the TISCH2 database, and the predictive value of PPS for immunotherapy response was evaluated in the IMvigor210 cohort.
RESULTS: A three-gene PPS (ZDHHC3, ZDHHC21, ZDHHC23) was identified and shown to independently predict survival in OS. Elevated PPS levels correlated with unfavorable clinical outcomes, diminished immune cell presence, and suppressed immune checkpoint molecule levels. Functional analysis revealed enrichment of oncogenic and immunosuppressive pathways in the high-PPS group. Single-cell analysis confirmed PPS gene expression in malignant and immune cells. In the IMvigor210 cohort, high PPS predicted worse response to anti-PD-L1 immunotherapy.
CONCLUSIONS: This study establishes a novel palmitoylation-related prognostic signature in osteosarcoma, which reflects tumor aggressiveness and immune evasion. PPS holds promise as both a stratification indicator and an intervention point for osteosarcoma treatment.

Keywords:  Osteosarcoma; Palmitoylation; Prognostic signature; Single-cell RNA sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-03364-8
Am J Cancer Res. 2025 ;15(7): 2911-2931

Lactylation-driven molecular taxonomy of melanoma: linking epigenetic modifications to immune evasion and clinical outcomes.

Lei Wang, Xue-Ying Jin, Li-Yuan Zhu, Yu-Chen Wu, Ru-Ning Qiu, Li-Feng Feng, Hong-Chuan Jin, Jian-Fang Wang.

  Lactylation, a post-translational modification derived from elevated lactate levels, has gained attention as a potential regulator of melanoma's tumor metabolism and immune responses. Here, we combined single-cell RNA sequencing and bulk transcriptome profiling of cutaneous melanoma samples to establish a lactation-centric prognostic model. Our analyses revealed melanocytes as the most acetylation-enriched cell population and identified a six-gene lactylation signature that stratified patients into high- and low-risk groups with distinct survival outcomes. Mechanistically, high-risk tumors demonstrated significant immunosuppressive features characterized by M2 macrophage accumulation and depleted CD8+ T-cell activity, corresponding to reduced sensitivity to certain chemotherapeutic drugs. Pathway enrichment studies implicated DNA repair, Hedgehog, and JAK-STAT signaling in driving the aggressive phenotype of high-acetylation tumors. Additionally, pseudotime trajectory analyses highlighted developmental shifts in gene expression related to lactylation during melanocyte differentiation. The signature demonstrated robust predictive accuracy in training, testing, and external validation cohorts. Functional validation confirmed the critical role of RAN in promoting proliferation and migration in vitro. These findings unveil lactylation as a critical epigenetic factor influencing melanoma progression and immune evasion, offering a novel prognostic framework and potential therapeutic targets for precision medicine.

Keywords:  Lactylation; immune microenvironment; melanoma; multi-omics; prognostic model; single-cell RNA sequencing

DOI:  https://doi.org/10.62347/WJNA8774
Adv Sci (Weinh). 2025 Aug 14. e11849

Lactate Dehydrogenase C4 Accelerates Triple-Negative Breast Cancer Progression by Promoting Acetyl-CoA Acyltransferase 2 Lactylation to Increase Free Fatty Acid Accumulation.

Zhaolei Cui, Chaoqiang Zheng, Yingying Lin, Zhenzhou Xiao, Yanhong Li, Wei Peng, Shijie He, Anyang Li, Xiufeng Wu, Yan Chen, Yang Sun.

  Lactate-induced protein lysine (K) lactylation is inherently connected to cellular metabolism and is implicated in oncogenesis. As a crucial glycolytic enzyme in lactate metabolism, lactate dehydrogenase C4 (LDHC4) has undefined yet potentially significant biological functions and mechanistic roles in triple-negative breast cancer (TNBC) that warrant further investigation. This study aims to determine whether and how LDHC4 affects TNBC progression by regulating protein lactylation. LDHC4 expression in human TNBC tissues and adjacent nontumor tissues is analyzed through immunoblotting and immunohistochemistry (IHC). Functional experiments verified the biological features of LDHC4 in human TNBC cells both in vitro and in vivo (subcutaneous, orthotopic, and pulmonary metastatic mouse models). 4D label-free lactylproteome expression analysis (4D-LFQP-LA), immunoblotting, and immunoprecipitation are utilized to confirm lactylation at specific lysine sites in acetyl-CoA acyltransferase 2 (ACAA2) following LDHC4 induction. Targeted lipidomic analysis is performed to characterize ACAA2-induced metabolite alterations. Immunoblotting, immunofluorescence, and transmission electron microscopy are performed to investigate the mechanisms underlying LDHC4-induced ACAA2 lactylation and tumor progression in TNBC. LDHC4 expression is upregulated in TNBC, and LDHC4 is an independent predictive factor for prognosis. Both in vitro and in vivo experiments demonstrated that LDHC4 promotes TNBC progression. Subsequent mechanistic investigation revealed that LDHC4 enhances the lactylation of ACAA2 at K214, resulting in increased ACAA2 catalytic activity. This increase in ACAA2 activity accelerates fatty acid (FA) metabolism, promotes TNBC progression both in vitro and in vivo, and leads to increased free fatty acid (FFA) generation and accumulation. The increase in FFAs in turn induces autophagy and promotes cell cycle activity in TNBC cells, thereby promoting TNBC progression. The findings reveal a novel pathway through which LDHC4 induces ACAA2 lactylation to regulate FA metabolism in TNBC cells, thus promoting TNBC progression, highlighting the critical role of LDHC4 in TNBC progression.

