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Radiation‐induced lung injury (RILI) is the major complication of thoracic radiation therapy, and no effective treatment is available. This study explored the role of high‐mobility group box 1 (HMGB1) in acute RILI and the therapeutic effect of glycyrrhizin, an inhibitor of HMGB1, on RILI. C57BL/6 mice received a 20 Gy dose of X‐ray radiation to the whole thorax with or without administration of glycyrrhizin. Severe lung inflammation was present 12 weeks after irradiation, although only a mild change was noted at 2 weeks and could be alleviated by administration of glycyrrhizin. Glycyrrhizin decreased the plasma concentrations of HMGB1 and sRAGE as well as TNF‐α, IL‐1β and IL‐6 levels in the bronchoalveolar lavage fluid (BALF). The expression of RAGE was decreased while that of TLR4 was significantly increased at 12 weeks, but not 2 weeks, after irradiation in mouse lung tissue. In vitro, the expression of TLR4 increased in RAW 264.7 cells after conditioning with the supernatant from the irradiated MLE‐12 cells containing HMGB1 but showed no change when conditioned medium without HMGB1 was used. However, conditioned culture had no effect on RAGE expression in RAW 264.7 cells. Glycyrrhizin also inhibited the related downstream transcription factors of HMGB/TLR4, such as NF‐κB, JNK and ERK1/2, in lung tissue and RAW 264.7 cells when TLR4 was activated. In conclusion, the HMGB1/TLR4 pathway mediates RILI and can be mitigated by glycyrrhizin.

Radiation-induced lung injury (RILI) remains a dose-limiting and life-threatening complication of thoracic radiotherapy. The present study aimed to evaluate the therapeutic efficacy and mechanism of the naturally extracted flavonoid, 5,7,8-trimethoxyflavone (HY-N7656), in inhibiting RILI. Lung injury in mice was evaluated using micro-computed tomography, histopathological analysis, enzyme-linked immunosorbent assay and western blotting. Network pharmacology was conducted to predict the potential therapeutic targets and signaling pathways of HY-N7656 in RILI. Cell Counting Kit-8, wound healing, immunofluorescence, reverse transcription-quantitative (RT-q) PCR and protein expression analyses were carried out in vitro using TGF-β-stimulated A549 cells to evaluate epithelial-mesenchymal transition (EMT) and signaling activity. Results of the present study revealed that HY-N7656 markedly alleviated pulmonary inflammation and fibrosis in irradiated mice, leading to a reduction in α-smooth muscle actin expression. In addition, EMT was effectively reversed following treatment with HY-N7656 in A549 alveolar epithelial cells treated with TGF-β, accompanied by restoration of E-cadherin expression and downregulation of mesenchymal markers, such as N-cadherin and vimentin. Network pharmacology analysis and molecular docking validation identified the PI3K/Akt pathway as a central target, which was subsequently confirmed via western blot analysis. Moreover, results of the present study demonstrated that HY-N7656 inhibited radiation-induced activation of PI3K and Akt. To the best of the authors' knowledge, the present study was the first to demonstrate that HY-N7656 modulates the PI3K/Akt signaling pathway to suppress the progression of EMT in RILI, establishing HY-N7656 as a multi-target inhibitor of RILI. These findings present a potential strategy to enhance the safety of radiotherapy, warranting further preclinical and clinical evaluation.

Radiation‐induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. It is characterized with two main features including early radiation pneumonitis and fibrosis in later phase. This study was to investigate the potential radioprotective effects of polydatin (PD), which was shown to exert anti‐inflammation and anti‐oxidative capacities in other diseases. In this study, we demonstrated that PD‐mitigated acute inflammation and late fibrosis caused by irradiation. PD treatment inhibited TGF‐β1‐Smad3 signalling pathway and epithelial–mesenchymal transition. Moreover, radiation‐induced imbalance of Th1/Th2 was also alleviated by PD treatment. Besides its free radical scavenging capacity, PD induced a huge increase of Sirt3 in culture cells and lung tissues. The level of Nrf2 and PGC1α in lung tissues was also elevated. In conclusion, our data showed that PD attenuated radiation‐induced lung injury through inhibiting epithelial–mesenchymal transition and increased the expression of Sirt3, suggesting PD as a novel potential radioprotector for RILI.

