ArticleJournal of experimental & clinical cancer research : CR2025
Lactate-driven lactylation of HNRNPA1 orchestrates PKM2 splicing and glycolytic reprogramming in bladder cancer.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- RNA N4-acetylcytidine modification in health and cancer: molecular mechanisms, cellular plasticity, and therapeutic opportunities.Biomarker research · 2026Review
- The lactate-lactylation axis in acute kidney injury: mechanisms from metabolic reprogramming to epigenetic regulation and clinical therapeutic prospects.International urology and nephrology · 2026Review
- Lactate metabolism and protein lactylation in inflammatory and tumor microenvironments.Molecular biomedicine · 2026Review
- RNA splicing in health and disease.Molecular biomedicine · 2026Review
- The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.Oncogene · 2026Review
- Review
- Targeting Pyruvate Kinase M2: Signal Transduction Pathways and Exploration of Cancer Therapeutic Strategies.The AAPS journal · 2026Review
- Machine learning-based integration identifies lactylation biomarkers for prognosis prediction and tumor microenvironment modulation in bladder cancer.Translational andrology and urology · 2026Article
- Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications.Biomarker research · 2026Review
- FN1 governs global protein lactylation in acute myocardial infarction: a metabolic-epigenetic axis driving cardiac injury and impeding stem cell repair.Frontiers in cell and developmental biology · 2026Article
- Lactylation in urological malignancies: emerging mechanisms and therapeutic direction.Frontiers in cell and developmental biology · 2026Review
- p300: expanding beyond acetylation to mastermind lactylation-dependent tumorigenesis.Frontiers in cell and developmental biology · 2026Review
- Metabolic reprogramming and epigenetic effects due to reducing sugars and glycation products in cancer.Frontiers in epigenetics and epigenomics · 2025Review
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12 authors.
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Abstract
backgroundLactylation, a recently identified post-translational modification derived from lactate, has emerged as a regulator of tumor metabolism. However, its functional relevance and molecular targets in bladder cancer (BLCA) remain unclear.
methodsWe performed immunohistochemistry on patient tissues, global lactylation proteomics using LC-MS/MS, and in vitro and in vivo functional assays. Gene editing via CRISPR/Cas9, overexpression systems, and pharmacological interventions were employed to study P300-mediated HNRNPA1-K350 lactylation in driving BLCA cell aggression. Metabolomics and glycolytic flux assays were used to assess the metabolic consequences of HNRNPA1 lactylation. Molecular characterization was validated through gene expression and splicing analyses. Small-molecule drug screening was conducted via molecular docking to identify potential inhibitors targeting HNRNPA1.
resultsProtein lactylation levels were significantly elevated in BLCA tissues, correlating with poor prognosis. HNRNPA1 was identified as a central lactylation target. Glycolysis-induced lactate production promoted P300-mediated lactylation of HNRNPA1 at lysine 350, which facilitated PKM pre-mRNA splicing toward the PKM2 isoform, enhancing glycolytic flux and supporting tumor growth. Inhibition of glycolysis or LDHA knockdown reduced HNRNPA1 lactylation, suppressed PKM2 expression, and impaired BLCA cell proliferation, migration, and invasion. Metabolomic profiling linked HNRNPA1-K350 lactylation with increased aerobic glycolysis in BLCA cells. A small-molecule inhibitor, identified through molecular docking, attenuated cell proliferation by binding to HNRNPA1 and suppressing PKM2 expression.
conclusionsThis study reveals a lactate-driven mechanism coupling alternative splicing to metabolic reprogramming via HNRNPA1 lactylation, identifying HNRNPA1-K350 lactylation as a key driver of glycolysis-dependent tumor progression. A therapeutic approach targeting HNRNPA1 in BLCA is proposed.
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