Keywords:  acetyl‐CoA acyltransferase 2; free fatty acids; lactate dehydrogenase C4; lactylation; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.202511849
Cancer Biol Ther. 2025 Dec;26(1): 2546219

Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism.

Zhuo Li, Qinghua Jiang, Quan Yang, Yujie Zhou, Jiansong Wang.

  Hypoxia-induced Pyrroline-5-Carboxylate Reductase 1 (PYCR1) is implicated in bladder cancer (BC), but its specific role remains elusive. This study investigated how PYCR1 promotes BC progression through glycolysis, histone H3 Lysine 18 Lactylation (H3K18la), and Solute Carrier Family 6 Member 14 (SLC6A14)-driven glutamine catabolism. Here, BC cell lines were cultured under hypoxia to evaluate changes in PYCR1 expression, glycolysis, and lactate production. The xenograft and metastasis models in nude mice were used to validate the role of the PYCR1/H3K18la/SLC6A14 axis in BC progression. GEPIA Bioinformatics database data showed that PYCR1 was upregulated in BC and was associated with poor prognosis. The PYCR1 positive expression rate in BC tissues was increased. Hypoxia induced PYCR1 expression in BC cells, enhancing glycolysis and lactate production, which increased H3K18la levels. Upregulated SLC6A14 expression promoted glutamine catabolism and enhanced BC cell proliferation, migration, and invasion. PYCR1 knockdown inhibited H3K18la levels, SLC6A14 expression, and BC cell aggressiveness; SLC6A14 overexpression reversed these effects. In vivo experiments confirmed that the PYCR1/H3K18la/SLC6A14 axis is critical for hypoxia-driven BC growth and metastasis. In summary, Hypoxia-induced PYCR1 enhances glycolysis, leading to increased lactate production and elevated H3K18la levels, which upregulates SLC6A14 transcription and glutamine catabolism, thereby promoting BC growth and metastasis.

Keywords:  Bladder cancer; H3K18la; PYCR1; SLC6A14; glutamine catabolism; glycolysis; histone lactylation; lactate

DOI:  https://doi.org/10.1080/15384047.2025.2546219
J Biol Chem. 2025 Aug 08. pii: S0021-9258(25)02426-3. [Epub ahead of print] 110575

Neddylation inhibitor MLN4924 enhances H3K18 lactylation via binding to LDH and downregulates ITGB4 to block metastasis.

Hongfei Yu, Qiyin Zhou, Yongxia Chen, Changxin Zhong, Tingting Fu, Xiufang Xiong, Feng Zhu, Linbo Wang, Yi Sun.

MLN4924, a small molecule neddylation inhibitor and a potent anti-cancer agent, was previously shown to has some neddylation-independent effects. Whether MLN4924 regulates histone lactylation in neddylation-dependent or independent manner is previously unknown. We reported here that MLN4924 significantly increased the lactate levels by activating lactate dehydrogenase (LDH) activity via inducing LDH tetramerization to promote histone H3K18 lactylation in breast cancer cells. Through combined analyses of CUT&Tag, RNA-seq and CHIP-PCR, we identified integrin ITGB4 as a downstream target, subjected to downregulation by MLN4924-induced H3K18 lactylation, occurred at the first intron of the ITGB4 gene. This MLN4924-mediated dose- and time-dependent ITGB4 downregulation is independent of its neddylation inhibition, but can be largely abrogated by siRNA-based LDH knockdown or treatment with oxamate, a small molecular inhibitor of LDH. Biologically, MLN4924 effectively suppresses the migration and invasion of breast cancer cells in vitro and metastasis in vivo, which is largely rescued by ITGB4 overexpression. Taken together, our study revealed a new mechanism by which MLN4924 suppresses the migration and invasion of breast cancer cells by epigenetically inhibiting ITGB4 expression via enhancing H3K18 lactylation.