Radiation‐induced lung injury (RILI), divided into early radiation pneumonia (RP) and late radiation‐induced pulmonary fibrosis (RIPF), is a common serious disease after clinical chest radiotherapy or nuclear accident, which seriously threatens the life safety of patients. There has been no effective prevention or treatment strategy till now. Epithelial‐mesenchymal transition (EMT) is a key step in the occurrence and development of RILI. In this study, we demonstrated that emetine dihydrochloride (EDD) alleviated RILI through inhibiting EMT. We found that EDD significantly attenuated EMT‐related markers, reduced Smad3 phosphorylation expression after radiation. Then, for the first time, we observed EDD alleviated lung hyperaemia and reduced collagen deposit induced by irradiation, providing protection against RILI. Finally, it was found that EDD inhibited radiation‐induced EMT in lung tissues. Our study suggested that EDD alleviated RILI through inhibiting EMT by blocking Smad3 signalling pathways. In summary, our results indicated that EDD is a novel potential radioprotector for RILI.

Radiation-induced lung injury (RILI) is a prevalent complication following thoracic radiation, and currently there is a lack of effective intervention options. The present study investigated the potential of Compound Kushen Injection (CKI), a botanical drug, to mitigate inflammatory responses in mice with RILI, along with its underlying mechanisms of action. C3H mice underwent total lung irradiation (TLI) and intraperitoneal injection of CKI (2, 4 or 8 ml/kg) once daily for 8 weeks. Pre-radiation treatment with 4 or 8 ml/kg CKI starting 2 weeks before TLI or concurrent treatment of 8 ml/kg CKI with TLI led to a significantly longer overall survival compared with the TLI vehicle-treated group. Micro-computed tomography evaluations showed that concurrent treatment with 8 ml/kg CKI was associated with a significantly lower incidence of RILI. Histological evaluations revealed that concurrent CKI (4 and 8 ml/kg) treatment significantly reduced grades of lung inflammation. Following radiation at 72 h, TLI plus vehicle-treated mice had significantly elevated serum IL6, IL17A, and transforming growth factor β (TGF-β) levels compared with non-irradiated normal mice. Conversely, mice that received TLI plus CKI displayed lower cytokine levels than those in the TLI plus vehicle-treated mice. Immunohistochemistry staining showed a reduction of TGF-β positive cells in the lung tissues of TLI mice after CKI treatment. The concurrent TLI CKI-treated mice had a significantly reduced cyclooxygenase 2 (COX-2) activity and COX-2 metabolites compared with TLI vehicle-treated mice. These data highlight that CKI substantially reduced radiation-induced lung inflammation, mitigated RILI incidence, and prolonged overall survival.

Background Symptomatic radiation pneumonitis (RP) may be a serious complication after thoracic radiation therapy (RT) for non-small cell lung cancer (NSCLC). This prospective observational study sought to evaluate the utility of a novel radiation-induced lung injury (RILI) grading scale (RGS) for the prediction of RP. Materials and methods Data of 41 patients with NSCLC treated with thoracic RT of 60–66 Gy were analysed. CT scans were scheduled before RT, one month post-RT, and every three months thereafter for one year. Symptomatic RP was defined as Common Terminology Criteria for Adverse Events grade ≥ 2. RGS grading ranged from 0 to 3. The inter-observer variability of the RGS was assessed by four senior radiologists. CT scans performed 28 ± 10 days after RT were used to analyse the predictive value of the RGS. The change in the RGS severity was correlated to dosimetric parameters. Results The CT obtained one month post-RT showed RILI in 36 (88%) of patients (RGS grade 0 [5 patients], 1 [25 patients], 2 [6 patients], and 3 [5 patients]). The inter-observer agreement of the RGS grading was high (Kendall’s W coefficient of concordance = 0.80, p  < 0.01). Patients with RGS grades 2–3 had a significantly higher risk for development of RP (relative risk (RR): 2.4, 95% CI 1.6–3.7, p  < 0.01) and RP symptoms within 8 weeks after RT (RR: 4.8, 95% CI 1.3–17.6, p  < 0.01) compared to RGS grades 0–1. The specificity and sensitivity of the RGS grades 2–3 in predicting symptomatic RP was 100% (95% CI 80.5–100%) and 45.4% (95% CI 24.4–67.8%), respectively. Increase in RGS severity correlated to mean lung dose and the percentage of the total lung volume receiving 5 Gy. Conclusions The RGS is a simple radiologic tool associated with symptomatic RP. A validation study is warranted.

