CERT attenuates acute radiation-induced lung injury by regulating sphingomyelin/ceramide homeostasis and epithelial apoptosis

Radiation-induced lung injury (RILI) is a critical dose-limiting toxicity that occurs during thoracic tumor radiotherapy, and the mechanisms underlying RILI remain incompletely understood. As previously reported, there is a demonstrable correlation between metabolic changes and RILI. To further investigate the regulatory mechanisms underlying RILI, the metabolomic analysis of bronchoalveolar lavage fluid (BALF) and transcriptomic analysis of lung tissue post ionizing radiation (IR) were performed. The results of the study revealed that the sphingolipid signaling pathway was activated in response to IR, characterized by a substantial decrease in sphingomyelin (SM) and an increase in ceramide (Cer). SM treatment significantly mitigated radiation-induced cell damage in BEAS-2B and RLE-6TN cells and reduced inflammatory infiltration in lung tissues of C57BL/6 mice, while C16-Cer showed the opposite effect. Furthermore, we identified that the ceramide transporter (CERT), a lipid transfer protein delivering Cer from the endoplasmic reticulum (ER) to the Golgi apparatus for SM synthesis, plays an indispensable protective role against RILI. Mechanistically, CERT expression is associated with protection against RILI, concomitant with an elevated SM/Cer ratio and alterations in PP2A abundance and AKT phosphorylation. This study provided a reliable theoretical and experimental foundation for developing novel therapeutic strategies that target CERT-mediated sphingolipid homeostasis in the progression of acute RILI.