bims-prolim 2025-11-23 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–11–23
ten papers selected by
Bruna Martins Garcia, CABIMER

HAT1 functions as a lactyltransferase and mediates RPA1 lactylation to promote DNA repair and radioresistance in lung adenocarcinoma.
CTHRC1-driven breast cancer progression: insights from palmitoylation networks and spatial heterogeneity.
The growing landscape of lysine lactylation links to immunosuppressive microenvironment.
Lactylation in cancer: Metabolic-epigenetic nexus and therapeutic frontiers.
zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.
Multi-omics analysis of the HMGB2+ tumor epithelial cells in lactylation subgroups in colorectal cancer.
IGFBP7 and CCT2 are novel lactylation-driven mediators of endothelial-to-mesenchymal transition in idiopathic pulmonary fibrosis.
Lactylated SPTAN1 Accelerates Hepatocellular Carcinoma Progression by Promoting NOTCH1/HES1 Activation and Immunosuppression.
PGK1 Persulfidation Promotes the Proliferation and Metastasis of Breast Cancer.
Knockdown of SUCLG2 inhibits glioblastoma proliferation and promotes apoptosis through LMNA acetylation and the mediation of H4K16la lactylation.

Cell Death Dis. 2025 Nov 21. 16(1): 851

HAT1 functions as a lactyltransferase and mediates RPA1 lactylation to promote DNA repair and radioresistance in lung adenocarcinoma.

Jiang He, Tangmin Lai, Yuzu Zhao, Zhiying Zhou, Liu Zhou, Dan Tao, Haonan Yang, Nan Li, Yu He, Shuheng Yang, Zheng Tang, Siwei Zeng, Erha Munai, Yanchen Liu, Yuanyuan Tan, Wei Zhou, Yongzhong Wu.

Lysine lactylation is a post-translational modification induced by lactate discovered in recent years. Abnormal lysine lactylation contributes to the occurrence and progression of various tumors. However, the mediators and downstream targets of lysine lactylation remain unclear. Here, we report that HAT1 serves as a potential lactyltransferase that can promote homologous recombination and lead to radioresistance by regulating lactylation of RPA1. Lactylation of RPA1 facilitates its binding to single-stranded DNA and MRE11-RAD50-NBS1 (MRN) complexes and promotes homologous recombination. HAT1 knockout inhibits DNA repair in lung adenocarcinoma cells, thereby increasing radiotherapy sensitivity. Interestingly, we also found that K15 auto-lactylation of HAT1 can modulate its lactyltransferase activity. In conclusion, our research reveals that HAT1-regulated RPA1 lactylation plays an important role in homologous recombination and radioresistance, suggesting that HAT1 may become a potential therapeutic target for reversing the radioresistance caused by lactate accumulation in cancer cells.

DOI: https://doi.org/10.1038/s41419-025-08113-x
BMC Cancer. 2025 Nov 21. 25(1): 1795

CTHRC1-driven breast cancer progression: insights from palmitoylation networks and spatial heterogeneity.

Shujia Yu, Jingyu Wu.



Keywords:  Biomarker; Breast cancer; CTHRC1; Diagnostic model; Machine learning; Palmitoylation

DOI:  https://doi.org/10.1186/s12885-025-15190-w
Eur J Pharmacol. 2025 Nov 19. pii: S0014-2999(25)01132-X. [Epub ahead of print] 178378

The growing landscape of lysine lactylation links to immunosuppressive microenvironment.

Chao Huang, Wei Zhu, Li Sun.

  Lysine lactylation (Kla) has emerged as an epigenetic-metabolic regulatory mechanism linking post-translational modification (PTM) to immunosuppressive TME formation. Evidence supports its complex role in TME by modulating immune state transitions and augmenting tumor malignancy. However, the existence of specialized lactyltransferases and multiple crosstalk mechanisms remain debated. This review summarizes upstream and downstream regulatory factors influencing lactylation modification, comparing differential substrate modification patterns that diverge in their requirements for Lactyl-CoA biosynthesis, which contributes to gene expression or protein function. Furthermore, we explore the mechanism that the lactate-Kla axis drives tumor progression by orchestrating metabolic reprogramming, fostering therapy resistance, and suppressing T-cell cytotoxicity. Finally, we summarize the burgeoning field of anti-lactylation pharmacology, evaluating prospective therapeutic strategies from preclinical and clinical studies.

Keywords:  Epigenetic regulation; Immunosuppressive tumor microenvironment; Lactate; Lactylation; Lactyltransferase

DOI:  https://doi.org/10.1016/j.ejphar.2025.178378
Crit Rev Oncol Hematol. 2025 Nov 19. pii: S1040-8428(25)00422-6. [Epub ahead of print] 105034

Lactylation in cancer: Metabolic-epigenetic nexus and therapeutic frontiers.

