S2517
Radiobiology – DNA damage repair
ESTRO 2026
Overexpression promoted proliferation, enhanced radioresistance, and accelerated DNA damage repair.Lactate-Mediated Reversal Exogenous lactate pretreatment dose- and time-dependently reversed the radiosensitizing effects of AARS1 knockdown, restoring proliferative capacity, colony-forming ability, expression of DNA repair proteins, and efficient γ - H2AX foci resolution.
Mini-Oral 2007 AARS1 promotes Nasopharyngeal cancer proliferation and radiotherapy resistance through lactylation Weisi Wang, Xiang Cao, Xia He Radiation therapy laboratory, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, China, NanJing, China Purpose/Objective: Nasopharyngeal carcinoma (NPC) is anatomically suited for radiotherapy, which dominates its treatment; yet radioresistance drives most recurrences. EBV-associated NPC exhibits enhanced glycolysis and lactate accumulation, which remodel the tumor microenvironment and promote progression via protein lactylation. This study examines alanyl- tRNA synthetase 1 (AARS1), a lactate transferase, in radioresistant NPC cells to define its role in metabolic reprogramming and lactylation-mediated radiotherapy resistance. Material/Methods: Clinical and Bioinformatics Analysis AARS1 expression was examined using public NPC gene expression datasets. Tumor biopsies and clinical data from patients treated with radical radiotherapy were collected. Immunohistochemistry (IHC) was used to assess AARS1 protein levels, and survival outcomes were analyzed via Kaplan-Meier and Cox regression models.In Vitro Functional Studies Stable AARS1 knockdown (shRNA) and overexpression (lentiviral) models were generated in CNE-2 and 5-8F NPC cell lines. Proliferation was evaluated by CCK-8 and EdU assays; clonogenic survival post-irradiation (0–8 Gy) was measured using colony formation assay. DNA damage response was monitored via γ -H2AX foci formation and persistence using immunofluorescence. Key proliferation (PCNA, Cyclin D1) and DNA repair proteins (Ku70, RAD51) were detected by Western blot.Lactate Rescue Experiments AARS1-knockdown cells were pretreated with pH-neutralized lactic acid (0, 5, 10, 20 mM; 6–24 h). Changes in proliferation, radiosensitivity, protein expression, and γ -H2AX foci resolution were reassessed post-irradiation. Results: Clinical Correlation AARS1 was significantly upregulated in NPC tumor tissues compared to normal nasopharyngeal epithelium in both public datasets and IHC validation. High AARS1 expression independently predicted poorer progression-free survival (P<0.01) and overall survival (P<0.05) after radiotherapy.Functional Effects AARS1 knockdown significantly inhibited cell proliferation, reduced clonogenic survival under irradiation, and delayed γ - H2AX foci clearance, indicating impaired DNA repair.
Conclusion: AARS1 is overexpressed in NPC and serves as a robust prognostic marker for radiotherapy failure. It confers radioresistance by promoting tumor cell proliferation and enhancing DNA damage repair. Critically, exogenous lactate fully rescues AARS1 knockdown- induced radiosensitivity, providing strong evidence that AARS1 drives radiotherapy resistance through lactate metabolism and protein lactylation. These findings establish AARS1 as a promising therapeutic target to overcome radioresistance in NPC. References: 1.Zong, Z., Ren, J., Yang, B. et al. Emerging roles of lysine lactyltransferases and lactylation. Nat Cell Biol 27, 563–574 (2025). https://doi.org/10.1038/s41556-025-01635-82.Li, H., Liu, C., Li, R. et al. AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases. Nature 634 1229–1237 (2024). https://doi.org/10.1038/s41586-024-07992-y3.Ju J,Xie Y,Yu T, et al. The alanyl-tRNA synthetase AARS1 moonlights as a lactytransferase to promote YAP signaling in gastric cancer. J Clin Invest.
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