Emerging roles of OSM and EDA2R-NIK signalling in cancer-associated muscle wasting

Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting that reduces physical function, compromises treatment tolerance, and contributes to cancer-related mortality. Although systemic inflammation is a major driver of CAC, the mechanisms through which circulating inflammatory signals are translated into muscle-specific catabolic programmes remain incompletely understood. Recent studies have identified oncostatin M (OSM), a member of the IL-6 cytokine family, as an important mediator of cancer-induced muscle wasting through OSM/JAK/STAT3 signalling. OSM also induces the expression of ectodysplasin A2 receptor (EDA2R) in skeletal muscle, which engages NF-κB-inducing kinase (NIK)-dependent non-canonical NF-κB signalling to promote atrophy-related gene expression, proteolysis, and metabolic dysfunction. Beyond CAC, the emerging association of EDA2R with aging, muscle-wasting disorders, and circulating disease signatures highlights its broader biological and translational relevance. In this review, we discuss recent advances in the understanding of mechanisms underlying skeletal muscle wasting linked to CAC. Specifically, we focus on OSM/JAK/STAT3 and EDA2R-NIK signalling and explore their potential implications for targeted therapeutic strategies.