Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation

Radiotherapy reduces the risk of cancer recurrence and death, but the fact that it's 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 that cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles to trigger skeletal muscle weakness upon radiotherapy. Mechanistically, irradiation-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of the SRM protein, facilitating SRM packaging into extracellular vesicles from the 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 radiotherapy, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of radiotherapy-mediated muscle weakness when combined with losartan treatment.