Cordycepin ameliorates spaceflight-induced osteoporosis by preventing BMSCs oxidative stress and senescence via interacting with PI3K p110α and regulating PI3K/Akt/FOXO3 signalling

Spaceflight-induced osteoporosis (SFOP) is a detrimental healthcare consequence during spaceflight. Weightlessness and ionizing radiation were main environmental factors that contribute to SFOP, especially in the manned deep space voyages. However, currently there is scarce effective method to treat SFOP. This study aims at discovering the role and mechanism of cordycepin (COR) in treating SFOP. A combined ionizing radiation and tail suspension (IR/IS) model is constructed in mice to simulate SFOP. COR injection exhibits certain dose-dependent therapeutic effects including better imageological bone index and improved histological bone regeneration in treating SFOP, which is most prominent at a dose of 20 mg/kg. A combined radiation and microgravity (R/M) model is established to treat BMSCs in vitro. 10 μM COR alleviates oxidative stress and cellular senescence of BMSCs. Through high-throughput sequencing, molecular docking and microscale thermophoresis (MST), we reveal a novel mechanism that COR interacts with p110α subunit in PI3K isoform α (PI3Kα) and inhibits PI3K kinase activity, which then regulates the PI3K/Akt/FOXO3 signalling. To elevate the bioavailability of COR in the SFOP treatment, a BMSCs-targeted delivery system that uses exosomes (Exos) modified with BMSC-affinity peptide E7 (E7-Exos) is constructed and loaded with COR. E7-Exos loaded COR reduces the dosage of COR to 5 mg/kg while enhancing the therapeutic effect than using 20 mg/kg COR alone in treating SFOP. In conclusion, COR shows promise as a potential agent in SFOP therapy.