S2565
Radiobiology – Normal tissue radiobiology
ESTRO 2026
to develop a novel nano-formulated HXF (NHXF) using an amphiphilic PEG-PCL copolymer and evaluate its efficacy, mechanisms, and safety in preventing acute RILI. Material/Methods: HXF was extracted and encapsulated into PEG-PCL micelles via solvent evaporation. The physicochemical properties of NHXF were characterized by DLS, TEM, UV-Vis, and HPLC-MS. In vitro radioprotective effects were assessed in RLE-6TN alveolar epithelial cells using colony formation, ROS, apoptosis, and mitochondrial membrane potential assays. A murine model of acute RILI was established by unilateral lung irradiation (20 Gy), followed by 4-week nebulized administration of NHXF. Histopathology, inflammatory cytokines, oxidative stress markers, and neutrophil infiltration were evaluated. Transcriptomic sequencing and molecular assays were performed to explore underlying mechanisms. Results: NHXF formed uniform spherical nanoparticles (123.45 ± 34.52 nm, PDI 0.223) with enhanced pulmonary retention after inhalation. In vitro, NHXF significantly suppressed radiation-induced ROS generation, preserved mitochondrial membrane potential, and reduced apoptosis, outperforming traditional HXF (p < 0.01). In vivo, nebulized NHXF (high dose) markedly ameliorated lung injury, reducing alveolar disruption, inflammatory infiltration, and pro-inflammatory cytokines (TNF- α , IL-6, IL-1 β ). It also significantly decreased oxidative stress (8-OHdG) and neutrophil recruitment (MPO+ cells) compared to IR controls (p < 0.001). Transcriptomics revealed that NHXF reversed radiation-induced dysregulation of ferroptosis-related genes (e.g., upregulated GPX4, FTH1; downregulated ACSL4) and modulated the PI3K-Akt pathway. NHXF showed more sustained protection than dexamethasone after drug withdrawal. Conclusion: NHXF represents an innovative nanomedicine platform that integrates traditional herbal medicine with modern nanotechnology to effectively prevent RILI. Its mechanisms involve suppression of oxidative stress, inflammation, and ferroptosis, highlighting its potential as a safe and durable strategy for lung radioprotection. Keywords: RILI, Nano Huaxian Formula, Ferroptosis Digital Poster Highlight 1832 5-MIAA attenuates radiation proctitis in the Mongolian gerbil model Jieping Zhang, Dan Zhong, Wencong Wang, Manqi Meng, Junyan Feng, Shaomin Zou, Lekun Fang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, GuangZhou, China Purpose/Objective: Radiation Proctitis (RP) is a severe complication of pelvic radiotherapy, characterized by gut inflammation, barrier dysfunction, and fibrosis[1]. However, available animal models are limited. Here, the Mongolian gerbil was utilized for model establishment due to several strengths: its rectum represents a higher percentage of the total rectal length[2], and its pronounced epithelial regenerative capacity[3] and inherent radio-resistance[4] collectively underpin critical tissue repair processes after radiation exposure. This study aimed to investigate the suitability of the Mongolian gerbils for developing an RP model and further elucidate the mechanisms of host-microbiota crosstalk. Material/Methods: To establish the RP model, the Gerbils received targeted pelvic irradiation (30Gy) using the RS2000 irradiator with lead shielding to expose the rectal area. Fecal metabolomics was performed using LC-MS/MS, with differential metabolites analyzed and visualized via MetaMapp and CytoScape. In 5-MIAA intervention studies, animals were pretreated with 5-MIAA or PBS one week before radiation procedure. Fecal Lactococcus reuteri (L.reuteri) abundance was assessed using qRT-PCR. In L.reuteri intervention studies, GF mice were orally gavaged with L. reuteri one week before radiation procedure. Pathological damage was evaluated via H&E, Masson, and immunofluorescence (IF) staining. Results: The gerbil RP model was established as shown in Figure 1A; H&E and Masson staining displayed characteristic radiation-induced damage. Fecal metabolomic profiling was performed to investigate gut metabolic alterations. Using MetaMapp, we visualized the network of differentially produced metabolites, identifying key clusters including tryptophan metabolites, amino acids, lipids, and benzenoids (Figure 1B). Based on the Mongolian gerbil RP model, we identified that 5-methoxyindole-3- acetic acid (5-MIAA) was the most downregulated tryptophan metabolite, and the abundance of L.reuteri, which produced the 5-MIAA, was also decreased (Figure 2A). Additionally, oral administration of 5-MIAA (Figure 2B) or gavage of Lactobacillus reuteri (Figure 2C) could mitigate RP.
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