bims-prolim 2025-09-28 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–09–28
eight papers selected by
Bruna Martins Garcia, CABIMER

Palmitoylation in cancer: decoding its roles in signal transduction, tumor immunity, and emerging therapeutic opportunities.
AARS1 and AARS2: From Protein Synthesis to Lactylation-Driven Oncogenesis.
Insights into recent findings and therapeutic potential of nonhistone lactylation in cancer.
Metabolic-epigenetic rewiring in cancer: The role of lactylation in tumor progression, immune evasion, and therapy resistance.
The role of succinylation-mediated metabolic reprogramming in tumor progression.
Targeting SQLE-mediated cholesterol metabolism to enhance CD8+ T cell activation and immunotherapy efficacy in hepatocellular carcinoma.
Chemical proteomic approaches to investigate S-prenylation.
Integrated multi-omics analysis reveals PTM networks as key regulators of colorectal cancer progression and immune evasion.

Front Immunol. 2025 ;16 1640016

Palmitoylation in cancer: decoding its roles in signal transduction, tumor immunity, and emerging therapeutic opportunities.

Qiguang Lu, Jiasheng Wu, Xiaoyan Yu, Juanjuan Qian, Zhengwei Song.

  Palmitoylation, a reversible post-translational modification involving the attachment of palmitic acid to cysteine residues of proteins, plays a critical role in the regulation of protein localization, stability, and function. Recent studies have revealed its significant involvement in various oncogenic processes, including tumor initiation, progression, metastasis, and immune evasion. This review comprehensively explores the molecular mechanisms of palmitoylation and its functional implications in different types of tumors. We discuss how palmitoylation modulates key signaling pathways such as Ras and Wnt/β-catenin, influencing tumor cell behavior and the tumor microenvironment. Additionally, we examine the impact of palmitoylation on anti-tumor immunity and its potential as a therapeutic target. Understanding the intricate roles of palmitoylation in cancer biology not only advances our knowledge of tumor pathogenesis but also opens new avenues for targeted cancer therapies. Future research directions and clinical applications are also highlighted to guide the development of novel interventions.

Keywords:  cancer therapy; palmitoylation; post-translational modification; signal transduction; tumorigenesis

DOI:  https://doi.org/10.3389/fimmu.2025.1640016
Biomolecules. 2025 Sep 16. pii: 1323. [Epub ahead of print]15(9):

AARS1 and AARS2: From Protein Synthesis to Lactylation-Driven Oncogenesis.

Lingyue Gao, Jihua Guo, Rong Jia.

  Aminoacyl-tRNA synthetases (AARSs), traditionally recognized for their essential role in protein synthesis, are now emerging as critical players in cancer pathogenesis through translation-independent functions. Lactate-derived lactylation, a post-translational modification, plays an increasingly important role in tumorigenesis in the context of high levels of lactate in tumor cells due to the Warburg effect. Current research has highlighted AARS1/2 as lactate sensors and lactyltransferases that catalyze global lysine lactylation in cancer cells and promote cancer proliferation, providing a new perspective for cancer therapy. This review synthesizes the canonical and non-canonical functions of AARS1/2, with a particular focus on their lactylation-related mechanisms; details how lactylation acts as a mechanistic bridge linking AARS1/2 to diverse oncogenic signaling pathways, thereby promoting cancer hallmarks such as metabolic reprogramming, uncontrolled proliferation, immune escape, and therapy resistance; and proposes strategies to target AARS1/2 or modulate relative lactylation, offering a potential avenue to translate these insights into effective cancer therapies.

Keywords:  AARS1; AARS2; cancer therapy; lactylation

DOI:  https://doi.org/10.3390/biom15091323
Front Mol Biosci. 2025 ;12 1661697

Insights into recent findings and therapeutic potential of nonhistone lactylation in cancer.

Jing Jia, Na Liu, Xiaoren Zhu, Minbin Chen.

  Lactylation, a recently identified post-translational modification, has become a crucial regulatory mechanism beyond its conventional metabolic role. Unlike histone lactylation, which regulates gene expression, nonhistone lactylation directly acts on effector proteins involved in processes such as signal transduction, metabolic reprogramming, and DNA damage repair. This article systematically reviews how nonhistone lactylation regulates biological processes related to cancer via mechanisms such as modulating protein interactions, stability, subcellular localization, and enzymatic activity. In addition, it comprehensively examines the potential applications and challenges in targeting nonhistone lactylation modification in antitumor treatment.