DOI: https://doi.org/10.1016/j.jbc.2025.110575
Cell Signal. 2025 Aug 07. pii: S0898-6568(25)00470-X. [Epub ahead of print]135 112055

O-GlcNAcylation of PRDX1 enhances its stability and promotes liver cancer progression via activating LRP6-mediated Wnt signaling.

Luo Dai, Zheng Xu, Yin Fan, Wei Gao, Guandou Yuan, Songqing He, Linfeng Mao.

   BACKGROUND: O-GlcNAcylation, a post-translational modification intricately implicated in oncogenic processes, has garnered significant attention as a potential therapeutic target in cancer biology. Peroxiredoxin 1 (PRDX1), a master regulator of reactive oxygen species (ROS) homeostasis and antioxidant defense systems, is increasingly recognized for its contributory role in the pathogenesis of diverse malignancies. However, the functional significance of PRDX1 in liver cancer pathogenesis and the mechanistic underpinnings of its regulation remain to be fully elucidated.
METHODS: In our preliminary investigations, we identified PRDX1 as a substrate amenable to O-GlcNAcylation via immunoprecipitation-mass spectrometry (IP-MS) profiling. Western blotting was performed to determine the levels of PRDX1 and O-GlcNAcylation in liver cancer tissues. Colony formation, scratch test, transwell assay and nude mouse tumor model assays were used to determine the roles of PRDX1 and O-GlcNAcylation in liver cancer progression. IP-MS was used to screen the interacting protein LRP6 of PRDX1, cycloheximide (CHX) chase assay, ubiquitination test were used to determine the stability, proximity ligation assay (PLA), immunofluorescent staining (IF) were performed the O-GlcNAcylation of PRDX1.
RESULTS: Herein, we demonstrate that PRDX1 exerts profound oncogenic effects, driving liver cancer progression in both in vitro and in vivo experimental models. Notably, we reveal that PRDX1 undergoes pronounced O-GlcNAcylation in liver cancer, a modification that enhances its protein stability by attenuating ubiquitin-proteasomal degradation. Furthermore, PRDX1 interacts with low-density lipoprotein receptor-related protein 6 (LRP6), stabilizing its expression and subsequently activating the canonical Wnt/β-catenin signaling cascade.
CONCLUSION: Our findings suggest that O-GlcNAcylation stabilizes PRDX1, promoting liver cancer progression. PRDX1-LRP6 interaction activates Wnt/β-catenin signaling, driving tumorigenesis. Targeting the O-GlcNAcylation-PRDX1-LRP6 axis holds therapeutic promise.

Keywords:  LRP6; Liver cancer; O-GlcNAcylation; PRDX1; Wnt pathway

DOI:  https://doi.org/10.1016/j.cellsig.2025.112055
Transl Oncol. 2025 Aug 13. pii: S1936-5233(25)00232-3. [Epub ahead of print]61 102501

Single-cell RNA sequencing reveals palmitoylation-driven cellular heterogeneity and prognostic biomarkers in lung adenocarcinoma.

Taibo Huang, Lijie Kou, Qianqian Zhang, Xueya Liu, Xingang Hu.