Chang Zhang, Qingfei Meng, Hui Jiao, Huixin Liu, Xiangchao Wang, Honglan Zhou, Yishu Wang.

  The revolutionary discovery of histone lactylation fundamentally reshapes our understanding of cancer metabolism, revealing how glycolytic lactate directly orchestrates protein modification. This review comprehensively synthesizes mounting evidence positioning lactylation as a critical, yet paradoxically dual, regulator of oncogenic processes. While often driving malignant phenotypes through mechanisms like MRE11-K673la-mediated DNA repair, lactylation can also exert tumor-suppressive effects, such as H3K18la-induced cell cycle arrest, highlighting its context-dependent complexity. We delve into the paradigm-shifting discovery of alanyl-tRNA synthetases (AARS1/2) as novel, CoA-independent lactylation catalysts, challenging long-held assumptions. Furthermore, we systematically dissect lactylation's intricate crosstalk with other post-translational modifications, unveiling competitive dynamics with acetylation (e.g., H3K18la vs. H3K18ac) and cooperative metabolic coupling with m6A methylation. Beyond fundamental mechanisms, this review illuminates the profound clinical potential of lactylation. We discuss how specific lactylation patterns, including histone (H4K12la) and non-histone (p53-K120la) modifications, emerge as promising biomarkers correlating with drug response across diverse malignancies. Addressing critical gaps, we establish a robust conceptual framework for lactylation as a dynamic metabolic sensor and propose actionable strategies for therapeutic targeting, paving the way for novel precision oncology approaches. This work bridges fundamental insights to translational applications, propelling forward the emerging and impactful field of metabolic-epigenetic regulation in cancer.

Keywords:  Cancer; Epigenetics; Lactylation; Metabolic Reprogramming; Targeted therapy

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105034
Int Immunopharmacol. 2025 Nov 18. pii: S1567-5769(25)01851-X. [Epub ahead of print]168(Pt 2): 115863

zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.

Cong Lu, Ying He, Le-Qing Zhang, Jing-Yi Miao, Wei Wang.

   BACKGROUND: Protein palmitoylation, catalyzed by the zDHHC family of palmitoyltransferases, has emerged as a critical post-translational modification implicated in tumor progression. However, the comprehensive role of zDHHCs-mediated palmitoylation in molecular subtyping, prognosis, and immune microenvironment modulation in pancreatic cancer (PC) remains unclear.
METHODS: We systematically integrated multi-cohort transcriptome, single-cell RNA-seq, and somatic mutation data for PC. Bioinformatic analyses included molecular subtyping based on zDHHCs expression, differential gene expression, functional enrichment, CIBERSORTx-based immune infiltration analysis, single-cell trajectory inference, cell-cell communication networks, and construction/validation of a palmitoylation-related gene signature (PRGS) prognostic model.
RESULTS: Two robust molecular subtypes based on zDHHCs expression were identified, displaying significant differences in patient prognosis and immune infiltration. High zDHHCs activity was associated with immunosuppressive features, including decreased CD8+ T cell infiltration and enrichment of macrophages/eosinophils. Single-cell analyses revealed dynamic upregulation of zDHHCs genes during epithelial differentiation, especially in metastatic lesions, with trajectory and enrichment analyses implicating palmitoylation in proliferation, cell cycle, and chromatin remodeling. Cell-cell communication networks uncovered zDHHCs-dependent remodeling of SPP1-CD44 and MHC-II pathways, linked to immune suppression. A 7-gene PRGS (DCBLD2, CXCL5, ASPH, LAMC2, KRT6A, TOP2A, NPNT) prognostic model demonstrated robust predictive accuracy across independent cohorts, correlating with tumor mutation burden, TP53/KRAS mutation frequency, and activation of proteasome, pyrimidine metabolism, and immune evasion pathways.
CONCLUSIONS: zDHHCs-mediated palmitoylation and its regulatory gene network critically shape pancreatic cancer heterogeneity, immune microenvironment, and prognosis. The PRGS model provides a novel molecular tool for patient stratification and may inform the development of precision therapies targeting palmitoylation-driven pathways in PC.

Keywords:  Cell–cell communication; Palmitoylation; Pancreatic cancer; Tumor immune microenvironment; zDHHC

DOI:  https://doi.org/10.1016/j.intimp.2025.115863
Cell Biosci. 2025 Nov 19. 15(1): 158

Multi-omics analysis of the HMGB2+ tumor epithelial cells in lactylation subgroups in colorectal cancer.

Shangshang Hu, Jinwei Lou, Muzi Ding, Yuhan Chen, Jian Qin, Zixuan Liu, Yue Li, QianNi Xiao, Mu Xu, Huiling Sun, Yuqin Pan, Shukui Wang.

