ArticleCell discovery2025
NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance.
Article in Cell discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Preoperative conversion therapy of camrelizumab combined with paclitaxel and nedaplatin for unresectable advanced esophageal squamous cell carcinoma: a phase 2 study.BMC medicine · 2025Trial
- Reprogramming of cell death in gastric cancer: From molecular mechanisms to therapeutic potential (Review).International journal of molecular medicine · 2026Review
- Lactate metabolism and protein lactylation in programmed cell death: From novel mechanism to therapeutic strategies in human diseases.Clinical and translational medicine · 2026Review
- Review
- The histone deacetylase family in health and disease.Signal transduction and targeted therapy · 2026Review
- KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.Cell death and differentiation · 2026Article
- Lactate Metabolism: Separating Correlation From Causation.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- The distinguished predictive value of CFIm25 in schistosomal and non-schistosomal colorectal cancer.Translational cancer research · 2026Article
- Lactylation Modification and Esophageal Cancer: Research Progress From Hypoxia-Induced Metabolic Reprogramming to Immune Escape.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Covalent allosteric inhibition of AARS1 lactyltransferase.Nature communications · 2026Article
- The alternative polyadenylation factor CFIm25 orchestrates macrophage antibacterial activity againstInfection and immunity · 2026Article
- Lysine l-Lactylation: Bridging Metabolism, Chromatin and Disease.Cell proliferation · 2026Review
- Beyond a Metabolite: Lactylation as a Pivotal Regulator of Colorectal Cancer Pathogenesis and Treatment Resistance.Journal of biochemical and molecular toxicology · 2026Review
- Characterization of the chicken insulin receptor gene: Genomic organization and alternative promoter regulation.Poultry science · 2026Article
- Copper homeostasis and cuproptosis rewire the tumor microenvironment: mechanisms, immune modulation, and therapeutic opportunities.Journal of hematology & oncology · 2026Review
- Role of Ferredoxin 1Cancer pathogenesis and therapy · 2026Review
- Alternative Polyadenylation Drives Runaway Pro-Inflammatory Macrophages in Periodontitis by Enabling Escape From miRNA Repression.Cell proliferation · 2026Article
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Stiripentol induces ER stress and pyroptosis in pancreatic cancer cells under metabolic stress by dysregulating SFAs/UFAs homeostasis.Cellular oncology (Dordrecht, Netherlands) · 2026Article
Corrections and comments
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alternative polyadenylation (APA) is critical for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3' untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3' UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation "writer" catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic "eraser". Clinically, elevated levels of both LDHA and NUDT21, as well as increased K23-lactylated NUDT21, are associated with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.
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Registered trials
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