J. Xu, S. Qin, and J. Xue; 1st Affiliated Hospital of Soochow University, Suzhou, China
Purpose/Objective(s):Radiation-induced fibrosis (RIF) remains a serious complication of radiation therapy.This study aims to elucidate that how radiation exposure enables skin cell to acquire the senescence-associated secretory phenotype(SASP) and how the persistence of cellular senescence can lead to RIF. Materials/
Methods: Skin cell senescence was assessed by measuring the amounts of senescence-associated ß-galactosidase and SASP-related protein expression. The role of fat mass and obesity-associated protein (FTO) in senescence regulation was explored using RNA immunoprecipitation assays. Mice subjected to radiation exposure were subcutaneous injected with PBS or meclofenac sodium targeting FTO. Histological analysis was performed to determine skin damage. Results: Skin cell senescence were markedly increased with the progression of RIF in patients and mouse models. Mechanistically, FTO-mediated m6A demethylation increased the expression of Z-DNA binding protein 1 (ZBP1) and mitochondrial transcription factor A (TFAM), which can enable the release of mitochondrial DNA (mtDNA) into the cytosol and transformation into a U-shaped structure, by enhancing their RNA stabilities. Cytosolic mtDNA in turn activates the cGAS-STING pathway resulting in the production of SASPs. Subcutaneous injection of meclofenac sodium targeting FTO suppressed cellular senescence propagation in skin and ameliorated RIF in vivo. Conclusion: This study provides evidences for the protective role of reducing cellular senescence in alleviating RIF, which is helpful for the development of therapy for late radiation-induced skin injury.
