Jiang Yu-Chen, Zhao Bin, Jiang Peng, Wang Si-Ying, Ma Lin, Wu Guo-Li, Wang Man-Li, Sun Hai-Ming
College of Pharmacy, Beihua University, Jilin, Jilin Province 132013, PR China.
Department of Intensive Care Medicine, Jilin Chemical Industry Hospital, Jilin, Jilin Province 132013, PR China.
Phytomedicine. 2025 Jun 15;145:156984. doi: 10.1016/j.phymed.2025.156984.
Radiation-induced lung injury (RILI) is a frequent side effect in patients with breast cancer receiving radiotherapy. Currently, there is no optimal radioprotective agent that is widely utilized for RILI treatment. Raspberry ketone (RK) is a natural aromatic compound found in raspberries (Rubus idaeus L.). A recent study by our research revealed that RK has strong anti-inflammatory and anti-fibrosis effects. However, its actual mechanism of action in inflammation-related lung injury remains elusive.
This study aimed to clarify whether RK can alleviate RILI and determine the possible underlying mechanisms. C57BL/6 mice were exposed to Coγ-rays to establish a lung injury model. RK was orally administered to the mice daily for 14 days, followed by STAT2 gene silencing. Lung tissue, serum, and bronchoalveolar lavage fluid were collected to detect lung injury-related biomarkers. Tissue morphological changes and biomarker expression related to the ECM, inflammation, EMT, and pyroptosis in the lung tissue were detected.
C57BL/6 mice were exposed to Coγ-rays to establish a lung injury model. RK was orally administered to the mice daily for 14 days, followed by STAT2 gene silencing. Primary lung fibroblasts were activated with TGF-β or supernatant under inflammatory conditions and incubated with RK or Nifuroxazide, respectively. BMDMs were also treated with LPS and RK to form a conditioned medium. Primary lung fibroblasts and BMDMs were injected with siRNA-STAT2.
RK could improve the levels of biochemical indicators in the lung tissue, suppress the expression of ECM markers, and downregulate the levels of inflammatory factors, such as IL-1β, in RILI. RK could also regulate radiation-induced histopathological damage and EMT progression and inhibit the upregulation of pyroptosis-related proteins. Furthermore, RK inhibited the expression of the downstream signals of STAT2 and P2 × 7r. In addition, STAT2 deletion inhibited the occurrence of ECM, inflammation, EMT, and pyroptosis. Notably, silencing the STAT2 gene led to a low expression of P2 × 7r and the NLRP3 inflammasome in the lung tissue of RILI mice, primary lung fibroblasts, and BMDMs. Primary lung fibroblasts were activated with conditioned medium from LPS-primed BMDMs, which resulted in significant enhance of EMT markers and inflammatory cytokines.
This study indicated that RK improved RILI through STAT2-P2 × 7r/NLRP3 signaling. RK might be a prospective therapeutic candidate, and its mechanism would be a novel approach for RILI treatment.
放射性肺损伤（RILI）是接受放疗的乳腺癌患者常见的副作用。目前，尚无广泛用于RILI治疗的最佳放射防护剂。覆盆子酮（RK）是一种存在于覆盆子（悬钩子属）中的天然芳香化合物。我们的研究最近表明，RK具有强大的抗炎和抗纤维化作用。然而，其在炎症相关肺损伤中的实际作用机制仍不清楚。
本研究旨在阐明RK是否能减轻RILI并确定可能的潜在机制。将C57BL/6小鼠暴露于Coγ射线以建立肺损伤模型。每天给小鼠口服RK，持续14天，然后进行STAT2基因沉默。收集肺组织、血清和支气管肺泡灌洗液以检测肺损伤相关生物标志物。检测肺组织中与细胞外基质（ECM）、炎症、上皮-间质转化（EMT）和细胞焦亡相关的组织形态学变化和生物标志物表达。
将C57BL/6小鼠暴露于Coγ射线以建立肺损伤模型。每天给小鼠口服RK，持续14天，然后进行STAT2基因沉默。在炎症条件下用转化生长因子-β（TGF-β）或上清液激活原代肺成纤维细胞，并分别与RK或硝呋太尔孵育。用脂多糖（LPS）和RK处理骨髓来源的巨噬细胞（BMDMs）以形成条件培养基。向原代肺成纤维细胞和BMDMs注射小干扰RNA（siRNA）-STAT2。
RK可改善肺组织中生化指标水平，抑制ECM标志物表达，并下调RILI中白细胞介素-1β等炎症因子水平。RK还可调节辐射诱导的组织病理学损伤和EMT进程，并抑制细胞焦亡相关蛋白的上调。此外，RK抑制STAT2和P2×7受体下游信号的表达。此外，STAT2缺失抑制ECM、炎症、EMT和细胞焦亡的发生。值得注意的是，沉默STAT2基因导致RILI小鼠、原代肺成纤维细胞和BMDMs肺组织中P2×7受体和NLRP3炎性小体表达降低。用LPS预处理的BMDMs的条件培养基激活原代肺成纤维细胞，导致EMT标志物和炎性细胞因子显著增加。
本研究表明，RK通过STAT2-P2×7受体/NLRP3信号通路改善RILI。RK可能是一种有前景的治疗候选物，其作用机制将为RILI治疗提供一种新方法。
