3101 - The Protective Role and Mechanism of SOCS6 in Radiation-Induced Lung Injury via mtDNA/cGAS/STING Signaling Axis-Mediated Pyroptosis

Purpose/Objective(s):

Radiation-induced lung injury (RILI) remains a major factor limiting radiation dose and treatment efficacy. Pyroptosis of pulmonary epithelial cells plays a significant role in RILI. However, the molecular mechanism is not clear. The aim of this study is to elucidate the role and mechanism of SOCS6-mediated pyroptosis in protective against RILI.

Materials/Methods:

CT and blood biomarkers were analyzed to determine the severity and probability of RILI during thoracic tumor radiotherapy. The primary mode of cell death in lung injury cells was detected using a Death screening PCR-array. Further investigation into the role of SOCS6 in radiation-induced pyroptosis and RILI was conducted using TEM, Western Blot, and qRT-PCR. Inhibitors combined with Western Blot, qRT-PCR, and cell biology experiments were used to analyze how SOCS6 regulates the mtDNA/cGAS/STING signaling axis.

Results:

Clinical data analysis revealed that patients undergoing thoracic radiotherapy experienced varying degrees of acute lung injury within 6 months post-radiotherapy. Among patients with locally advanced cancer receiving chemoradiotherapy, the incidence of grade 2 or higher RILI was 29% for lung cancer, 13.4% for esophageal cancer, and 18% for breast cancer. PCR-array results indicated that pyroptosis is the primary mode of cell death in RILI. Furthermore, through TEM, Western Blot, and qRT-PCR, we found that overexpression of SOCS6 can inhibit radiation-induced oxidative stress, mitochondrial damage, and pyroptosis. Finally, we discovered that SOCS6 can reverse mitochondrial damage in lung epithelial cells, inhibit the release of mtDNA, and further suppress the expression of cGAS/STING, ultimately inhibiting pyroptosis and alleviating RILI.

Conclusion:

SOCS6 alleviates RILI by suppressing mtDNA/cGAS/STING signaling axis-mediated pyroptosis.