Keywords:  anti-tumor therapy; cancer metabolism; lactylation; nonhistone; post-translational modification

DOI:  https://doi.org/10.3389/fmolb.2025.1661697
Pathol Res Pract. 2025 Sep 23. pii: S0344-0338(25)00437-6. [Epub ahead of print]275 156244

Metabolic-epigenetic rewiring in cancer: The role of lactylation in tumor progression, immune evasion, and therapy resistance.

Mokhtar Rejili.

  Research shows that lysine lactylation (kla) represents a novel post-translational modification that links cancer metabolism with epigenetic regulation. The production of lactate through the Warburg effect is associated with the lactylation of both histone and non-histone proteins, which regulate key gene expression programs linked to tumor progression, therapy resistance, and immune evasion. This review integrates recent findings on how elevated glycolysis levels, along with increased lactate concentrations in the tumor microenvironment (TME), trigger transcriptional activation through lactylation-mediated mechanisms. It highlights how lactylation interacts with other acylations, contributes to the development of cancer stemness, remodels the immune landscape, and reduces drug efficacy across various tumor types. Elevated lactylation expression correlates with poor patient outcomes, diminished CD8⁺ T cell infiltration, and increased expression of immune checkpoint proteins at tumor sites, thereby creating an immunosuppressive environment. The survival of cancer cells depends in part on lactylation, as it enhances DNA repair efficiency, protects against ferroptosis, and regulates genes associated with therapeutic resistance. Researchers are currently evaluating novel therapeutics that target enzymes involved in lactate metabolism (LDH, MCTs) and epigenetic "writers" of lactylation, such as p300/ CREB-binding protein, to disrupt oncogenic signaling pathways. The diagnostic relevance of lactylation is also gaining attention, as it serves as a potential biomarker for tumor progression and treatment response. As a critical epigenetic regulatory mechanism, lactylation opens new avenues for the development of precise cancer therapies, warranting further in-depth investigation.

Keywords:  Drug resistance; Epigenesis; Glycolysis; Immune Evasion; Post-translational modifications; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2025.156244
Mol Biol Rep. 2025 Sep 26. 52(1): 954

The role of succinylation-mediated metabolic reprogramming in tumor progression.

Siyi He, Chunduo Wang, Ranran Li, Kexin Xu, Wuzhiyi Zhang, Binbin Feng, Shengtao Cheng, Jihua Ren, Juan Chen.

  Metabolic reprogramming is a hallmark of tumors, whereby cancer cells remodel their own metabolism to meet the biosynthetic, energetic, and signaling demands required for rapid proliferation and malignant transformation. Posttranslational modifications (PTMs) serve as dynamic molecular switches that fine-tune cellular metabolic networks by precisely modulating the activity, stability, and subcellular localization of metabolic enzymes. This regulatory plasticity drives context-dependent metabolic reprogramming in tumor cells, enabling them to adapt to fluctuating physiological demands or pathological stressors while establishing tumor-specific metabolic signatures critical for survival and progression. Among PTMs, lysine succinylation-a recently identified modification catalyzed by succinyl-CoA-has emerged as a critical regulator of cancer metabolism. This unique modification involves the transfer of a negatively charged four-carbon succinyl group to lysine residues, inducing conformational and functional changes in target proteins. Notably, succinylation is evolutionarily conserved across eukaryotes and prokaryotes and has a broad influence on central metabolic pathways, including the tricarboxylic acid (TCA) cycle, amino acid metabolism, and lipid homeostasis. Mounting evidence highlights its dual roles in both sustaining tumorigenic metabolism and directly activating oncogenic signaling cascades. This review summarizes current insights into how succinylation rewires tumor metabolism and delineates its mechanistic contributions to cancer progression.

Keywords:  Cancer; Lysine succinylation; Metabolic reprogramming; Posttranslational modification; Succinyl-CoA

DOI:  https://doi.org/10.1007/s11033-025-11061-6
J Immunother Cancer. 2025 Sep 26. pii: e012345. [Epub ahead of print]13(9):

Targeting SQLE-mediated cholesterol metabolism to enhance CD8+ T cell activation and immunotherapy efficacy in hepatocellular carcinoma.

Shuang Qiao, Hao Zou, Yulan Weng, Yi-Fan Liu, Weihao Li, Xing-Juan Yu, Lian Li, Limin Zheng, Jing Xu.

