Unacylated ghrelin counteracts mitochondrial dysfunction and neuromuscular junction disruption in cancer cachexia.

Cancer cachexia is a multifactorial metabolic syndrome that profoundly reduces muscle mass, strength, efficacy of chemotherapy, and survival, yet no effective therapy exists. Unacylated ghrelin (UnAG), the predominant form of circulating ghrelin, promotes muscle growth and mitochondrial bioenergetics, but its role in cancer cachexia remains unknown. Four- to 5-mo-old male C57Bl/6N mice were assigned to three groups: nontumor-bearing (NTB), tumor-bearing (TB), and tumor-bearing treated with UnAG (TB + UnAG). Lewis lung carcinoma cells were inoculated subcutaneously in the flank of the mice. Body weight, food intake, and tumor size were monitored for 4 wk. Lower limb muscle mass, contractile function, mitochondrial respiration, and reactive oxygen species (ROS) production were measured, in conjunction with Western blot, proteomic, and immunohistochemical analyses. Compared with NTB controls, TB mice exhibited marked loss of muscle mass and function, whereas UnAG treatment preserved ∼50% of the muscle mass and ∼70% of the contractile force. UnAG enhanced mitochondrial oxygen consumption, reduced ROS generation, and preserved mitochondrial DNA copy number and downregulated DNA mutation frequency. TB mice demonstrated increased oxidative stress and activation of protein degradation pathways, along with neuromuscular junction disruption-both of which were normalized by UnAG. These findings collectively demonstrate that UnAG mitigates cancer cachexia by modulating mitochondrial bioenergetics, oxidative and proteolytic stress, and neuromuscular junction integrity. UnAG represents a promising therapeutic candidate that may mitigate cachexia and improve both chemotherapy efficacy and the quality of life of patients with cancer.