bims-prolim 2025-10-05 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–10–05
eleven papers selected by
Bruna Martins Garcia, CABIMER

Impact of lactylation on the pathogenesis of cancer and its clinical application potential (Review).
Lactylation in cancer: Advances and opportunities for treatment resistance.
PARK7-driven IGF2BP3-K76 lactylation mediates ferroptosis and HAIC resistance in hepatocellular carcinoma.
H3K18 lactylation-hexokinase 2 positive feedback loop promotes osteogenesis of ASPCs in facial infiltrating lipomatosis.
Construction of lactylation-related prognostic signature for glioma.
From metabolic reprogramming to epigenetic modification: association network and targeted treatment strategy between histone lactylation and tumor progression.
Post-translational governance of NF-κB in cancer immunity: mechanisms and therapeutic horizons.
Research advances of lactylation modification in breast cancer.
ZDHHC11-mediated palmitoylation alleviates chondrocyte senescence and serves as a therapeutic target for osteoarthritis.
Integrating bulk RNA-seq, scRNA-seq, and spatial transcriptomics data to identify novel post-translational modification-related molecular subtypes and therapeutic responses in hepatocellular carcinoma.
Integrated proteome, phospho-proteome and malonyl-proteome revealed a molecular alteration of breast cancer.

Mol Med Rep. 2025 Dec;pii: 336. [Epub ahead of print]32(6):

Impact of lactylation on the pathogenesis of cancer and its clinical application potential (Review).

Xiaomei Wang, Jiaqing Chen, Bing Wang, Yanping Li, Xinyue Zhou, Yingqiu Song, Chenggui Miao, Yurong Huang.

  Dysregulation of lactate metabolism is a hallmark of multiple pathologies, including cancer, which coordinates metabolic reprogramming and malignant progression. Lactylation, a lactate‑derived post‑translational modification, is a key regulator of tumor cell adaptation, aggressive behavior and immune escape. This modification mechanism links lactate accumulation to carcinogenic signaling and epigenetic dysregulation, providing novel insights into cancer pathogenesis. The present review summarizes the roles of lactylation in tumor microenvironment (TME) remodeling, therapeutic resistance and immunomodulation, and outlines the challenges to clinical translation. Lactate drives the lactylation of histone and non‑histone proteins, and alters chromatin structure and transcriptional programs to maintain tumorigenesis. In the TME, lactylation modulates the phenotypes of stromal cells (such as cancer‑associated fibroblasts) and immune cells (including macrophages and T cells), forming an immunosuppressive niche. Lactylation can also polarize macrophages towards a tumor‑promoting state, inhibit CD8+ T cells and upregulate immune checkpoints. Clinically, lactylation is associated with chemotherapy resistance (such as paclitaxel in breast cancer) and a poor prognosis, highlighting its usefulness as a biomarker. Notably, therapeutic strategies targeting lactate synthesis (such as lactate dehydrogenase A inhibitors), lactate transport (for example, monocarboxylate transporter 1/4 blockers) or lactase (such as histone lactate transferase) have shown promise in preclinical models. In conclusion, lactylation promotes tumor progression while also providing a viable therapeutic target. Deciphering its environment‑dependent mechanisms, particularly its interactions with immune checkpoints and metabolic vulnerabilities, may advance precision oncology. Validating biomarkers and therapies centered on lactylation is a key frontier in improving clinical outcomes.

Keywords:  cancer; clinical application potential; drug resistance; lactate; lactylation

DOI:  https://doi.org/10.3892/mmr.2025.13702
Clin Transl Med. 2025 Oct;15(10): e70478

Lactylation in cancer: Advances and opportunities for treatment resistance.

Keke Xu, Yiyi Shou, Ruiqi Liu, Hao Xiong, Xiaomeng Dai, Xuanwen Bao, Xiaoyan Chen, Luanluan Huang, Hailong Sheng, Haibo Zhang, Yanwei Lu.

