bims-meprid 2025-03-02 papers

Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00058-0. [Epub ahead of print]44(2): 115287

Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.

Enric Mocholi, Edward Corrigan, Theo Chalkiadakis, Can Gulersonmez, Edwin Stigter, Bas Vastert, Jorg van Loosdregt, Stefan Prekovic, Paul J Coffer.

Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4+ T cells in the synovial fluid (SF) of affected joints. JIA CD4+ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4+ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4+ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.

Keywords: CP: Immunology; CP: Metabolism; T cells; autoimmune disease; glucose metabolism; histone acetylation; juvenile idiopathic arthritis; pyruvate dehydrogenase

DOI: https://doi.org/10.1016/j.celrep.2025.115287

Chembiochem. 2025 Feb 23. e202401086

Glyoxalase 2 coordinates de novo serine biosynthesis.

Marissa N Trujillo, Erin Q Jennings, Dominique O Farrera, Naoya Kitamura, Colin C Anderson, Sarah Gehrke, Julie A Reisz, Mogens Johannsen, James R Roede, Angelo D'Alessandro, James Galligan.

Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme in de novo Ser biosynthesis. Numerous metabolic pathways rely on Ser as a precursor, most notably one-carbon metabolism, glutathione biosynthesis, and de novo nucleotide biosynthesis. To facilitate proliferation, many cancer cells shunt glycolytic flux through this pathway, placing PHGDH as a metabolic liability and feasible therapeutic target for the treatment of cancer. Herein, we demonstrate the post-translational modification (PTM) of PHGDH by lactoylLys. These PTMs are generated through a non-enzymatic acyl transfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Knockout of the primary LGSH regulatory enzyme, glyoxalase 2 (GLO2), results in increased LGSH and resulting lactoylLys modification of PHGDH. These PTMs reduce enzymatic activity, resulting in a marked reduction in intracellular Ser. Using stable isotope tracing, we demonstrate reduced flux through the de novo Ser biosynthetic pathway. Collectively, these data identify PHGDH as a target for modification by lactoylLys, resulting in reduced enzymatic activity and reduced intracellular Ser.

Keywords: 3-phosphoglycerate dehydrogenase (PHGDH); cell metabolism; glycolysis; lactoylation

DOI: https://doi.org/10.1002/cbic.202401086

Theranostics. 2025 ;15(6): 2338-2359

Histone lactylation-driven B7-H3 expression promotes tumor immune evasion.

Zhibo Ma, Jincui Yang, Wenlong Jia, Le Li, Yixin Li, Junjie Hu, Wei Luo, Ronghui Li, Dawei Ye, Peixiang Lan.

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous immune checkpoints, particularly those within the B7 family. Elucidating the mechanisms that govern the induction of B7 family molecules is crucial for the advancement of immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, is suggested may play a role in reshaping the tumor microenvironment and facilitating immune evasion. Methods: We analyzed the glycolysis pathway's enrichment in patients with immune-evading tumors and assessed the impact of lactate treatment on the antitumor immunity of CD8+ T cells in the tumor microenvironment. We interrupted glycolysis using lactate dehydrogenase A (LDHA) knockdown and sodium oxamate, and evaluated its effects on CD8+ T cell cytotoxicity. Additionally, we investigated the correlation between B7-H3 expression and the glycolysis pathway, and explored the molecular mechanisms underlying lactate-induced B7-H3 expression. Results: Our findings revealed that the glycolysis pathway was highly enriched in immune-evading tumors. Lactate treatment inhibited the antitumor immunity of CD8+ T cells, whereas interruption of glycolysis via LDHA knockdown or treatment with sodium oxamate augmented the cytotoxicity of CD8+ T cells, effectively counteracting tumor immune evasion. B7-H3 expression was found to be closely linked with the glycolysis pathway. Mechanistically, lactate-upregulated H3K18la directly bound to the B7-H3 promoter in conjunction with the transcription factor Creb1 and its co-activator Ep300, leading to increased B7-H3 expression and contributing to tumor progression by compromising the proportion and cytotoxicity of tumor-infiltrating CD8+ T cells. In mouse tumor bearing models, inhibiting glycolysis and B7-H3 expression suppressed tumor cell growth, activated tumor-infiltrating CD8+ T cells, and demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced the efficacy of anti-PD-1 treatment. Conclusions: This study uncovers a novel mechanism by which lactate modulates the immune microenvironment through the glycolysis pathway and B7-H3 expression, providing new avenues for lactate metabolism-targeted tumor immunotherapy.

Keywords: B7-H3; Glycolysis; H3K18la; Histone lactylation; Immune evasion

DOI: https://doi.org/10.7150/thno.105947

Exp Cell Res. 2025 Feb 22. pii: S0014-4827(25)00070-9. [Epub ahead of print] 114474

Lactate promotes the epithelial-mesenchymal transition of liver cancer cells via TWIST1 lactylation.

Wang Huimin, Wu Xin, Yu Shan, Zhang Junwang, Wen Jing, Wang Yuan, Liu Qingtong, Li Xiaohui, Yao Jia, Yuan Lili.

Elevated lactate levels increase the risk of liver cancer progression. However, the mechanisms by which lactate promotes liver cancer progression remain poorly understood. Epithelial-mesenchymal transition (EMT), characterized by the loss of epithelial cells polarity and cell-cell adhesion, leading to the acquisition of mesenchymal-like phenotypes, is widely recognized as a key contributor to liver cancer progression. TWIST1 (Twist Family BHLH Transcription Factor 1) plays a central role in inducing EMT. Here, we investigated the role of lactate in promoting EMT in liver cancer and the underlying regulatory mechanisms. High levels of lactate significantly promoted EMT progression in liver cancer cells. Mechanistically, lactate-induced lactylation of TWIST1 in vivo and in vitro. Mutation assay confirmed that Lysine 33 (K33) is the major site of TWIST1 lactylation. Moreover, cell fractionation & luciferase reporter assay results identified that TWIST1-K33R mutant impaired the EMT process via inhibiting nuclear import and the transcriptional activity. Thus, our findings provide novel insights into the regulatory role of lactate in EMT in liver cancer pathogenesis. Additionally, targeting of lactate-driven lactylation of TWIST1 may boost the therapeutic strategy for liver cancer.

Keywords: EMT; TWIST1; lactate; lactylation; live cancer

DOI: https://doi.org/10.1016/j.yexcr.2025.114474