   BACKGROUND: The sustained effectiveness of anti-programmed cell death protein-1 (PD1) treatment is limited to a subgroup of patients with hepatocellular carcinoma (HCC) due to the tumor microenvironment heterogeneity, highlighting the need to identify targetable biomarkers that synergize with PD1 blockade. Abnormal cholesterol metabolism plays a critical role in HCC progression, along with growing evidence indicating its complex immunomodulatory effects within the tumor microenvironment. However, the interplay between cholesterol homeostasis and immune evasion remains elusive.
METHODS: Transcriptomic and clinical data from HCC datasets were analyzed to identify cholesterol metabolism-related targets. Multiplex immunostaining and flow cytometry were applied to examine the immune landscape association with squalene epoxidase (SQLE) in human and murine tumors. Mechanistic studies were conducted in vitro, and co-culture experiments of tumor cells and T cells were followed by metabolomics and transcriptome analyses. Therapeutic efficacy was evaluated in mouse HCC models.
RESULTS: We demonstrated that elevated SQLE expression in human HCC was associated with poor clinical outcomes and correlated with reduced CD8+ T cell infiltration and activation. Pharmacological inhibition or genetic knockdown of SQLE in tumor cells promoted CD8+ T cell proliferation and activation in co-culture experiments. Untargeted metabolomics identified 27-hydrocholesterol, an oxysterol derived from tumor cells, as a key factor impairing CD8+ T cell function via cholesterol dysregulation. SQLE inhibition in tumor cells suppressed oxysterols secretion, therefore overcoming cholesterol restrictions and enhancing the immune responses of CD8+ T cells. Moreover, SQLE targeting with terbinafine restored antitumor immunity and synergized with anti-PD1 therapy in HCC.
CONCLUSION: Targeting tumorous SQLE restores CD8+ T cell function by overcoming cholesterol restrictions via oxysterol-SREBP2 signaling, highlighting SQLE as a potential therapeutic target to enhance immunotherapy efficacy in HCC.

Keywords:  Hepatocellular Carcinoma; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2025-012345
Methods Enzymol. 2025 ;pii: S0076-6879(25)00220-4. [Epub ahead of print]719 299-316

Chemical proteomic approaches to investigate S-prenylation.

Sarah Hassan, James Zhang, Wouter Kallemeijn, Edward W Tate.

  Protein S-prenylation is a post-translational lipid modification that occurs at C-terminal cysteines. While S-prenylation has been widely studied in the context of disease biology and drug discovery, only in the last decade have robust proteomic techniques emerged to study the complex dynamics between different classes of protein prenyltransferases, significantly aiding the development and application of tools and inhibitors. Herein, we describe the use of S-prenylation probes as a chemical proteomic technique to interrogate S-geranylgeranylation and S-farnesylation, the two classes of protein prenylation, from sample preparation to mass spectrometry analysis.

Keywords:  Chemical probes; Chemical proteomics; Lipidation; Post-translational modifications; Prenylation

DOI:  https://doi.org/10.1016/bs.mie.2025.06.012
Discov Oncol. 2025 Sep 26. 16(1): 1725

Integrated multi-omics analysis reveals PTM networks as key regulators of colorectal cancer progression and immune evasion.

Guiting Yang, Liu Ji, Chengmei Lv, Chen Zhao, Riliang Ma, Ying Li, Yanyan Hu, Linghui Pan.

   BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality, with treatment resistance often driven by molecular heterogeneity and an immunosuppressive tumor microenvironment (TME). Post-translational modifications (PTMs) regulate key oncogenic processes, but their comprehensive role in CRC progression and immune evasion remains unexplored.
METHODS: We integrated multi-omics data from bulk RNA-seq (GEO/TCGA, n = 1,783), single-cell transcriptomics (41,143 cells), and Mendelian randomization. Differential expression, GSVA, and machine learning (LASSO/SVM/Random Forest) were used to identify PTM-associated signatures. Functional validation included spatial transcriptomics, and immune profiling.
RESULTS: Multi-omics analysis identified dysregulation in 80% of PTM pathways in CRC, with ubiquitination sustaining Wnt/β-catenin signaling and GALNT6-mediated glycosylation driving immune evasion through PD-L1 stabilization and CD8 + T cell exclusion. Single-cell analysis revealed GALNT6-specific enrichment in immune-excluded goblet cells (p < 0.05). Machine learning derived a 5-gene PTM Activity Signature (CCNB1IP1, GALNT6, NEDD4L, PSMD14, UBE2C) that distinguish between patients with diseases and those without (AUC = 1.00). GALNT6 was validated as a causal risk factor (OR = 1.10, 95%CI:1.01-1.18), with its inhibition synergizing with anti-PD-1 to enhance CD8 + T cell infiltration (p < 0.01).
CONCLUSION: This study establishes PTM networks as central regulators of CRC progression and immune resistance. The PTM-AS framework enables precision subtyping, while GALNT6 emerges as a novel therapeutic target for overcoming immunotherapy resistance.

Keywords:  Biomarkers; Colorectal cancer; Post-translational modifications; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-03445-8