Raspberry ketone alleviates radiation-induced lung injury through the STAT2-P2X7r/NLRP3 signaling pathway.

BACKGROUND

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.

PURPOSE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.