   BACKGROUND: Lung adenocarcinoma (LUAD) is marked by significant variation within tumor cells and continues to be a major global cause of cancer deaths. Palmitoylation is a dynamic lipid-based modification that occurs after protein synthesis and influences the behavior and lifespan of various cancer-related proteins. However, its role in shaping cellular complexity and predicting outcomes in LUAD patients is not yet fully clarified.
METHODS: We examined single-cell RNA sequencing datasets from LUAD samples to identify distinct malignant cell groups. Palmitoylation-related gene activity was estimated using GSVA and ssGSEA techniques. To further define cellular characteristics, we applied copy number variation mapping, pseudotime progression modeling, transcription factor regulatory scoring, and cell-cell interaction analyses. A 12-gene risk model was developed using marker genes from the cluster (C1) with the most prominent palmitoylation pattern. This model was trained on The Cancer Genome Atlas (TCGA) dataset and confirmed using separate GEO datasets. To evaluate tumor immune context, we analyzed immune cell presence and tumor mutational burden across different risk levels. Laboratory experiments involving both upregulation and silencing of aspartate beta-hydroxylase (ASPH) in LUAD cell cultures were conducted to validate its biological significance.
RESULTS: We identified six tumor cell subsets (C0 to C5), with cluster C1 showing peak palmitoylation levels, distinct genomic alterations, and stronger communication with stromal and immune cells. The 12-gene model effectively categorized LUAD patients into high- and low-risk profiles, showing marked survival differences (p < 0.001) and strong performance in time-dependent ROC analysis. Patients in the high-risk group had increased tumor mutational burden and a more immunosuppressive tumor environment. Laboratory findings revealed that raising ASPH expression promoted cell growth, motility, and epithelial-mesenchymal transition. In contrast, reducing ASPH levels triggered cell death and decreased invasiveness.
CONCLUSIONS: Our single-cell analysis focused on palmitoylation reveals new dimensions of tumor diversity in LUAD and establishes a validated 12-gene risk signature. Functional studies highlight ASPH as a promising candidate for therapeutic targeting. These results deepen our understanding of palmitoylation-associated pathways and present a foundation for both outcome prediction and precision-based treatment strategies in LUAD.

Keywords:  Copy number variations (CNVs); Lung adenocarcinoma (LUAD); Prognostic biomarkers; Single-cell RNA sequencing (scRNA-seq); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.tranon.2025.102501
Trends Pharmacol Sci. 2025 Aug 14. pii: S0165-6147(25)00156-7. [Epub ahead of print]

Targeting glycosylation to enhance tumor immunotherapy.

Qiang Zhu, Xiaoming Chen, Xiaotao Duan, Jianwei Sun, Wen Yi.

  Glycans are complex sugar modifications found on cell surfaces that play crucial roles in biological processes. Glycosylation patterns are aberrantly altered in the tumor microenvironment (TME), which helps cancer cells escape immune surveillance by creating a tumor-specific 'glyco-code' that weakens immune responses and reduces immunotherapy effectiveness. Recent studies have illustrated the potential to improve antitumor immune responses by manipulating glycosylation in the TME. We review the effects of aberrant glycosylation on the regulation of tumor immunity and the corresponding strategies for manipulating glycosylation to enhance antitumor immunity. These strategies include inhibiting glycan-receptor interactions, engineering cell-surface glycans, and remodeling the extracellular matrix. This Review highlights the importance of glycosylation in designing effective and personalized cancer treatments.

Keywords:  glycoengineering; glycosylation; immunotherapy; lectins; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tips.2025.07.013
Int J Biol Macromol. 2025 Aug 11. pii: S0141-8130(25)07324-6. [Epub ahead of print] 146767

Integrative multi-omics analysis N4-acetylcytidine modification landscape and the role of TMEM65 in breast cancer.

Dan Yang, Yifei Yun, Yan Ma, Ye Gao, Yao Ou, Chenyu Zhao, Xiaoyue Zhou.

  N4-acetylcytidine (ac4C), an evolutionarily conserved RNA modification regulated by NAT10, is increasingly recognized for its role in post-transcriptional gene regulation. However, the modification patterns and clinical significance of ac4C remain largely unclear in breast cancer (BC). In this study, we performed single-cell transcriptomic analysis to investigate the heterogeneity of ac4C-related gene (acRG) activity within the BC microenvironment for the first time. A total of 2135 acRGs were used to quantify acRG activity across different cell types, revealing that ac4C signaling was primarily enriched in tumor epithelial cells and associated with enhanced intercellular communication and immunosuppressive features. Leveraging publicly available BC cohorts, we developed a robust prognostic signature (acRGBS) through machine learning algorithm combinations and validated its predictive power across multiple datasets. The final five-gene signature effectively stratified patients by overall survival and correlated with diminished anti-tumor immune responses, underscoring its potential clinical utility. Notably, our functional validation reveals TMEM65 as an oncogenic driver associated with BC cell proliferation and apoptosis inhibition, establishing its role as a druggable target. Collectively, this study represents the first comprehensive exploration of ac4C modification in BC, introducing acRGBS as a novel biomarker that holds substantial prognostic and therapeutic implications. The identification of TMEM65 further highlights the translational potential of our findings in directing targeted therapeutic development, thus contributing significantly to the evolving landscape of precision medicine in BC.

Keywords:  Breast cancer; Immunotherapy response; Machine learning; N4-acetylcytidine RNA modification; Prognostic signature; TMEM65

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146767