Radiation‐induced lung injury (RILI) can be caused by thoracic tumor radiotherapy. Qingdi mixture (QDM) has been routinely used in preventing RILI during tumor radiotherapy. However, the molecular mechanisms of QDM remain to be fully elucidated. Initially, we employed network pharmacology to identify potential therapeutic targets and their related signaling pathways. Secondly, molecular docking was applied to validate the interactions between the QDM components and hub targets. Furthermore, we retrospectively collected clinical data from RILI patients who received basic therapy combined with QDM. To investigate the therapeutic potential, we established both in vitro RILI cell models and in vivo murine models. We elucidated the molecular mechanisms of QDM's protective effects against RILI. The network pharmacology results showed that 157 common targets were identified for RILI. Enrichment analysis indicated that NF‐κB, JAK‐STAT, and necroptosis signaling pathways were involved in the QDM treatment of RILI. The molecular docking results indicated that ligands from multiple compounds exhibited strong interactions with inflammatory cytokines, including IL‐6, IL‐1α, IL‐4, and so on. The therapeutic efficacy of QDM was verified by clinical observation of patients with RILI. In vitro experiments demonstrate that QDM promotes cell proliferation after radiation therapy. Meanwhile, in vivo experiments showed that QDM reduced inflammatory factor levels and enhanced the therapeutic effects of basic treatment. Finally, the western blot experiments were conducted to verify the activation of the NF‐κB signaling pathway, as predicted by network pharmacology. This study demonstrated that QDM effectively alleviates RILI and holds promise for broad clinical application. Radiation‐induced lung injury (RILI) is a common complication of thoracic radiotherapy, and Qingdi mixture (QDM) has shown efficacy in its prevention. Through network pharmacology, molecular docking, and experimental validation, QDM was found to mitigate RILI primarily by inhibiting the NF‐κB signaling pathway and reducing inflammatory cytokines. Clinical and preclinical studies confirm that QDM enhances the therapeutic outcome of basic treatment and holds promise for broader clinical application.

Radiation therapy (RT) is essential for treating thoracic malignancies but often causes significant lung damage. FLASH‐RT, an ultra‐high dose rate irradiation technique, shows potential in reducing radiation‐induced lung injury (RILI) while maintaining tumor control. However, the underlying immune mechanisms remain poorly understood. This study investigates the immune and cellular responses to FLASH‐RT versus conventional dose rate (CONV) RT during the early phase of RILI. Using single‐cell RNA sequencing (scRNA‐seq), a dynamic landscape of the lung microenvironment is pictured during RILI within one‐week post‐irradiation. The analysis reveals that FLASH‐RT induces a more immediate but transient cellular response, while CONV‐RT causes sustained inflammation. FLASH irradiation significantly reduces neutrophil infiltration compared to CONV irradiation, particularly within the pro‐inflammatory Ccrl2+ subset. FLASH irradiation also triggers stronger activation of CD4+ CD40L+ Th cells, which are critical for regulating immune responses and balancing inflammation. Moreover, FLASH irradiation attenuates pro‐inflammatory activation and intercellular signaling of Mefv⁺ monocytes, thereby restraining excessive macrophage‐driven inflammation. Additionally, FLASH irradiation enhances TGF‐β signaling and epithelial‐mesenchymal transition (EMT) in alveolar type 1 (AT1) cells, promoting tissue repair. These findings highlight FLASH‐RT's superior immune modulation and reparative potential, providing valuable insights into its clinical application for minimizing radiation damage and enhancing lung recovery. Single‐cell RNA sequencing reveals distinct immune responses to FLASH versus conventional dose rate irradiation in early radiation‐induced lung injury. FLASH irradiation reduces Ccrl2⁺ neutrophil infiltration, activates CD4⁺ CD40L⁺ Th cells, restrains pro‐inflammatory Mefv⁺ monocytes, and enhances epithelial repair via TGF‐β signaling, underscoring its therapeutic potential in mitigating radiation‐induced lung damage.