  Colorectal cancer (CRC) is a prevalent malignancy, yet the role of lactylation in its progression remains unclear. This study investigates High Mobility Group Box 2 positive tumor epithelial cells (HMGB2+Epi), a lactylation-associated subpopulation. By integrating multi-omics data, including proteomics, single-cell, spatial, and bulk transcriptomics, we explored the function of HMGB2+Epi in CRC. Elevated lactylation levels in CRC tissues were correlated with poor prognosis. Single-cell analysis identified HMGB2+Epi as a central lactylation-enriched subpopulation. Functionally, HMGB2 enhanced the Warburg effect, promoting CRC cell proliferation, migration, and invasion. HMGB2 knockout reduced lactylation levels and inhibited tumor progression. Mechanistically, NFYB directly bound to the HMGB2 promoter, forming the NFYB-HMGB2 axis that drives lactylation and metabolic reprogramming. Cell-cell communication analysis revealed enhanced interactions between HMGB2+Epi and fibroblasts, endothelial cells, and T/NK cells. Molecular dynamics and in-vitro assays suggest that BI-2536 downregulates HMGB2 and lactylation in CRC cells. A risk model based on HMGB2+Epi outperformed 125 previously published models in independent cohorts. In summary, HMGB2+Epi represents a key lactylation-enriched subgroup, with the NFYB-HMGB2 axis driving CRC progression via lactylation. BI-2536 as a tool compound implicating the HMGB2-lactylation axis, and the HMGB2+Epi-based risk model provides a novel target for precision CRC therapy.

Keywords:  Colorectal cancer; HMGB2; Lactylation; Multi-omics

DOI:  https://doi.org/10.1186/s13578-025-01491-x
Funct Integr Genomics. 2025 Nov 20. 25(1): 250

IGFBP7 and CCT2 are novel lactylation-driven mediators of endothelial-to-mesenchymal transition in idiopathic pulmonary fibrosis.

Li Wenhao, Huang Ling, Fang Wanqing, Wang Wanrong, Cao Chao, Wang Ran.

  Lactylation is a post-translational modification that can influence the onset and progression of various diseases.However, its role in Idiopathic Pulmonary Fibrosis (IPF) has not been systematically investigated. Single-cell sequencing and bulk RNA sequencing techniques were utilized to assess lactylation levels in IPF patients and health people. The clinical significance of lactylation was explored through survival and correlation analyses. Optimal feature genes of lactylation were identified using correlation analysis, multiple machine learning algorithms, Cox regression analysis and Mendelian randomization. The potential mechanisms of these Optimal feature genes were inferred through pseudotime analysis and gene pathway activity analysis, followed by experimental validation. Cell-cell communication and metabolic assessments were employed to explore the reasons for elevated lactylation levels in IPF, and relevant findings were verified through in vitro cellular experiments. Both single-cell sequencing and bulk RNA sequencing consistently demonstrated elevated lactylation levels in the IPF patients. High lactylation levels were associated with worse lung function and poorer prognosis. Through the integration of five machine learning algorithms, Cox regression analysis and Mendelian randomization, two optimal feature genes IGFBP7 and CCT2 were identified. These optimal feature genes were found to be significantly highly expressed in vascular endothelial cells, and this conclusion was experimentally validated. Pseudotime analysis results combined with RNA interference (RNAi) and wound healing assays demonstrated that both optimal feature genes promoted endothelial-mesenchymal transition (EndMT) in endothelial cells. Through cell-cell communication analysis, we discovered that TGF-β can promote metabolic reprogramming in endothelial cells, leading to increased lactate production and ultimately elevated expression of the optimal feature genes. Lactylation levels are significantly increased in IPF patients. TGF-β can induce metabolic reprogramming in endothelial cells, leading to high expression of IGFBP7 and CCT2, thereby promoting EndMT.

Keywords:  Cell-cell communication; Idiopathic pulmonary fibrosis; Lactylation; Post-translational modification; Single-cell sequencing

DOI:  https://doi.org/10.1007/s10142-025-01761-4
Adv Sci (Weinh). 2025 Nov 16. e07068

Lactylated SPTAN1 Accelerates Hepatocellular Carcinoma Progression by Promoting NOTCH1/HES1 Activation and Immunosuppression.

Zengbin Wang, Dongjie Ye, Linqing Wu, Jiayu Liu, Banglun Pan, Zhu Zhang, Xiaoxia Zhang, Yuxin Yao, Nanhong Tang.

