Ginkgetin alleviates cisplatin-induced muscle atrophy via inhibition of the macrophage cGAS-STING pathway.

Chemotherapy-induced muscle atrophy is a severe side effect, impairing patients' quality of life and overall survival. However, the persistence of muscle atrophy in cancer survivors long after treatment completion suggests that it is driven not only by the agent's direct toxicity, but also by a persistent, chemotherapy-induced pathological immune microenvironment. Elucidating the interplay between chemotherapy drugs, the immune microenvironment, and muscle cells is essential for identifying mechanisms and potential therapeutic targets. In this study, we investigated the critical role of macrophages in potentiating cisplatin-induced muscle atrophy by identifying a novel "amplification effect". Specifically, conditioned medium from cisplatin-activated macrophages synergized with cisplatin to induce severe myotube atrophy. We identify that cisplatin activates the cGAS-STING pathway in macrophages by inducing cytosolic DNA leakage, which drives their M1 polarization and pro-inflammatory cytokines release. The pro-inflammatory microenvironment amplifies the myotoxicity of cisplatin and promotes severe muscle atrophy. Notably, ginkgetin reverses the cisplatin-induced inflammatory microenvironment by binding to the STING protein within macrophage. The mechanism of the cisplatin-macrophage-muscle cell axis was also validated in an in vivo mouse model of cisplatin-induced muscle atrophy. Furthermore, we discovered that multiple chemotherapeutic agents could promote macrophages to polarize towards the M1 phenotype and release various inflammatory factors. These findings suggest that the macrophage cGAS-STING pathway is a key common mechanism and a broad-spectrum therapeutic target for treating chemotherapy-induced muscle atrophy. Collectively, this study elucidates the critical role of macrophage-mediated microenvironment in cisplatin-induced muscle atrophy, thereby providing a promising therapeutic target for chemotherapy-induced muscle atrophy.