40 | Role of glucocorticoids in cancer cachexia: focus on lipocalin 2 and iron homeostasis

E. Wyart¹, Giada Fregnan¹, M. Colombera¹, A. Scalera¹, A. Menga², P.E. Porporato¹ | ¹Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Italy; ²Department of Health Sciences, Center for translational Research on Autoimmune & Allergic Diseases, University of Eastern Piedmont, Novara, Italy.

Cachexia is a severe wasting syndrome characterized by profound skeletal muscle atrophy that significantly contributes to mortality across various diseases, including cancer. However, its underlying mechanisms remain poorly understood. We previously identified major alterations of iron metabolism in the skeletal muscle of cachectic tumor-bearing mice and in particular a decrease in mitochondrial iron content, resulting in mitochondrial dysfunction. Lipocalin 2 (LCN2), an iron-chelating protein, has been identified as one of the most upregulated genes in various models of skeletal muscle atrophy. Being known the role of glucocorticoids in muscle wasting and that LCN2 is a transcriptional target of the glucocorticoid receptor (GR), we hypothesized its involvement in the dysregulation of iron metabolism during muscle wasting. Firstly, we confirmed the increased expression of LCN2 in the skeletal muscle of both C26 tumor-bearing mice and dexamethasone-treated mice, recapitulating the cachectic phenotype. Consistently, in vitro LCN2 overexpression induced a significant reduction in C2C12 myotube diameter and, oppositely, its silencing was sufficient to prevent dexamethasone-induced atrophy. Moreover, iron supplementation prevented glucocorticoid-induced atrophy in vitro and mitigated the cachectic phenotype in our two mouse models. Importantly, local expression of LCN2 promoted markers of iron deprivation in vivo. These results suggest that iron metabolism acts as a key contributor to skeletal muscle atrophy. Our findings shed light on both cancer and glucocorticoid-induced skeletal muscle wasting mechanisms, highlighting LCN2 as a potential therapeutic target for muscle wasting diseases.