  Nonerythrocytic alphaII-spectrin (SPTAN1) is crucial for neuronal functions, yet its role in oncogenic processes remains inadequately characterized. This study investigates the lactylation (kla) modification of SPTAN1 (SPTAN1-kla) and its mechanistic contributions to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Results indicate that SPTAN1 undergoes lactylation at lysine residues K1952 and K1957 specifically in HBV-positive HCC tissues. Alanyl-tRNA synthetase 1 (AARS1) mediates SPTAN1-kla formation, while histone deacetylase 1 (HDAC1) acts as a delactylase. HBV infection enhances lactate production by inducing the expression of HK2, promoting SPTAN1-kla formation, and disrupting the liquid-liquid phase separation (LLPS) of cytoplasmic SPTAN1, thereby facilitating its nuclear translocation. Within the nucleus, SPTAN1-kla interacts with core-binding factor β (CBFB) to activate NOTCH1/HES1 signaling, thereby promoting HCC cell proliferation. Furthermore, SPTAN1-kla activates the COX2/mPGES1 pathway through NOTCH1/HES1 signaling, thereby enhancing the biosynthesis of prostaglandin E2 (PGE2) and increasing the infiltration of exhausted CD8⁺ T cells. Therapeutic targeting of SPTAN1-kla using specific inhibitory peptides significantly attenuates HCC tumor growth in preclinical models. Our research identifies SPTAN1-kla as a novel oncogenic driver in HBV-related HCC, functioning via metabolic reprogramming and immune modulation. These findings position SPTAN1-kla as a promising therapeutic target for developing precision interventions against HBV-related HCC.

Keywords:  CD8+ Tex; HCC; NOTCH1/HES1; SPTAN1; lactylation

DOI:  https://doi.org/10.1002/advs.202507068
Antioxid Redox Signal. 2025 Nov 12. 0

PGK1 Persulfidation Promotes the Proliferation and Metastasis of Breast Cancer.

Chenghua Luo, Mengmeng Zhao, Yalu Wang, Yuxiang Xu, Shuai Chen, Weihua Liang, Kaige Yang, Jianming Hu.

  Aims: Endogenous hydrogen sulfide (H2S) is involved in the occurrence and development of breast cancer, while its underlying mechanism is not yet clear. Here, we aimed to focus on the molecular mechanism of endogenous H2S promoting the proliferation and metastasis of breast cancer. Results: In this study, four major findings were revealed: (1) Inhibition of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) increased the content of glucose in the supernatant of breast cancer cell and decreased the production of intracellular lactic acid and adenosine triphosphate. (2) Phosphoglycerate kinase 1 (PGK1) was persulfidated at Cys108 and Cys316, and its persulfidation level in breast cancer tissue was significantly higher than that in paracancerous tissue. (3) Blocking the persulfidation of PGK1 inhibited glycolysis and malignant biological behaviors of breast cancer cell. (4) The CSE inhibitor reduced the persulfidation of PGK1 and inhibited the growth and metastasis of xenograft tumors, whereas sodium hydrosulfide reversed the effect of CSE inhibitor. Preface PGK1 is not the only potential target for persulfidation. Innovation and Conclusion: This study revealed a novel mechanism involved in the upregulation of endogenous H2S in breast cancer. Endogenous H2S regulates glycolysis of breast cancer cells by mediating PGK1 persulfidation modification at Cys108 and Cys316, thereby promoting tumor proliferation and metastasis. This study offers a potential therapeutic strategy through targeting the upregulated endogenous H2S and persulfidation of PGK1. Antioxid. Redox Signal. 00, 000-000.

Keywords:  PGK1; breast cancer; hydrogen sulfide; persulfidation

DOI:  https://doi.org/10.1177/15230864251394334
Cell Death Discov. 2025 Nov 17. 11(1): 534

Knockdown of SUCLG2 inhibits glioblastoma proliferation and promotes apoptosis through LMNA acetylation and the mediation of H4K16la lactylation.

Wenshan Li, Qingqing Zhang, Hang Yin, Qiao Li, Shangyu Liu, Juncheng Wang, Guoqiang Yuan, Yawen Pan.

Glioblastoma (GBM) is the most aggressive primary tumour in the central nervous system, and dynamic clonal evolution and interactions within the microenvironment cause its significant spatiotemporal heterogeneity. These interactions primarily manifest as metabolic reprogramming, mitochondrial dynamic imbalance, and epigenetic remodelling. SUCLG2 has been implicated in the progression of GBM; however, the underlying mechanism is unclear. This study aimed to investigate the role of SUCLG2 in the proliferation and apoptosis of GBM cells. SUCLG2 was found to interact with LMNA, leading to acetylation modification of its amino acid residue K470 and affecting limited oxidative phosphorylation levels and mitochondrial damage. SUCLG2 interacted with DLAT, reducing the binding of lactate-regulated protein H4K16la to promoter regions and cis-regulatory elements. This suppressed the expression of BEST1, GRAMD4, and MBD6, affecting the proliferation and apoptosis of GBM cells. These findings reveal a new SUCLG2-mediated mechanism in lactate metabolism and mitochondrial apoptosis in GBM and offer novel therapeutic and preventive targets for GBM.

DOI: https://doi.org/10.1038/s41420-025-02856-4