   BACKGROUND: Lactylation, a recently identified post-translational modification that utilizes lactic acidas a substrate, has emerged as an important regulator of gene expression andprotein function. Since its discovery in 2019, lactylation has beenincreasingly recognized for its roles in cancer biology and treatment response.
MAIN TEXT: Lactylationis strongly associated with tumor progression and malignancy, underscoring itspotential as a therapeutic target. Recent studies also link lactylation tocancer treatment resistance, suggesting that modulating this modification couldenhance therapeutic efficacy. As treatment resistance remains a major clinicalchallenge in oncology, accumulating evidence indicates that dysregulatedlactylation contributes to resistance across chemotherapy, immunotherapy, targeted therapy, and radiotherapy. Preclinical and clinical research has begunto delineate the molecular pathways through which lactylation shapes theseresistance processes, and experimental approaches targeting lactylation arebeing explored to restore therapeutic sensitivity.
CONCLUSION: This review systematically summarizes the mechanisms of lactylation and its roles intreatment resistance, highlighting the interplay between lactylation andtherapeutic response. We discuss current and emerging strategies that targetlactylation, providing a foundation for future therapeutic development aimed atovercoming resistance and improving cancer treatment outcomes.
KEY POINTS: Lactylation links glycolysis to tumor progression and therapeutic response. Modulating lactylation writers and erasers restores treatment sensitivity. Aberrant lactylation drives resistance tomultiple cancer therapies. Crosstalk with other post-translational modifications suggests novel combination strategies.

Keywords:  chemotherapy; immunotherapy; lactylation; targeted therapy; treatment resistance

DOI:  https://doi.org/10.1002/ctm2.70478
Redox Biol. 2025 Sep 26. pii: S2213-2317(25)00382-9. [Epub ahead of print]87 103869

PARK7-driven IGF2BP3-K76 lactylation mediates ferroptosis and HAIC resistance in hepatocellular carcinoma.

Zhiwen Zhu, Xinyu Xia, Yuanxiang Lu, Danfeng Li, Xincheng He, Baohua Zhang, Ge Xiong, Wanguang Zhang, Huifang Liang, Hong Zhu.

  Oxaliplatin/5-fluorouracil (OXA/5-FU)-based hepatic artery infusion chemotherapy (HAIC) represents a promising strategy against advanced hepatocellular carcinoma (HCC), yet acquired resistance frequently impedes its efficacy. Here, we identify lactylation of IGF2BP3 at lysine 76 (IGF2BP3-K76lac) as a key driver of HAIC resistance. IGF2BP3-K76lac overexpression enhances chemoresistance in vitro and in vivo. Mechanistically, lactylation at IGF2BP3 K76 strengthens its affinity for m6A-modified FSP1 mRNA, upregulating FSP1 and conferring ferroptosis resistance. Blocking of IGF2BP3-K76lac bolsters OXA/5-FU-induced ferroptosis, disrupts antioxidant defenses, and curbs tumor growth. Moreover, PARK7 functions as a lactyltransferase to facilitate IGF2BP3-K76lac via increasing the binding of lactate at IGF2BP3-K76 site. Finally, blocking antibody targeting IGF2BP3-K76lac was shown to work synergistically with OXA/5-FU to restore chemosensitivity. Taken together, our findings reveal a critical role for the PARK7-IGF2BP3-K76lac-FSP1 axis in HAIC resistance, highlighting IGF2BP3-K76lac as a potential therapeutic target in HCC.

Keywords:  Chemoresistance; Ferroptosis; IGF2BP3; Lactylation; PARK7

DOI:  https://doi.org/10.1016/j.redox.2025.103869
Stem Cell Res Ther. 2025 Oct 01. 16(1): 538

H3K18 lactylation-hexokinase 2 positive feedback loop promotes osteogenesis of ASPCs in facial infiltrating lipomatosis.

Hongrui Chen, Chen Hua, Shih-Jen Chang, Yajing Qiu, Xiaoxi Lin, Bin Sun.

