Presenter(s)
P. Li1, Y. Qin2, X. Liang3, Z. Zhang4, J. Yuan4, B. Tian1, F. Wang4, Y. Xu4, Y. Mo1, D. Chen4, and R. Xiao5; 1Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 2Shandong University Cancer Center, Jinan, Shandong, China, 3Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 4Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 5Shandong Cancer Hospital and Institute, Jinan, shandong, China
Purpose/Objective(s):
Radiotherapy has revolutionized the treatment of thoracic malignancies. However, its clinical benefits are substantially limited by radiation-induced lung injury (RILI), which frequently leads to treatment interruption or discontinuation. Tannic acid (TA) is a natural polyphenolic compound with potent anti-inflammatory and anti-fibrotic properties, but its effects on RILI and the underlying molecular mechanisms remain unclear. This study aims to explore the effects of TA on RILI and clarify the underlying mechanisms.Materials/Methods:
The RILI model of C57BL/6 mice was established by local 20 Gy lung irradiation using a small animal radiation research platform (SARRP). TA (10 mg/kg, oral administration, five times per week for one month) was administered as treatment. A total of 1,409 TA-related target genes were identified through integration of multiple databases. Differentially expressed genes (DEGs) were analyzed from a human alveolus-on-a-chip model of RILI (GSE242706, P < 0.05, |log2FC| = 0.5), and 1,250 DEGs were identified, including 647 upregulated genes. Intersection analysis identified 30 overlapping target genes, which were further analyzed by constructing a protein-protein interaction (PPI) network for hub gene screening. Single-cell RNA sequencing (scRNA-seq) data from an RILI mouse model revealed alveolar type II epithelial (AT2) cells as a key pathogenic cell subpopulation. The binding affinity between TA and its potential targets was assessed using molecular dynamics simulations and surface-plasmon resonance (SPR). Finally, Sftpc-Cre; Ptpn11f/f mice and cell lines (A549 and MLE-12) were utilized to functionally validate the epithelial-mesenchymal transition (EMT) mediated by SHP-2.Results:
TA significantly alleviated radiation-induced inflammation and fibrosis in mice by targeting SHP-2. scRNA-seq and immunofluorescence revealed radiation-specific upregulation of SHP-2 in AT2 cells, where SHP-2 hyperactivation drove the EMT. Both TA treatment and siRNA knockdown PTPN11 effectively reversed EMT-related pathological changes. Importantly, AT2-specific SHP-2 knockout mice recapitulated the protective effects of TA, alleviating both early radiation pneumonitis and late-stage fibrosis. Additionally, HE staining revealed that TA exhibited no significant toxicity to major organs such as the heart, liver, spleen, and kidneys in mice, supporting its potential as a targeted therapeutic candidate for RILI.Conclusion:
By integrating multi-omics and experimental validation, this study provides systematic evidence that TA alleviates RILI by targeting SHP2 to suppress EMT in AT2 cells, thereby improving both early radiation pneumonitis and late-stage fibrosis. Notably, TA exhibits a favorable safety profile, supporting its potential as a targeted therapeutic candidate for RILI.