ArticleSignal transduction and targeted therapy2025
Irinotecan alleviates chemoresistance to anthracyclines through the inhibition of AARS1-mediated BLM lactylation and homologous recombination repair.
Article in Signal transduction and targeted therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06766266 (A Phase I, Open-Label Clinical Study of Irinotecan Liposomes Combined with Epirubicin in Recurrent Non-Muscle Invasive Bladder Urothelium Carcinoma After Anthracyclines Treatment), which is not on this map. Cited by 31 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase I, Open-Label Clinical Study of Irinotecan Liposomes Combined with Epirubicin in Recurrent Non-Muscle Invasive Bladder Urothelium Carcinoma After Anthracyclines Treatment
Who cites it
31 citing papers in PubMed.
- Metabolites and cancer metastasis.Oncogene · 2026Review
- KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.Cell death and differentiation · 2026Article
- The long non-coding RNA-encoded microprotein MKKS3 drives colorectal cancer chemoresistance.Experimental & molecular medicine · 2026Article
- Covalent allosteric inhibition of AARS1 lactyltransferase.Nature communications · 2026Article
- Lysine l-Lactylation: Bridging Metabolism, Chromatin and Disease.Cell proliferation · 2026Review
- Crosstalk between lactylation and other post-translational modifications in health and diseases.Molecular biomedicine · 2026Review
- Review
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Lactate-Induced ZMYM2 K529 Lactylation Stabilizes ZMYM2 and Promotes Platinum Resistance in Ovarian Cancer.International journal of molecular sciences · 2026Article
- BLM regulates MALT1-driven NF-κB signalling and is targetable in B-cell malignancies.Cell death & disease · 2026Article
- TDP-43 Dysfunction Causes Hyper-Lactate State, Increased AARS1 Expression and Enhanced Protein Lactylation.Neurotoxicity research · 2026Article
- [Research progress on protein lactylation modification in malignant tumors].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2026Review
- Metabolic drivers of genome instability in cancer: mechanisms and therapeutic opportunities.Experimental hematology & oncology · 2026Review
- Comprehensive pan-cancer analysis of AARS1, a newly identified lactyltransferase in human cancers.Cancer cell international · 2026Article
- Protein lactylation: a metabolic signal driving cancer therapy resistance.Cell death discovery · 2026Review
- FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression.Cell death discovery · 2026Article
- Focus on Lactate and Lactylation Modification: The Potential Role in Ophthalmic Disease Treatment.International journal of molecular sciences · 2026Review
- Lactylation as a metabolic-epigenetic switch in cancer: dual roles in cell death resistance and therapeutic vulnerability.Cell death & disease · 2026Review
- Dynamic regulation of TBK1 lactylation shapes antiviral immune responses.Cellular & molecular immunology · 2026Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Chemoresistance remains the major barrier to cancer treatment. Metabolic and epigenetic reprogramming are involved in this process; however, the precise roles and mechanisms are largely unknown. Here, we report that lactate-induced lactylation promotes chemoresistance to anthracyclines by regulating homologous recombination (HR) repair. Using the global lactylome, we revealed the landscape of differentially lactylated sites and proteins in cancer cells isolated from resistant and nonresistant tumors. Specifically, BLM, a crucial helicase in the HR repair process, is highly lactylated at Lys24 by AARS1 in response to chemotherapy. Mechanistically, hyperlactylation of BLM improves its stability by inhibiting MIB1-mediated ubiquitination and increasing its interaction with DNA repair factors, promoting DNA end resection and HR repair. Delactylation of BLM via the Lys24 mutation impairs HR repair and increases anthracycline chemosensitivity. Irinotecan shows synergistic effects and safety for alleviating anthracycline resistance by targeting BLM lactylation and suppressing HR repair in pancancer PDX models. A single-arm, phase I study (identifier NCT06766266) initiated by us suggested that the combination of irinotecan liposomes plus EPI is a feasible and safe treatment strategy for patients with anthracycline-resistant bladder cancer who experience recurrence. These findings exemplify how glycolytic reprogramming regulates HR repair through promoting protein lactylation and highlight the promising therapeutic potential of irinotecan for reversing anthracycline chemoresistance by suppressing BLM lactylation.
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