   BACKGROUND: Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by adipose hyperplasia and osseous overgrowth, driven by somatic PIK3CA mutations. While PIK3CA-induced metabolic reprogramming elevates lactate levels, the role of histone lactylation in FIL pathogenesis remains unclear.
METHODS: Adipose stem and progenitor cells (ASPCs) from FIL adipose tissue were isolated. Glycolysis inhibitors (2-DG, oxamate), lactate supplementation, and siRNA-mediated knockdown were used to modulate lactylation. CUT&Tag sequencing, Western blot, qPCR, ChIP-qPCR and functional assays (osteogenic/adipogenic differentiation) were performed to elucidate the potential mechanism.
RESULTS: FIL-ASPCs exhibited hyperlactylation, particularly at H3K18. H3K18la promoted osteogenesis by activating osteogenic genes, while adipogenesis remained unaffected. Inhibition of lactylation via glycolysis inhibitors or LDHA/LDHB knockdown suppressed osteogenic differentiation, whereas lactate supplementation reversed these effects. TGF-β1 stimulation could increase lactylation levels and promote osteogenic differentiation. Moreover, H3K18la upregulated hexokinase 2 (HK2), enhancing glycolysis and lactate production, thereby forming a lactate-H3K18la-HK2 positive feedback loop.
CONCLUSIONS: This study identified H3K18 lactylation as a key epigenetic driver of FIL-associated osseous hyperplasia via a lactate-H3K18la-HK2 feedback loop. Targeting this axis may offer therapeutic potential for FIL and related metabolic bone disorders.

Keywords:  Adipose stem and progenitor cells; Facial infiltrating lipomatosis; H3K18 lactylation; Hexokinase 2; Osteogenesis

DOI:  https://doi.org/10.1186/s13287-025-04651-5
Discov Oncol. 2025 Sep 30. 16(1): 1783

Construction of lactylation-related prognostic signature for glioma.

Yi Huang, Shenbao Shi, Qiuchan Yan, Ziwen Qiu, Zhiming Zeng.

   BACKGROUND: Glioma was a kind of malignant tumor associated with high mortality and recurrence. Therefore, it was urgent to establish effective prognostic models to guide clinical treatment in glioma. Protein lactylation was discovered in various malignant tumor, but only a few studies on glioma focused on protein lactylation.
METHODS: The expression levels of lactylation-related genes were identified from the TCGA database. A lactylation-related prognostic signature was established using various combinations of 10 different excellent machine learning methods. The prognostic value of the signature was assessed and further validated in the CGGA cohorts. Patients were divided into two groups according to the risk score (RS). Independent prognostic value assessment, pathways enrichment analysis and protein-protein interaction analysis were conducted. Finally, we verified the functions of C19orf53 through vitro experiments.
RESULTS: A robust lactylation-related prognostic signature of low-grade glioma (LGG) was established, which was consisted of 14 genes. Patients with higher RS had poorer clinical outcomes in all the cohorts. More immune-related and pro-cancer pathways were enriched in high-RS subgroup. Moreover, the 14 lactylation-related prognostic genes had close interaction relationships, and 11 of them had independent prognostic value. Vitro experiments proved that shRNA-mediated C19orf53 down-regulation impeded the migration and proliferation of LGG cells.
CONCLUSIONS: The lactylation-related prognostic signature exhibited robust predictive efficiency in LGG, providing a new perspective for the prognosis evaluation of LGG patients and the subsequent studies on therapeutic targets.

Keywords:  C19orf53; Glioma; Lactylation; Machine learning; Therapy target

DOI:  https://doi.org/10.1007/s12672-025-03636-3
Front Immunol. 2025 ;16 1542664

From metabolic reprogramming to epigenetic modification: association network and targeted treatment strategy between histone lactylation and tumor progression.

Yi Li, Lu Feng, Qian Shen, Xiaochen Jiang, Fudong Liu, Chuanlong Zhang, Runzhi Qi, Bo Pang.

