ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Lactate Dehydrogenase C4 Accelerates Triple-Negative Breast Cancer Progression by Promoting Acetyl-CoA Acyltransferase 2 Lactylation to Increase Free Fatty Acid Accumulation.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- SIRT5-Mediated Desuccinylation of ACAA2 Protects Against Calcium Oxalate-Induced Kidney Injury by Regulating Fatty Acid Oxidation to Suppress Mitochondrial Oxidative Injury and Ferroptosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lactate metabolism and protein lactylation in inflammatory and tumor microenvironments.Molecular biomedicine · 2026Review
- LDHC4 drives lung adenocarcinoma progression by inducing lactylation of RB1 at lysine 900 to disrupt the RB1-E2F1 complex.Journal of translational medicine · 2026Article
- A novel programmed-cell-death-related prognostic risk model for cervical cancer based on mitochondrial genes.Translational cancer research · 2026Article
- LDHA-driven ACAA2 lactylation at K270 reprograms fatty acid metabolism to promote clear cell renal cell carcinoma progression.Scientific reports · 2026Article
- LDHC4 promotes ovarian cancer progression through H4K12 lactylation to regulate PGK1 expression and modulate glycolysis.Journal of translational medicine · 2026Article
- Development and validation of an interpretable machine learning model identify the lactylation-related protein SUSD3 as a prognostic and therapeutic biomarker for breast cancer.Frontiers in immunology · 2026Article
- When metabolic enzymes meet lactylation: a bidirectional dialogue in health and disease.Frontiers in cell and developmental biology · 2026Review
- Histone H4K8 lactylation promotes glioblastoma progression by inducing NUPR1-mediated autophagosome‒lysosome fusion.Theranostics · 2026Article
- Emerging role of histone and non-histone lactylation in metabolic reprogramming of female-specific malignancies.World journal of surgical oncology · 2025Review
- Targeting Lactylation for Cancer: Mechanisms, Effects, and Therapeutic Prospects.International journal of molecular sciences · 2025Review
- Lactate Dehydrogenase C4 Accelerates Triple-Negative Breast Cancer Progression by Promoting Acetyl-CoA Acyltransferase 2 Lactylation to Increase Free Fatty Acid Accumulation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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11 authors.
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Abstract
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.
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