Recently, the research team, led by Professors CAO Jianping and JIAO Yang from the Center for Radiobiology at the School of Radiation Medicine and Protection, undertook mechanistic studies on radiation-induced lung injury (RILI) utilizing USP11 knockout mice. The study's findings, entitled "USP11 Exacerbates Radiation-Induced Pneumonitis by Activating Endothelial Cell Inflammatory Response via OTUD5-STING Signaling," were published in the International Journal of Radiation Oncology, Biology, and Physics (https://doi.org/10.1016/j.ijrobp.2024.01.220).
Radiotherapy is essential for treating thoracic tumors, but its use is limited by RILI, which arises from lung tissue's sensitivity to ionizing radiation (IR). In recent years, this research team has conducted in-depth studies on radiation-induced lung injury, successively revealing the roles of methylation-related genes, tetrahydrobiopterin, and its metabolites in regulating this process. They adopted the previously established RILI model using Usp11 knockout (Usp11-/- ) mice, and revealed that USP11 knockout reduced the progression of radiation-induced pneumonia (RIP) and radiation-induced pulmonary fibrosis (RIPF). Intraperitoneal injection of the USP11 inhibitor mitoxantrone (MIX) also alleviated RILI in these mice. The study's focus on USP11 in pulmonary vascular endothelial cells showed that USP11 deficiency reduced vascular permeability and decreased neutrophil and macrophage infiltration after IR. Usp11-/- mice had increased proliferation and reduced apoptosis in irradiated pulmonary vascular endothelial cells, while USP11 overexpression increased proinflammatory cytokine expression and reactive oxygen species (ROS) production in irradiated endothelial cells. Proteomics and ubiquitin modification profiling analyses revealed that USP11 overexpression upregulates deubiquitinating enzymes, including USP22, USP33, and OTUD5, which stabilize the STING signaling pathway, promoting endothelial cell inflammatory responses and accelerating the progression of radiation pneumonitis. This study offers novel insights and experimental support for the development of therapeutic agents targeting deubiquitinating enzymes to treat RILI.
Figure 1. Schematic Diagram of the Mechanism by Which USP11 Promotes RIP.
This research was supported by the State Key Laboratory of Radiation Medicine and Radiation Protection. Yiting TANG, a 2019 doctoral candidate from the School of Radiation Medicine and Radiation Protection (now a postdoctoral fellow at Southern Medical University), is the first author of this paper. Professors Jianping CAO and Yang JIAO are the co-corresponding authors. The study was funded by the National Natural Science Foundation of China Joint Fund Project (U1967220), the National Natural Science Foundation of China General Program (82073339, 12375348), and the National Key R&D Program (2022YFC2503700, 2022YFC2503703).