  Metabolic reprogramming and epigenetic modification have been widely observed in cancer research. Based on accumulating experimental evidence in recent years, beginning with metabolic reprogramming driven by carcinogenic signals, the accumulation of key metabolites, represented by lactate, continuously affects cellular plasticity and alters the epigenetic landscape. As a new post-translational modification of histone, histone lactylation not only changes the nucleosome structure, but also regulates chromatin dynamics and gene expression, which is closely related to the poor prognosis of tumors, contributing to immune escape, immune monitoring and angiogenic events in tumor progression. Before the discovery of histone lactylation in 2019, there was a lack of systematic understanding of the lactate regulation of tumor metabolism, immune effects and microenvironmental homeostasis. From metabolic changes to stable gene expression, histone lactylation has become an important entry point in tumor research, connecting the relationship network of metabolic reprogramming, Tumor microenvironment (TME) and epigenetic modification. It represents an important conceptual link between metabolism and epigenetics, and emerging evidence suggests it may be a promising area for understanding tumor progression and developing targeted therapies. In this review, we focus on how tumor cell metabolic reprogramming reshapes the epigenetic landscape into histone lactylation. Besides, we discussed the plasticity of tumor metabolism regulated by histone lactylation in reverse, involving TME biological processes such as immunity and metabolism. Finally, we reviewed the new molecular targets and targeted therapeutic strategies of histone lactylation for cancer treatment. Elucidating these problems will provide theoretical basis for further research and clinical application in this field in the future.

Keywords:  epigenetic modification; histone lactylation; metabolic reprogramming; targeted therapy; tumor

DOI:  https://doi.org/10.3389/fimmu.2025.1542664
Front Immunol. 2025 ;16 1627084

Post-translational governance of NF-κB in cancer immunity: mechanisms and therapeutic horizons.

Yue Hong, Ying Fu, Qian Long.

  Nuclear factor-κB (NF-κB) is a central transcriptional orchestrator of inflammation, immune modulation, and tumor progression. Beyond canonical signal transduction, the immunological functions of NF-κB are intricately governed by a spectrum of post-translational modifications (PTMs)-including phosphorylation, acetylation, ubiquitination, and methylation-that fine-tune its activation, nuclear translocation, DNA binding, and transcriptional specificity. In this Review, we explore how these context-dependent PTMs dynamically shape NF-κB's role in cancer immunity: promoting macrophage polarization, controlling antigen presentation by dendritic cells, regulating T cell exhaustion, and sustaining immunosuppressive networks within the tumor microenvironment. We further delineate how PTM-mediated NF-κB signaling interfaces with immune checkpoint expression-particularly PD-L1 and IDO1-and fuels resistance to immunotherapies. Emerging pharmacological strategies targeting NF-κB-modifying enzymes or degradation via PROTACs hold promise to reprogram the immune landscape. By integrating mechanistic insight with translational potential, we position NF-κB's post-translational regulation as a fertile axis for next-generation immunotherapeutic innovation.

Keywords:  NF-κB signaling; Tumor immune microenvironment; immune evasion; immunotherapy resistance; post-translational modifications; precision immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1627084
Discov Oncol. 2025 Oct 03. 16(1): 1811

Research advances of lactylation modification in breast cancer.

Pu Shen, Meng Yang.

  Breast cancer (BC), a leading cause of cancer mortality in women, involves complex molecular mechanisms including post-translational modifications (PTMs). While common PTMs are well-studied, lactylation-a novel PTM linking metabolism to epigenetics-has emerged as a critical regulator in BC pathogenesis. The high concentration of lactate caused by the Warburg effect makes lactylation in tumor tissue possible. Machine learning enhances the discovery and analysis of lactylation sites by processing large datasets, revealing patterns that influence tumor behavior and patient outcomes. This review offers a comprehensive analysis of the role of lactylation in breast cancer development and progression. It focuses on the impact on the proliferation, migration, and invasion of breast cancer cells and their association with chemotherapeutic resistance. This review provides valuable insights for the development of targeted therapeutic strategies that may enhance early diagnosis, treatment, and prognostic evaluation of breast cancer. The findings presented here open new avenues for future research and clinical practice.

Keywords:  Breast cancer; Epigenetic therapy; Lactylation; Machine learning; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-03663-0
Nat Aging. 2025 Sep 30.