Background Radiation‐induced lung injury (RILI) is a common consequence of thoracic radiation therapy that lacks effective preventative and treatment strategies. Dihydroartemisinin (DHA), a derivative of artemisinin, affects oxidative stress, immunomodulation, and inflammation. It is uncertain whether DHA reduces RILI. In this work, we investigated the specific mechanisms of action of DHA in RILI. Methods Twenty‐four C57BL/6J mice were randomly divided into four groups of six mice each: Control group, irradiation (IR) group, IR + DHA group, and IR + DHA + Brusatol group. The IR group received no interventions along with radiation treatment. Mice were killed 30 days after the irradiation. Morphologic and pathologic changes in lung tissue were observed with hematoxylin and eosin staining. Detection of hydroxyproline levels for assessing the extent of pulmonary fibrosis. Tumor necrosis factor α (TNF‐α), transforming growth factor‐β (TGF‐β), glutathione peroxidase (GPX4), Nuclear factor erythroid 2‐related factor 2 (Nrf2), and heme oxygenase‐1 (HO‐1) expression in lung tissues were detected. In addition, mitochondrial ultrastructural changes in lung tissues were also observed, and the glutathione (GSH) content in lung tissues was assessed. Results DHA attenuated radiation‐induced pathological lung injury and hydroxyproline levels. Additionally, it decreased TNF‐α and TGF‐β after irradiation. DHA may additionally stimulate the Nrf2/HO‐1 pathway. DHA upregulated GPX4 and GSH levels and inhibited cellular ferroptosis. Brusatol reversed the inhibitory effect of DHA on ferroptosis and its protective effect on RILI. Conclusion DHA modulated the Nrf2/HO‐1 pathway to prevent cellular ferroptosis, which reduced RILI. Therefore, DHA could be a potential drug for the treatment of RILI. In this study, we found that post‐radiation mice showed significant lung inflammation and ferroptosis. Through the Nrf2/HO‐1 pathway, dihydroartemisinin (DHA) prevented ferroptosis and reduced radiation‐induced lung injury (RILI). According to our research, ferroptosis and the Nrf2/HO‐1 pathway could be potential targets for the treatment of RILI, and DHA may be an applicable drug in RILI prevention and treatment

Hyperactivity of the NOTCH pathway is associated with tumor growth and radiotherapy resistance in lung cancer, and NOTCH/γ‐secretase inhibitors (GSIs) are a potential therapeutic target. The therapeutic outcome, however, is often restricted by the dose‐limiting toxicity of combined treatments on the surrounding healthy tissue. The NOTCH signaling pathway is also crucial for homeostasis and repair of the normal airway epithelium. The effects of NOTCH/γ‐secretase inhibition on the irradiation of normal lung epithelium are unknown and may counteract antitumor activity. Here we, therefore, investigated whether normal tissue toxicity to radiation is altered upon NOTCH pathway inhibition. We established air‐liquid interface pseudostratified and polarized cultures from primary human bronchial epithelial cells and blocked NOTCH signaling alone or after irradiation with small‐molecule NOTCH inhibitor/GSI. We found that the reduction in proliferation and viability of bronchial stem cells (TP63+) in response to irradiation is rescued with concomitant NOTCH inhibition. This correlated with reduced activation of the DNA damage response and accelerated repair by 24 hours and 3 days postirradiation. The increase in basal cell proliferation and viability in GSI‐treated and irradiated cultures resulted in an improved epithelial barrier function. Comparable results were obtained after in vivo irradiation, where the combination of NOTCH inhibition and irradiation increased the percentage of stem cells and ciliated cells ex vivo. These encourage further use of normal patient tissue for toxicity screening of combination treatments and disclose novel interactions between NOTCH inhibition and radiotherapy and opportunities for tissue repair after radiotherapy.