Cancer cell-secreted spermidine synthase induces skeletal muscle fibrosis upon radiotherapy (Gastrocnemius muscle KD)

Radiotherapy (RT) reduces the risk of cancer recurrence and death, while accompanied by multiple side effects including muscle fibrosis and weakness, seriously affects the life quality of patients. However, the underlying mechanism is poorly defined. Here, we identify cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles (sEVs) to trigger skeletal muscle weakness upon RT. Mechanistically, RT-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of SRM protein, facilitating SRM packaging into EVs from primary tumor. Circulating SRM results in spermidine accumulation in skeletal muscle and type I collagen fiber biosynthesis in an eIF5A-dependent manner. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon RT, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of RT-mediated muscle weakness when combined with losartan treatment.