ZDHHC11-mediated palmitoylation alleviates chondrocyte senescence and serves as a therapeutic target for osteoarthritis.

Kefan Wang, Wei He, Zhe Gong, Jun Gao, Tianyou Gao, Nan Pan, Dongze Wu, Yijie Yang, Zhuang Li, Xing Zhao, Mingliang Ji, Shuying Shen.

Osteoarthritis (OA) is a whole-joint disorder that interferes with the quality of life in older individuals. Here we report that ZDHHC11 is highly expressed in articular chondrocytes but is downregulated in the degenerated cartilage of aged mice and patients with OA. ZDHHC11 prevents chondrocyte senescence and promotes cartilage anabolism, culminating in an improved OA phenotype. The deletion of Zdhhc11 in mice (Zdhhc11fl/fl) exacerbates OA progression in a destabilized medial meniscus model. Specifically, we identify ZDHHC11 as a key palmitoyltransferase whose depletion leads to a GNB2-dependent E3 ubiquitin ligase-mediated proteasomal degradation of APOD. Mechanistically, ZDHHC11-mediated palmitoylation alleviates OA progression by deactivating the GATA4-P65 signaling pathway. We also propose an original lipid nanoparticle-based platform for Zdhhc11 mRNA delivery to rejuvenate impaired cartilage by specifically targeting chondrocytes in vivo. Collectively, ZDHHC11-dependent palmitoylation is essential for ameliorating OA, and the targeted delivery of ZDHHC11 may serve as a promising strategy for future OA treatment.

DOI: https://doi.org/10.1038/s43587-025-00968-1
Cancer Cell Int. 2025 Oct 03. 25(1): 330

Integrating bulk RNA-seq, scRNA-seq, and spatial transcriptomics data to identify novel post-translational modification-related molecular subtypes and therapeutic responses in hepatocellular carcinoma.

Shiling Chen, Yunjie Li, Jichang Hu, Heli Li, Chen Hu, Jinzhu Zhao, Hong Qian, Shuya Bai, Zhouping Tang, Yangyang Feng.



Keywords:  Hepatocellular carcinoma; Immunotherapy; Multi-omics analysis; Post-translational modification

DOI:  https://doi.org/10.1186/s12935-025-03964-y
Sci Rep. 2025 Sep 30. 15(1): 34004

Integrated proteome, phospho-proteome and malonyl-proteome revealed a molecular alteration of breast cancer.

Chenxu Guo, Mingliang Zhang, Xin Jin, Chao Zhu, Rui Xu, Jiahe Sun, Jun Qian.

  Breast cancer is a heterogeneous disease with a high incidence, but its proteomes have not yet been thoroughly characterized. To construct a comprehensive dynamic network of breast cancer-related proteins, we integrated the whole-cell proteome (WCP), phospho-proteome, malonyl-proteome of breast cancer tumor tissues and adjacent healthy tissues. We identified 2,417 differentially expressed proteins (DEPs), 646 differentially phosphorylated proteins (DPPs), and 107 differentially malonylated proteins (DMPs). Functional enrichment analysis revealed that these differentially expressed proteins are involved in extracellular matrix (ECM) interactions and immune-related pathways. Protein‒protein interaction (PPI) analysis revealed posttranslational modification (PTM) crosstalk between proteins involved in phosphorylation and malonylation. The acetyltransferase EP300 and deacetylase HDAC1 are involved in the DPP network, whereas the phosphatase PKM is a hub protein in the DMP network. Kinase-substrate enrichment analysis (KSEA) revealed the activation of the kinases CSNK1D, ROCK1, ROCK2, and CDK2. Overall, this study provides a foundation for understanding the functions of phosphorylation and malonylation in breast cancer. It systematically reveals critical features of breast cancer, providing a resource for exploring PTM crosstalk within and across proteins involved in the disease.

Keywords:  Breast cancer; Malonylation; Phosphorylation; Posttranslational modification

DOI:  https://doi.org/10.1038/s41598-025-11573-y